Garmendia Sofiem 2020

THÈSE PRÉSENTÉE
POUR OBTENIR LE GRADE DE
DOCTEUR DE
L’UNIVERSITÉ DE BORDEAUX ET UNIVERSITY OF
WARWICK
École Doctorale des Sciences Chimiques
Spécialité : Polymères
Par Sofiem GARMENDIA
Synthesis of new N-Heterocyclic Carbene (NHC)-based Single

Chain Nanoparticles (SCNPs) as catalytically active nanoreactors
Synthèse de nouvelles nanoparticules composées de chaines uniques basé sur de carbènes

N-hétérocycliques comme de nanoréacteurs catalytiquement actifs
Sous la direction de : Pr. Andrew P. DOVE, Pr. Daniel TATON et Pr. Rachel K. O’REILLY
Soutenue le 22/ 01/ 20
Membres du jury :
M. POMPOSO, Jose A., Professeur, University of the Basque Country Rapporteur

M. DROCKENMULLER, Eric, Professeur, Université de Lyon 1 Rapporteur
M. PERRIER, Sebastién, Professeur, University of Warwick Examinateur
M. CLOUTET, Eric, Professeur, Université de Bordeaux President du Jury
M. DOVE, Andrew P., Professeur, University of Birmingham Directeur de thèse
M. TATON, Daniel, Professeur, Université de Bordeaux Directeur de thèse
M. O’REILLY, Rachel K., Professeur, Université de Birmingham Directeur de thèse
Table of Contents
Acknowledgements…………………………………………………………………………………….6-7
Declaration of Authorship……………………………………………………………………….………8
List of Publications…………………………………………………………………………...………9-10
Summary…………………………………………………………………………………………..……11
Abbreviations……………………………………………………………………………………….12-16
List of Figures……………………………………………………………………………….………17-22
List of Schemes………………………………………………………………………………………23-24
List of Tables……………………………………………………………………………………………25
Chapter I: Introduction to Single Chain Nanoparticles (SCNPs) as nanoreactors
1.1 Single Chain Nanoparticles (SCNPs) ……………...........................................…..………31
1.1.1 Introduction ……………………………………………..…...................…….31-32
1.1.2 Synthetic methods towards single-chain nanoparticles.….....….........................…32
1.1.2.1 SCNPs via irreversible and reversible bonds.……….....................…..32-33
1.1.2.1.1 Covalent bonds………………..…................….........……33-39
1.1.2.1.2 Organometallic bonds…………….................…..…..……39-44
1.1.2.1.3 Supramolecular chemistry……………..................…...….44-50
1.1.2.1.4 Dynamic covalent chemistry…………...................…...….50-54
1.1.3 Characterisation of Single Chain Polymer Nanoparticles: analytical
techniques………………………………………………………………….…54-55
1.1.3.1 Size exclusion chromatography (SEC)………….................…..…..….55-57
1.1.3.2 Spectroscopic characterisation of SCNPs…………..................……….....57
1.1.3.2.1 NMR spectroscopy ………………………………….……...57-59
1.1.3.2.2 IR, UV-VIS, CD and fluorescence spectroscopy……………59-62

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1.1.3.3 Characterisation of Single Chain Nanoparticles morphology……….……62
1.1.3.3.1 Morphological characterisation via TEM…...…....................62-63
1.1.3.3.2 Morphological characterisation via AFM….......................…63-64
1.1.3.3.3 Morphological characterisation via scattering (DLS, SAXS,
SANS) ……………………………..............................................................…65-65
1.1.4 Applications………………………….…………………………………………68-69
1.1.4.1 Nanomedicine…………………………..…………………….…..…..…..69
1.1.4.1.1 Drug delivery and imaging………..…………………..…….69-72
1.1.4.2 Nanoreactors for catalysis.………………………..........................………73
1.1.4.2.1 Organocatalysis …………………………….....................…73-77
1.1.4.1.2 Organometallic catalysis………….……....................…...…77-85
1.1.4.1.3 Enzymatic catalysis …………………....................……...…85-86
1.1.4.3 Other uses……………………………..……………….................…...86-89
1.3 Conclusions and aims of the PhD thesis......................................................……...…....89-91
1.4 References………………………….…………………………...…................……….91-97
Chapter II: Facile Synthesis of Reversibly Crosslinked Poly(ionic liquid)-type Gels: Recyclable
Supports for Organocatalysis by N-Heterocyclic Carbenes
2.1. Abstract………………………………………………………………….…………101-102
2.2. Introduction………………………………………………………………………..102-104
2.3. Synthesis, characterisation…………………………………………………………105-110
2.4. Manipulation of gel-supported pre-catalyst…………………………..……………110-113
2.5. Organocatalysis from gel-supported NHCs…………………………..……………113-116
2.6. Conclusions……………………………………………………………..…………116-117
2.7. References…………………………………………………………………………117-119
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2.8 Experimental section…………………………………………………..…………..120-135
Chapter III: Reversible Ionically-crosslinked Single Chain Nanoparticles as Bioinspired and
Recyclable Nanoreactors for N-Heterocyclic Carbene Organocatalysis
3.1. Abstract…………………………………………………………………………………139
3.2. Introduction………………………………………………………………………..140-142
3.3. Synthesis of catalytically active SCNPs……………………………………………143-148
3.4. Benzoin condensation catalyzed by SCNP 5………………………………………148-152
3.5. Conclusions……………………………………………………………..………………153
3.6. References…………………………………………………………………………153-157
3.7 Experimental section………………………………………………………………158-169
Chapter IV: Self-catalysed folding of single chain nanoparticles (SCNPs) by NHC-mediated
intramolecular benzoin condensation
4.1. Abstract............................................................................................................................173
4.2. Introduction..............................................................................................................174-176
4.3. Synthesis of catalytically active SCNPs....................................................................176-182
4.4. Transesterification reaction catalysed by SCNP 5.....................................................182-186
4.5 Conclusions..............................................................................................................186-187
4.6. References................................................................................................................187-189
4.7. Experimental section................................................................................................190-209
Chapter V: Catalytically Active N-Heterocyclic Carbene Release from Single-Chain Nanoparticles
following a Thermolysis-driven Unfolding Strategy
5.1. Abstract……………………………………………………………………..…………..213
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5.2. Introduction………………………………………………………………..………214-215
5.3. Synthesis of catalytically-active SCNPs…………………………………...………216-220
5.4. NHC-mediated benzoin condensation reaction………………………….…………220-223
5.5. Conclusions…………………………………………………………..…………………223
5.6 References…………………………………………………………...…………….224-227
5.7. Experimental Section…………………………………………...………………….228-239
Chapter VI: Summary, principal conclusions and outlook
6.1. Summary……………………………………………………………..…………………243
6.2. Principal conclusions………………………………………...…………………………243
6.2.1. Importing PILs to SCNPs technology…………………...…………………243-244
6.2.2. Different SCNPs folding techniques………………….……………………244-245
6.2.3 SCNPs as catalytically active nanoreactors………………..………………245-246
6.3. Outlook…………………………………………………………………………….246-247
7.1. Sommaire…………………………………………………………..…………………...248
7.2. Conclusions principales……………………………………...…………………………248
7.2.1. Importacion de PILs dans la technologie SCNPs…………………………..248-249
7.2.2. Différentes techniques de pliage SCNPs……………….…………………..249-250
7.2.3 SCNPs en tant que nanoréacteurs catalytiquement actifs…………………250-251
7.3. Prespectives……………………………………………………………………….251-252
5
Acknowledgements
Firstly, I would like to give my sincere thanks to my supervisors, Professor Andrew P. Dove, Professor
Daniel Taton and Professor Rachel K. O’Reilly for the opportunity to work in their groups in such an
amazing field. I am truly grateful for all of your invaluable guidance, advice and continuous support
throughout all my research during this PhD. I would also like to thank the three of you for all the
comprehension and all the back up you offered regardless the institution I was carrying out my research
in, making easier and more comfortable the development of it. Continuous meetings and numerous
scientific exchanges have allowed not only to expand my scientific focus but also learning how to
perfectly balance to think in and out of the box.
The biggest thanks go to Dove Group, Taton Team and O’Reilly group members, who throughout all my
period in one and each of the groups have hardly worked on making my time more enjoyable both socially
and scientificaly. Making out any simple conversation the perfect time to discuss about scientifical
suggestions, disagreements or deep conceptual brainstorming. Moreover, without your support it would
have been possible to overcome so many challenging situations. It would not be fair to cite only a few
numbers of the people who have considerably helped to get throughout this whole research period because
I would certainly forget to cite few of these names. However, I could not progess writing these lines
without especially thanking in the incredible Taton Team people like Dr. Romain Lambert, Anne-Laure
Wirotius, Dr. Leila Mezzasalma or Beste Ohran, Quentin Sobczak and as on-ground-mentor, Dr. Joan
Vignolle. My genuine thanks also go to the spectacular people from both Dove and O’Reilly groups like
Sètuhn Jimaja, Noe Fanjul, Panos Bexis, Coralie Jehanno, Prof. Mathieu Tschan, Dr. Jeff Foster or Prof.
Benoit Couturaud. Especial thank is also dedicated to the people like Dr. Julien Rosselgong, Dr. Joshua
Wroch, Dr. Daniele Mantione, Siobhan Kilbride or Dr. Wei Yu, who have rendered the lab a more
entertaining place to deploy my research.
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I would also dedicate my deepest thank to all those who made the effort and offered the opportunity to
jointly work on papers or projects which have not been as successful, especial mention to, Dr. Stefan B.
Lawrenson and Dr Maria Chiara Arno and again Dr. Romain Lambert and Anne-Laure Wirotius, because
without any of you it would not have been possible to achieve anything developed in this manuscript.
I would also like to acknowledge the European Commission for their support and funding and the
University of Bordeaux, University of Warwick and University of Birmingham for enabling the use of
their facilities and infrastructure. Equally, I must show my gratitude to all the technical staff from the
different departments in all the different universities who have kindly helped me with their assistance,
continuous support and valuable pieces of advice.
Finally, there are no words to show all my gratitude to the most important people in my life; my family.
You have given me love, energy and support in every single second you noticed I needed it. I am the
result of what you have constantly helped to shape, coddled and harvested with all your patience and
effort, so this is the result of the “ we” who as a team managed to reach so far and has made us invincibles.
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Declaration of Authorship
This thesis manuscript is both submitted to the University of Bordeaux and the University of Warwick in
support for the double degree of Doctor of Philosophy. I have totally been composed by myself and has
not been submitted in any other previous application of any other degree.
All the work presented (the data generated and data analysis) was completely carried out by the author
and except from the introduction all the experimental chapters have been published in scientific journals
as detailed in Section “List of Publications”
8
List of Publications
1. Facile synthesis of reversibly crosslinked poly(ionic liquid)-type gels: Recyclable supports for
organocatalysis by N-heterocyclic carbenes
Sofiem Garmendia, Romain Lambert, Anne-Laure Wirotius, Joan Vignolle, Andrew P. Dove, Rachel K.
O'Reilly, Daniel Taton., European Polymer Journal, 2018, 107, 82-88.
2. Reversible ionically-crosslinked single chain nanoparticles as bioinspired and recyclable nanoreactors
for N-heterocyclic carbene organocatalysis
Sofiem Garmendia, Andrew P. Dove, Daniel Taton, Rachel K. O'Reilly, Polym. Chem., 2018, 9, 5286-
5294.
3. Self-catalysed folding of single chain nanoparticles (SCNPs) by NHC-mediated intramolecular benzoin
condensation
Sofiem Garmendia, Andrew P. Dove, Daniel Taton, Rachel K. O'Reilly, Polym. Chem., 2019, 10, 2282-
2289.
4. Catalytically Active N-Heterocyclic Carbene Release from Single-Chain Nanoparticles Following a
Thermolysis-Driven Unfolding Strategy
Sofiem Garmendia, Stefan B. Lawrenson, Maria C. Arno, Rachel K. O’Reilly, Daniel Taton, Andrew P.
Dove, Macromol. Rapid Commun., 2019, 40, 1900071-1900079
5. Catalytically Active N-Heterocyclic Carbene Release from Single-Chain Nanoparticles Following a
Thermolysis-Driven Unfolding Strategy (Cover Picture)
Sofiem Garmendia, Stefan B. Lawrenson, Maria C. Arno, Rachel K. O’Reilly, Daniel Taton, Andrew P.
Dove, Macromol. Rapid Commun., 2019, 40 (15), 1970033
6. Pd(II)–NHC coordination-driven formation of water-soluble catalytically active single chain
nanoparticles
9
Romain Lambert, Anne-Laure Wirotius, Sofiem Garmendia, Pierre Berto, Joan Vignolle, Daniel Taton,
Polym.Chem., 2018, 9, 3199-3204
10
Summary
Chapter One aims at describing existing synthetic methodologies to SCNPs, related characterisation
techniques and potential applications reported in the recent literature for these nanoobjects.
Chapter Two discusses the use of a PIL-based gel catalytic precursor which show a thermo-responsive
behavior. This particularly versatile NHC-based organocatalysts can easily be restored recycled and
reused by simply cooling down and no external chemical agent.
Chapter Three considers a novel-type of non-covalently bound SCNPs. The nature of PIL parent linear
precursors allows and mild anion-metathesis driven intramolecular folding. The resulting SCNPs could
be thermally activated for NHC-mediated organocatalysis purpose, showing higher catalytic efficiency
compared to molecular/linear polymer models as a result of the confinement effect.
Chapter Four reveals a self-catalysed folding strategy to form SCNPs via an intramolecular NHC-
mediated benzoin condensation, exploiting the thermo-latent NHC-precatalyst supported in the linear
parent precursor. Importantly, the thermo-latent NHC retained their catalytic activity and further
implemented organocatalysing transesesterification reactions.
Chapter Five employs Ag(I)-crosslinked SCNPs and demonstrate their application as catalysts.
Metalation of the benzimidazolium by Ag(I) was obtained under relatively mild conditions. These Ag-
NHC linkages could be subsequently thermally cleaved delivering active NHC moieties organocatalysing
a benzoin condensation reaction.
Chapter Six summarises the research herein presented, giving general conclusions to the discussion of
the potential for future investigations in this research field.
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Abbreviations
3D: three-dimensional
δ: chemical shift
η: dynamic viscosity
λ: wavelength
AIBN: Azobis(2-methylpropionitrile)
AFM: atomic force microscopy
Ar: aromatic
ATRP: atom transfer radical poylmerisation
BCP: block copolymer
br: broad
Bz: benzyl
ca.: circa
Cat: catalyst
CMRP: cobalt-mediated radical polymerisation
coPIL: copoly(ionic liquid)
Cryo: cryogenic
CTA: chain transfer agent
Dh: hydrodynamic diameter
DM: molar-mass dispersity
DLS: dynamic light scattering
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DMF: dimethyl formamide
DMSO: dimethyl sulfoxide
DOSY: diffusion ordered spectroscopy
DP: number average degree of polymerisation
DSC: differential scanning calorimetry
DVB: divinylbenzene
Et2O: diethyl ether
Eq.: equivalents
EtOH: ethanol
eV: electron volts
FTIR: Fourier transform infrared
GPC: gel permeation chromatography
I: initiator
IC: ionic conductivity
IL: ionic liquid
kDa: kiloDalton
KHCO3: potassium hydrogen carbonate
KHDMS: potassium bis(trimethylsilyl)amide
KPF6: potassium hexafluorophosphate
LiTFSI: lithium bis(trifluorosulfonyl)imide
MA: methyl acrylate
MALDI-ToF: matrix-assisted laser desorption ionisation time-of-flight
13
Mn: number average molar mass
Mw: weight average molar mass
MeOH: methanol
mg: milligram(s)
mL: millilitre(s)
MMA: methyl methacrylate
mol: mole
mmol: milimol
MWCO: molecular weight cut off
NaBF4: sodium tetrafluoroborate
NaCl: sodium chloride
NH4BF4: ammonium tetrafluoroborate
NHC: N-heterocyclic carbene
NHC-CO2: azolium-2-carboxylate
[NHC(H)][HCO3]: azolium hydrogen carbonate
NMP: nitroxide mediated polymerisation
NMR: nuclear magnetic resonance
OAc: acetate
PEDOT: poly(3,4-ethylendioxythiophene)
PEG: poly(ethylene glycol)
PEO: poly(ethylene oxide)
Ph: phenyl
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PILs: poly(ionic liquid)s
PMA: poly(methyl acrylate)
PMMA: poly(methyl methacrylate)
Poly(NHC): poly(N-heterocyclic carbene)
Poly(NHC-CO2): poly(N-heterocyclic carbene-carboxylate) adduct
Poly[NHC(H)][HCO3]: poly(N-vinyl-3-alkylimidazolium hydrogen carbonate)
ppm: parts per million
PS: poly(styrene)
RAFT: reversible addition-fragmentation chain transfer
Rg: radius of gyration
RI: refractive index
ROMP: ring-opening metathesis polymerisation
ROP: ring-opening polymerisation
RT/rt: room temperature
SAXS: small-angle X-ray scattering
SCNPs: single chain nanoparticles
Seb: sebacate
SEC: size exclusion chromatography
SEM: scanning electron microscopy
St: styrene
t: time
T: temperature
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TEM: transmission electron microscopy
TFSI: bis(trifluorosulfonyl) imide
Tg: glass transition temperature
Tm: melting temperature
TGA: thermogravimetric analysis
THF: tetrahydrofuran
TMS: trimethylsilane
TMSCN: trimethylsilyl cyanide
UV: ultraviolet
v: volume
VAc: vinyl acetate
wt.%: weight percent
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List of Figures
Figure 1.1 Modes for intramolecular collapse through cross-linking of a single polymer chain, forming
SCNPs………………………………………………………………………………………………...…32
Figure 1.2 (A) The introduction of appropriate ligand functionalities in the polymer chain allowing SCNP
folding and catalytic functionalitisation in one step. (B) Nanoparticle formation via an external trigger
and subsequent metal ion loading.36………………………………………………………………….39
Figure 1.3. SEC UV detector traces obtained in THF at 40 °C for reaction of styrene functionalized P1
with AIBN to yield NP1-0.77…………………………………………………………………………….56
Figure 1.4 1H NMR overlay spectrum of polymer (P1) and nanoparticle (NP1) in CDCl3…………....58
Figure 1.5 DOSY spectra of linear precursor and corresponding SCNP CD2Cl2.18……..…59
Figure 1.6. FTIR spectra of a) linear polymeric precursor and b) corresponding SCNP.84………….60
Figure 1.7 (A) UV-vis absorbance of the polymer precursors (smooth lines) and the corresponding SCNPs
(dashed lines), (B) Emission spectra of the formed SCNPs and (C) photograph of a solution of SCNPs
under a hand-held UV-lamp (λ = 366 nm).85…………………………………………………………61
Figure 1.8 CD spectra of different particles (P1, P2 and P3) at 20 °C during 120 min of 350 nm UV
irradiation.62……………………………………………………………………………………………...62
Figure 1.9. TEM images of SCNPs at different zooms stained with ammonium molybdate.87……..…63
Figure 1.10 AFM height imaged of SCNPs capture of two-steps of the molecular folding process (A)
62
before and (B) after UV irradiation. The top right insets show magnifications of the framed areas. 64
Figure 1.11 (A) Dynamic light scattering (DLS) data (number distributions) for the folded and unfolded
polymer (P6). (B) DLS data for the folded and unfolded polymer P16 in presence of different
solvents/salts…………………………………………………………………………………………….66
Figure 1.12 (A) Form factor from SAXS of precursor (circles) , SCNPs following protocol I (diamonds)
and II (crosses) in THF. (B) Form factor from MD simulations of the precursor (circles) and the SCNPs
synthesised through protocol I (diamonds) and II (crosses)…………………………………………….67
Figure 1.13 Potential applications of SCNPs………………………………………………………….69
Figure 1.14 (A) Dual-pathway synthetic of SCNPs via Thiol-Michael addition following the organic route
(yellow) and aqueous route (blue). (B) Release of Rif from SCNPs by measuring UV-vis absorption at
334 nm.96…………………………………………………………………………………………………71
Figure 1.15 (A) Formation of SCNPs and loading with Gd(III) following a two-step route for their
incorporation using CuAAC-based chemistry. (B) Relaxivity values for Gd-SCNPs compared to
commercially available reference Magnevist®………………………………………………………….72
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Figure 1.16 Chemical structure of L-proline functionalised catalytic polymer and schematic
representation of the unfolded polymer and the formation of the compartimentalised catalytic structure in
water……………………………………………………………………………………………………..75
Figure 1.17 Schematic illustration of the use of SCNPs as bionpired nanoreactors for the synthesis of
polymers through ring-opening polymerisation.109……………………………………………………..77
Figure 1.18 Size and size-dependent photoluminescence spectra of CNDs. TEM image and size histogram
of big CND (A) and small ones (B). Photoluminiscent spectra of surface oxidised at 340 nm of small
CND (green line C) and big CND (blue line C) and spectra of reduced surface (green line D and blue line
C, respectively).128……………………………………………………………………………………….88
Figure 2.1. 1H NMR (DMSO-d6) showing the insertion of the sebacate forming the physical gel (PS-co-
Poly[ViEBIm]Seb) (5) from (PS-co-Poly[ViEBIm]Cl) (3)……………………………………………107
Figure 2.2. Synthesis of ((PS-co-Poly[ViEBIm]Cl)(3). 13C NMR spectra in DMSO-d6………………108
Figure 2.3. Synthesis of ((PS-co-Poly[ViEBIm]Seb)(5). 13C NMR spectra in DMSO-d6………….…108
Figure 2.4. Synthesis of Polystyrene-co-poly(4-vinylbenzylethyl-(benz)imidazolium sebacate) (PS-co-
Poly[ViEBIm]Seb) (5) overlay with starting materials .FTIR spectra…………………………………109
Figure 2.5. (PS-co-Poly[ViEBIm]Cl) (3), (PS-co-Poly[ViEBIm]Seb) (5) and Sebacic Acid plotting with
corresponding proposed degradation steps for each case……………………………………………110
Figure 2.6. PS-co-Poly[ViEBIm]Seb (5) gelation procedure for heterogeneous supported catalyst
synthesis in THF………………………………………………………………………………………111
Figure 2.7. SEM pictures of polymer 5 as a heterogeneous catalyst support in organocatalysis showing
pore sizes between 100 nm to 10 µm……………………………………………………………………111
Figure 2.8. 1H NMR spectra overlay (PS-co-Poly[ViEBIm]TFSI)-1 (4) and (PS-co-Poly[ViEBIm]TFSI)-
2 (7) in DMSO-d6……………………………………………………………………………………….112
Figure 2.9. SEC traces corresponding (PS-co-Poly[ViEBIm]TFSI)-1 (4) (in blue) and (PS-co-
Poly[ViEBIm]TFSI)-2 (7) in (red) using 10 mM LiTFSI THF as eluent using a RI detector….. 113
Figure 2.10. Synthesis of PS- co -poly(4-vinylbenzyl-NHC-CS2 (6) . 13C NMR spectra in DMSO-d6…114
Figure 2.11. Different benzoin condensation, transesterification and cyanosililation average conversions
obtained after 5 cycles using 10 mol % amount of catalyst in heterogeneous conditions………………..116
Figure S2.1. Synthesis of Polystyrene-co-poly(4-vinylbenzylethyl-(benz)imidazolium chloride) (PS-co-
Poly[ViEBIm]Cl) (3) . 1H NMR spectra in DMSO-d6…………………………………………………125
Figure S2.2. Synthesis of Polystyrene-co-poly(4-vinylbenzylethyl-(benz)imidazolium sebacate) (PS-co-
Poly[ViEBIm]Seb)(5) . 1H NMR spectra in DMSO-d6…………………………………………………126
Figure S2.3. TGA plot of (PS-co-Poly[ViEBIm]Cl) (3)………………………………………………126
18
Figure S2.4. TGA plot of (PS-co-Poly[ViEBIm]Seb) (5)……………………………………………127
Figure S2.5. TGA plot of Sebacic Acid………………………………………………………………128
Figure S2.6. DSC plot of (PS-co-Poly[ViEBIm]Cl) (3)……………………………………………….128
Figure S2.7. DSC plot of (PS-co-Poly[ViEBIm]Seb) (5)……………………………………... 129
Figure S2.8. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-1 (4). 1H NMR spectra in DMSO-d6……..129
Figure S2.9. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-2 (7) .1H NMR spectra in DMSO-d6………130
Figure S2.10. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-1 (4). 19F NMR spectra in DMSO-d6……….131
Figure S2.11. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-2 (7). 19F NMR spectra in DMSO-d6………131
Figure S2.12. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-1 (4). 13C NMR spectra in DMSO-d6………132
Figure S2.13. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-2 (7). 13C NMR spectra in DMSO-d6……….133
Figure S2.14. Benzoin Condensation Conversion. 1H NMR spectra in DMSO-d6……………………..134
Figure S2.15. Transesterification Conversion 1H NMR spectra in DMSO-d6………………………….134
Figure S2.16. Cyanosililation Conversion 1H NMR spectra in DMSO-d6.…………………………….135
Figure 3.1: 1H NMR spectrum in DMSO-d6 of linear precursor 4 (A) and SCNP 5 (B) after folding…..145
Figure 3.2: Attenuated total reflection Fourier transform infrared (ATR-FTIR) analysis for linear starting
copolymeric precursor 4 (red) and folded SCNP 5 (blue)………………………………………………145
Figure 3.3. A) SEC responses (in DMF in presence of 10 mM NH4BF4; RI detector) of SCNP 5 (red line)
obtained via cross-linking of copolymer precursor 4 (blue line) by anion exchange. B) DLS analysis of
SCNP 5 at rt (solid red line) and at catalysis temperature (solid black line) distributed by volume in THF
(conc. = 5 mg/mL). C) TEM images of SCNP 5 (conc. = 1 mg/mL in methanol) stained with uranyl
acetate; scale bar = 50 nm. D) Kratky Log-Log plot from SAXS analysis of precursor 4 (solid red line)
and folded 5 (solid blue line) in THF (conc. = 1 mg/mL; fitted to compact particle model)………….147
Figure 3.4. Multi-T DLS analysis of SCNP 5 from 20 to 80 °C in THF with volume (black line) and
number (red line) distributions (Conc: 5 mg/mL)………………………………………………………147
Figure 3.5. 1H NMR (A) 13C NMR (B) spectra of CS2 post-functionalization reaction in SCNP 6 in
DMSO-d6…………………………………………………………………………………………...…..149
Figure S3.1. Original figure of DOSY measurements of the precursor copolymer 4 and SCNP 5, recorded
in DMSO-d6…………………………………………………………………………………………162
Figure S3.2: 13C NMR spectrum in DMSO-d6 of linear precursor 4 (A) and SCNP 5 (B) after folding163
Figure S3.3: 1H NMR (A) 13C NMR (B) spectra of CS2 post-functionalization reaction in SCNP 6 in
DMSO-d6…………………………………………………………………………………………….....164
Figure S3.4. 1H NMR spectrum of molecular model catalyst in DMSO-d6…………………………….165
Figure S3.5. 1H NMR spectrum of catalyst linear copolymer model in DMSO-d6…………………166
19
Figure S3.6. SEC traces of Linear Copolymer model (in Cl- amion form) in DMF (10 mM ammonium
tetrafluoroborate) with RI detector («Đ= 1.18; Mn = 14.8 kDa: Universal calibration)………………166
Figure S3.7. Reaction of benzoin condensation with benzaldehyde catalyzed by SCNP 5 and conversion
obtained 1
H NMR spectroscopy in DMSO-d6……………………………………………………167
Figure S3.8. Reaction of benzoin condensation with benzaldehyde catalyzed by molecular model and
conversion obtained 1H NMR spectroscopy in DMSO-d6……………………………………………167
Figure S3.9. Reaction of benzoin condensation with benzaldehyde catalyzed by linear copolymer model
and conversion obtained 1H NMR spectroscopy in DMSO-d6…………………………………………168
Figure S3.10. 1H NMR spectra of the SCNP 5 in D2O…………………………………………………169
Figure 4.1. 1H NMR spectrum of copolymer 2 in DMSO-d6…………………………………179
Figure 4.2. 13
C NMR spectrum of copolymer 4 in DMSO-d6………………………………………180
Figure 4.3. A) SEC traces (in DMF with 10 mM NH4BF4) of SCNP 5 (blue line) obtained via
intramolecular cross-linking of coPIL 2 (red line) by self-catalysis (UV detector). B) DLS analysis of
coPIL 2 (red line) and SCNP 5 (blue line) diameters at 20 °C distributed by volume in THF (conc. 1 mg
mL-1). C) TEM images of SCNP 5 (conc. 1 mg mL-1 in methanol) stained with uranyl acetate. Scale bar
= 20 nm……………………………………………………………………………………………181
Figure 4.4. Hydrodynamic diameter-temperature correlation obtained for SCNP 5 by variable
temperature dynamic light scattering (DLS) in THF (Conc.: 1 mg mL-1; 173° back-scattering detector;
average value of 4 runs is reported along with the error corresponding to the standard deviation in the
measurements; solid red line corresponds to values obtained for the volume distribution, whilst the solid
black refers to the number distribution)………………………………………………………………181
Figure 4.5. FTIR spectrum of SCNP 5 (in red) and NHC-CS2 functionalised SCNP 6 (in blue) showing
the appearance of the characteristic vibrational signal of CS2- (at ~1030 cm-1) when forming the betaine
Figure 4.6. Kinetics for transesterification reaction at 1 mol.% (blue line), 5 mol.% (red line) and 10
mol.% (black line) using A) SCNP 5, B) 7 and C) 8 as catalysts………………………………………185
Figure S4.1. 13C NMR spectrum of copolymer 2 in DMSO-d6………………………………………193
Figure S4.2. 1H NMR spectrum of copolymer 3 in DMSO-d6…………………………………..194
Figure S4.3. 13C NMR spectrum of copolymer 3 in DMSO-d6………………………………………194
Figure S4.4. 1H NMR spectrum of SCNP 5 in DMSO-d6…………………………………………195
Figure S4.5. 13
C NMR spectrum of coPIL 5 in DMSO-d6…………………………………………195
Figure S4.6. Representative multiplicity-edited HSQC spectrum of SCNP 5 in DMSO-d6, with tertiary
and primary carbons identified in blue, and quaternary and secondary carbons identified in red……….196
Figure S4.7. Representative FTIR spectrum of SCNP 5 (in black), linear polymer 3 (in red) and linear
20
polymer 2 (in blue)……………………………………………………………………………………196
Figure S4.8. DOSY NMR spectroscopy in DMSO-d6 for linear precursor 2 (A) and folded SCNP 5 (B197
Figure S4.9. 13
C NMR spectrum of SCNP 6 in DMSO-d6…………………………………………198
Figure S4.10. 1H NMR spectrum of SCNP 6 in DMSO-d6…………………………………………198
Figure S4.11. 1H NMR spectrum of linear model 7 in DMSO-d6………………………………………199
Figure S4.12. SEC trace corresponding to (bis(trifluoromethane)sulfonimide) TFSI-decorated linear
model 7 in DMF (10 mM NH4+BF4-; UV detector; SEC analysis: ĐM = 1.1; Mn =12.7 kDa)……...…199
Figure S4.13.Reaction kinetics for run 1 (Table 4.1) monitored by 1H NMR spectroscopy in DMSO-
d6……………………………………………………………………………………………………….200
Figure S4.14. Reaction kinetics for run 2 (Table 4.1) monitored by 1H NMR spectroscopy in DMSO-
d6..200Figure S4.15. Reaction kinetics for run 3 (Table 4.1) monitored by 1H NMR spectroscopy in
DMSO-d6……………………………………………………………………………………………….201
d6……………………………………………………………………………………………………….202
d6……………………………………………………………………………………………………….203
d6……………………………………………………………………………………………………….204
d6………………………………………………………………………………………………………205
d6………………………………………………………………………………………………………206
d6……………………………………………………………………………………………………….206
d6……………………………………………………………………………………………………….207
d6. ……………………………………………………………………………………………………..208
Figure S4.25. 1H NMR spectrum of copolymer 4 in DMSO-d6. …………………………………….208
Figure 5.1. A) Ag-NHC complexation reaction monitored by 1H NMR spectroscopy (400 MHz; 298 K;
DMSO-d6) at different time points (t0 = blue line, 24 h = red line, 72 h = green line). B) SEC curves (in
DMF with 10 mM NH4BF4) of 2 (red line), 3 (blue line) and 4 (black line) using RI detector polystyrene
standard. C) TEM micrograph of SCNPs 4 (scale bar = 50 nm). D) Hydrodynamic mean diameter of
21
SCNPs 4 (blue line volume distribution; red line number distribution) using multi-temperature DLS
analysis from 20 ºC to 80 ºC in THF (Conc. 5 mg mL-1)……………………………………………..219
Figure 5.2. 13C NMR spectra (100.7 MHz; 298 K; DMSO-d6) of 2 (blue), SCNP 3 (red), SCNP 4 (green),
and copolybetaine 5 (yellow)…………………………………………………………………………...221
Fig. S5.1. 1H NMR spectrum of linear precursor 2 (400 MHz; 298 K; DMSO-d6; *1 methanol; *2 water
and *3 DMSO) …………………………………………………………………………………………232
Fig.S5.2. 13C NMR spectrum of linear precursor 2 (100.7 MHz; 298 K; DMSO-d6; *1 methanol and *2
DMSO)…………………………………………………………………………………………………233
Fig. S5.3. 1H NMR spectrum of SCNP 3 (400 MHz; 298 K; DMSO-d6; *1 dichloromethane; *2 water and
*3 DMSO)………………………………………………………………………………………………233
13
Fig. S5.4. C NMR spectrum of SCNP 3 (100.7 MHz; 298 K; DMSO-d6; *1 dichloromethane and *2
DMSO)…………………………………………………………………………………………………234
Fig. S5.5. 1H NMR spectrum of SCNP 4 (400 MHz; 298 K; DMSO-d6; *1 methanol; *2 water and *3
DMSO)………………………………………………………………………………………………....234
Fig. S5.6. 13C NMR spectrum of SCNP 4 (100.7 MHz; 298 K; DMSO-d6; *1 methanol and *2 DMSO).235
Fig. S5.7. 19F NMR spectrum of SCNP 4 (376.5 MHz; 298 K; DMSO-d6)…………………………..235
Fig. S5.8. 1H NMR spectrum of SCNP 5 (400 MHz; 298 K; DMSO-d6; *1 tetrahydrofuran; *2 water and
*3 DMSO)………………………………………………………………………………………………236
13
Fig. S5.9. C NMR spectrum of SCNP 5 (100.7 MHz; 298 K; DMSO-d6; *1 tetrahydrofuran and *2
DMSO)…………………………………………………………………………………………………236
Fig. S5.10. 1H NMR spectrum of benzoin condensation catalysis using 10 mol% of catalyst 2 (400 MHz;
298 K; DMSO-d6; *1 tetrahydrofuran; *2 DMSO)…………………………………………………….237
Fig. S5.11. Mean hydrodynamic diameter of SCNP 3 by volume (black line), number distribution (blue
line) and by intensity (red line) obtained by DLS in THF. Concentration 1 mg mL-1 analysis was
performed at room temperature..............................................................................................................237
Fig. S5.12. Correlation function of SCNP 3 obtained by DLS in THF. Concentration 1 mg mL-1 analysis
was performed at room temperature.........................................................................................................238
Fig. S5.13. Mean hydrodynamic diameter of linear precursor 2 by volume (black line), number
distribution (blue line) and by intensity (red line) obtained by DLS in THF. Concentration 1 mg mL-1
analysis was performed at room temperature…………………………………………………………...238
Fig. S5.14. Correlation function of linear precursor 2 obtained by DLS in THF. Concentration 1mg mL-
1 analysis was performed at room temperature…………………………………………………………239
22
List of Schemes
Scheme 1.1 Different type of nature of cross-linkings of SCNPs……………………………………… 33
Scheme 1.2. Synthesis of linear polymer precursor based on poly(MMA)-co-(AEMA) and subsequent
cross-linking induced by addition of trimethylolpropane triacrylate
(TMPTA).29………………………………………….………………………………………….……….36
Scheme 1.3. Chemical structure of the parent copolymer P1, its photochemically induced folding into
SCNP1 and subsequent ligation to SCNP1-co-
PEG.35…………………………………….……………………………………………………………..38
Scheme 1.4. Synthesis of copolymer P1 via NMP of styrene and 4-(diphenylphosphino)styrene. The
subsequent addition of [Pt(cod)Cl2] results in SCNPs formation.45…………………………………….42
Scheme 1.5. Schematic illustration of the preparation of the linear poly(COD) by ROMP and subsequent
metal complexation (in this particular case iridium is shown as an example).47……………………......43
Scheme 1.6 a) SCNPs formation based on a triblock copolymer bearing BTA and UPy motifs, b) chemical
composition of the employed linear copolymeric precursor, c) helical BTA H-bonding driven self-
assembly and d) photoinduced dimerization of UPys via quadrupole H-bonding.62……………………48
Scheme 1.7 Schematic representation of the SCNP folding of poly(styrene-co-pentafluorostyrene) block
copolymer in solution.66…………………………………………………………………………………49
Scheme 1.8 Dynamic behaviour of PIL SCNPs by release of radicals after UV-induced homo/heterolytic
cleavage for MMA polymerisation initiation.70…………………………………………………………53
Scheme 1.9 Overview of the dynamic covalent folding and unfolding of SCNPs using hetero-Diels-Alder
(HDA) chemistry.73……………………………………………………………………………………..54
Scheme 1.10 Design of catalytically active SCNPs for transfer hydrogenation of ketones in water in a
BTA-supramolecular interactions based nanoreactors………………………………………………….80
Scheme 1.11 (A) Reduction of benzyl benzamide using Ir-SCNPs and (B) biphenyl production catalysed
by Rh-SCNPs.47…………………………………………………………………………………………83
Scheme 1.12 Illustration of a SCNP folding into a Pt-containing nanoreactor employed for the amination
of allyl alcohol which can be further recycled.45……………………………………………………….84
Scheme 1.13 Preparation of dextran-based SCNPs and subsequent incorporation of the Tn-Antigen.12086
Scheme 1.14 Schematic representation of the sensing function of the BiPy-BTA functional polymers.5389
Scheme 2.1. Synthetic route to (PS-co-Poly[ViEBIm]Cl) (3) by free radical copolymerizacion of
[ViEBIm]Cl and styrene in methanol, followed by the synthesis of physically crosslinked (PS-co-
Poly[ViEBIm]Seb) (5) by anion exchange. Synthesis of (PS-co-Poly[ViEBIm]TFSI)-1 (4) is also
23
displayed………………………………………………………………………………………………..106
Scheme 2.2. Two different pathways followed for the synthesis of TFSI anion-containing copolymers (4,
7) supporting the anion-exchange mediated decrosslinking of the gel…………………………………112
Scheme 2.3. Benzoin condensation, transesterification and cyanosilylation organocatalyzed by NHC-
supported physically crosslinked porous gel under heterogeneous conditions…………………………115
Scheme 3.1. Design of catalytically active SCNPs for benzoin condensation reaction……………….142
Scheme 3.2. Synthetic route to the parent linear copolymer 4 by RAFT copolymerization of 2, 3, 4
vinylbenzoic acid and styrene, followed by a folding step caused by anion-metathesis leading to the
formation of SCNP 5. Unfolded copolymer, 6 could be obtained by irreversibly post-functionalizing
SCNP 5 with CS2………………………………………………………………………………………143
Scheme S3.1. Synthetic route to prepare molecular catalyst model based on the active monomer and linear
catalyst model…………………………………………………………………………………………164
Scheme 4.1. Strategies to conduct SCNP synthesis for use as catalytic nanoreactors. A) Classic route
involving the addition of external reagents to induce chain folding. B) Self-catalysed SCNPs folding
mediated by supported thermally latent NHC precatalysts…………………………………………….175
Scheme 4.2. Synthetic route to functional linear copolymer 3 and subsequent self-catalysed folding step
leading to catalytically active SCNP 5. The NHC-CS2 functionalised versions of both linear precursor (4)
and obtained SCNP (6) as well as corresponding active NHC intermediates are also represented.......178
Scheme 5.1. Folding of a single-chain polymer into a nanoparticle structure via addition of a metal ion
source (i.e. Ag2O). These SCNPs are then employed as sources of free NHC upon thermal decomposition
of the organometallic Ag-NHC bond in the nanoreactor to form an active catalyst species………….215
Scheme 5.2. Synthesis of copolymer 2 via RAFT polymerization of styrene and 1 in methanol. The
subsequent addition of Ag2O results in the formation of 3 as SCNPs. Further anion exchange was
performed by inserting a non-coordinating anion (NTf2-) into 3 to confer less dynamic behavior (4).216
Scheme 5.3. Application of SCNPs 3 as a catalytic platform (B) for the benzoin condensation reaction by
exposing active NHC upon heating (C) Indirect evidence of the formation of active NHC intermediate
(A)……………………………………………………………………………………………………...220
24
List of Tables
Table 1.1. Illustrations of chemical transformations used as well as the structure of the covalent cross-
links employed in SCNPs.5 ………………………………………………………..…………………...35
Table 1.2 Illustrations of chemical transformations used as well as the structure of the organometallic
cross-links employed in SCNPs………………………………………………………………………...40
Table 1.3 Illustrations of chemical transformations used as well as the structure of the supramolecular
cross-links employed in SCNPs…………………………………………………………………………45
Table 1.4 Illustrations of chemical transformations used as well as the structure of the dynamic covalent
cross-links employed in SCNPs…………………………………………………………………………50
Table 1.5 Summary of reactions catalysed by SCNPs as organocatalysts………………………………74
Table 1.6 Summary of reactions catalysed by SCNPs as organometallic catalyst……………………77
Table 3.1. Benzoin condensation reactions of benzaldehyde under different conditions using NHC-
containing SCNPs and control experiments……………………………………………………………151
Table 4.1. Transesterification between benzyl alcohol and vinyl acetate under different reaction
conditions using masked NHC-containing SCNPs and control experiments…………………………183
Table 5.1. Condensation reaction of benzaldehyde under different conditions using Ag-NHC SCNPs and
a small molecule model as catalysts ……………………………………………………………………222
25
26
Chapter I: Introduction to Single Chain Nanoparticles
(SCNPs) as nanoreactors
27
28
Table of Contents
Chapter I: Introduction to Single Chain Nanoparticles (SCNPs) as nanoreactors
1.1 Single Chain Nanoparticles (SCNPs) ……………...........................................…..……...………31
1.1.1 Introduction ……………………………………………..…...................…………….31-32
1.1.2 Synthetic methods towards single-chain nanoparticles.….....….....................................…32
1.1.2.1 SCNPs via irreversible and reversible bonds.……….................................…..32-33
1.1.2.1.1 Covalent bonds………………..…................…................……33-39
1.1.2.1.2 Organometallic bonds…………….................…….....…..……39-44
1.1.2.1.3 Supramolecular chemistry…………….........................…...….44-50
1.1.2.1.4 Dynamic covalent chemistry…………........................…...….50-54
1.1.3 Characterisation of Single Chain Polymer Nanoparticles: analytical
techniques………………………………………………………………………….…54-55
1.1.3.1 Size exclusion chromatography (SEC)………….................………….…..….55-57
1.1.3.2 Spectroscopic characterisation of SCNPs………….............................……….....57
1.1.3.2.1 NMR spectroscopy ………………………………………….……...57-59
1.1.3.2.2 IR, UV-VIS, CD and fluorescence spectroscopy……………………59-62
1.1.3.3 Characterisation of Single Chain Nanoparticles morphology……………………62
1.1.3.3.1 Morphological characterisation via TEM…...…...............................62-63
1.1.3.3.2 Morphological characterisation via AFM…..................................…63-64
1.1.3.3.3 Morphological characterisation via scattering (DLS, SAXS, SANS)
……………………………..........................................................................…65-67
1.1.4 Applications………………………….………………………………………....………68-69
1.1.4.1 Nanomedicine…………………………..…………………….………….…..…..69
1.1.4.1.1 Drug delivery and imaging………..…………………..…….69-72

29
1.1.4.2 Nanoreactors for catalysis.………………………..........................………73
1.1.4.2.1 Organocatalysis …………………………….....................…73-77
1.1.4.1.2 Organometallic catalysis………….……....................…...…77-85
1.1.4.1.3 Enzymatic catalysis …………………....................……...…85-86
1.1.4.3 Other uses……………………………..……………….................…...86-89
1.3 Conclusions and aims of the PhD thesis......................................................………...…...…....89-91
1.4 References………………………….…………………………...…...........................……….91-97
30
1.1 Single Chain Nanoparticles (SCNPs)
1.1.1 Introduction
Many applications, such as biomedicine or catalysis, require soft matter-based particles that feature sizes
in the nanometer range. In nature, precisely defined linear polymers folded into functional
nanoarchitectures are recurrent. In this light, it seems reasonable to exploit our understanding of
biomolecules to mimic this behavior at the laboratory scale. This is most often achieved using advances
in controlled polymerisation techniques in combination with established theories of modern polymer
physics.1–3 The folding of proteins into secondary, tertiary or even quaternary structures is found to
dramatically influence their properties and functions.4 The utility of biomacromolecules mainly derives
from their 3D orientation with functionality located either on the surface or in the interior of the structure.
For this, tertiary/quaternary structures can occur as a consequence of the precise primary structure, which
is unavailable by synthetic methods. Still, in recent years, advances in controlled polymerisation
techniques have enabled the precise synthesis of well-defined and -even sequence defined- (co)polymers.
With the aim at attaining synthetic globular 3D structures, different polymer structures, such as
dendrimers, hyperbranched polymers, foldamers, micelles or star polymers have been considered as a
means to synthetically emulate biomacromolecules from nature. However, either their synthesis is tedious
and leads to low yields, or they lack of specificity in their structure.5
As an alternative to the aforementioned polymer structures mimicking folded biomacromolecules, so-
called single chain nanoparticles (SCNPs) have gained an icreasing attention. SCNPs consist of a single
linear polymer chain precursor that is further intramolecularly collapsed into a folded nanostructure and
in a defined manner.6–10 First examples were reported by Wooley et al.11,12 and Mecerreyes et al.13 two
decades ago. Since then, the field has been considerably extended. SCNPs are usually distinguished, as a
function of the nature of cross-linking moieties, into theree different categories, as depicted in Fig. 1.1.
Namely, one can differentiate: i) homofunctional crosslinks where motifs are all the same, ii)
31
heterofunctional crosslinks involving distinct cross-linking motifs and iii) use of an external cross-linker
for the folding process.8
Figure 1.1 Modes for intramolecular collapse through cross-linking of a single polymer chain, forming SCNPs.
This chapter aims at describing existing synthetic methodologies to SCNPs, related characterisation
techniques, and potential applications discussed in the recent literature for these nanoobjects.
1.1.2 Synthetic methods towards single-chain nanoparticles
1.1.2.1 SCNPs via irreversible and reversible bonds
32
A wide variety of synthetic approaches to SCNPs have been developed. The most common route is based
on the post-functionalisation of a linear, generally well-defined (co)polymer precursor, under highly dilute
conditons (ca. < 1 mg mL-1). Such conditions indeed promote intra-chain over inter-chain cross-linking.5
Biomolecules in nature exploit different orthogonal non-covalent interactions (e.g. hydrogen bonding or
van der Waals interactions), covalent interactions (e.g. disulfides) or dynamic covalent interactions (e.g.
reversible acetal formation). These modus operandi have largely inspired synthetic approaches to
SNCPs.14 The following discussion about the intra-chain cross-linking process will take into account the
types of crosslinks generated, namely, covalent, organometallic, ionic, supramolecular and dynamic
covalent bonds (Scheme 1.1)
SCNPs cross-linkings
Covalent Dynamic
Covalent
Organometallic Supramolecular
Ionic
Scheme 1.1 Different type of nature of cross-linkings of SCNPs.
1.1.2.1.1 Covalent bonds
These organic SCNPs could be obtained following different synthetic approaches applying well-known
chemistries, as summarised in Table 1.1.

33
Covalent chemistry
Entry Before cross-linking Structure of cross-linking Type of Ref
chemistry .
15
1 Friedel-Crafts
alkylations
16
2 Olefin
metathesis
17,18
3 Azide-
alkyne « click
» chemistry
19,20
4 Mensuchtkin
reactions
34
21
5 Ugi
21,22
6 Passerini
reactions
23
7 Thiol-ene
« click »
chemistry
24
8 Glasser-Hay
couplings
25–
9 UV-light
27
dimerisations
Table 1.1. Illustrations of chemical transformations used as well as the structure of the covalent cross-links
employed in SCNPs.5
35
Pomposo et al. have thoroughly analysed the reported examples of covalently cross-linked SCNPs.28 Their
analysis reveals that, unexpectedly, covalent SCNPs can adopt an open, sparse morphology resembling
that of intrisically disordered proteins (IDPs), rather than a globular architecture like of naturally occuring
biomolecules. The covalent nature of cross-links in this type of SCNPs confers them an enhanced
robustness and decreasing their probability for further aggregation and/or inter-crosslinking after the
critical folding step. This may be crucial for certain applications, particularly where conditions are
relatively harsh, such as at high temperatures, extreme pH or concentrated environments.
As representative example of the aforementioned properties regarding covalently cross-linked SCNPs,
Diesendruck et al. improved the molecular toughness of synthetic polymers by introducing intramolecular
covalent cross-links (Scheme 1.2). The use of covalent cross-links in the SCNPs was envisaged to study
mechanochemical reactions when applying shear (by sonication). Unexpectedly, the collapsed structure
of the polymer underwent mechanochemical reactions at accelerated rates, although the scission occurred
in sacrificial bonds that did not lead to fragmentation of the chains. This outcome proved that covalently
cross-linked SCNPs showed enhanced mechanical properties by mantaining their properties under harhs
conditions.29
Scheme 1.2. Synthesis of linear polymer precursor based on poly(MMA)-co-(AEMA) and subsequent cross-linking
induced by addition of trimethylolpropane triacrylate (TMPTA).29
36
Inspired by reported reactions at the molecular level, covalently bound SCNPs repeat these reactions all
along the polymeric structure leading to multiple covalent linkages in the same nanoparticle. As
summarised in Table 1.1, elementary reactions implemented to fold the linear polymeric precursors into
single (co)polymer chains have been used following different fashions.
One of the earliest examples was reported by Dubrovina et al., who derived linear polystyrene containing
50% and 100% of chloromethylated phenyl residues. Intramolecular cross-links were successfully
obtained via Friedel-Craft alkylations in presence of SnCl4 leading to particles with radius ca. 17 nm and
cross-linking degrees of 60%. This synthesis pathway required however relatively harhs conditions (i.e.
80 °C for 100 h in dichloroethane) (Table 1.1 ; Entry 1).15
In another example, Coates et al. synthesised vinyl-pendant linear polycarbonates using a Zn-derived
catalyst (i.e. [(BDI)ZnOAc]2). Subsquently, intramolecularly cross-linked nanoparticles were obtained by
cross-metathesis reaction of pendant vinyl groups using Grubbs 2nd generation catalyst. The high catalytic
efficiency of the Grubbs catalyst was translated in the fast rate at which cross-links were obtained. In fact,
more than 42% of pendant vinyl groups reacted within 15 min, albeit metathesis slowed down as the
reaction progressed. However, the use of different metals remains as a potential drawback for biomedical
applications or electronics (Table 1.1 ; Entry 2).16
High efficiency, high functional (group) tolerance, and relatively mild reaction conditions render “click
chemistry” reaction an attractive approach for obtaining SCNPs. So far, copper-mediated azide-alkyne
cycloaddition (CuAAC) (Table 1.1 ; Entry 3) ,17,18 Mensuchtkin reaction (Table 1.1 ; Entry 4),19,20
multicomponent Ugi (Table 1.1 ; Entry 5) 30 and Passerini (Table 1.1 ; Entry 6) 22,31 reactions or thiol-
ene addition (Table 1.1 ; Entry 7) 23,32 (to cite few) have been used as cross-linking “click” methods for
SCNP fabrication.
37
Having the lack of group tolerance as main drawback to circumvent, Pomposo et al. directly polymerised
terminal alkynes via redox-initiated RAFT (reversible addition-fragmentation chain transfer)
polymerisation. The obtained functional linear precursor was exposed under diluted conditions to copper-
catalysed Glaser-Hay coupling conditions to form SCNPs with no previous deprotection process (Table
1.1 ; Entry 8).
Photochemical chemistry is often clean, relatively fast and high yielding and often requires no external
catalyst. Therefore, several reactions have been applied in the SCNPs domain such as photoinduced nitrile
imine mediated tetrazole-ene cycloaddition33 or photo-dimerisations of anthracene27 or coumarin,34 for
instance (Table 1.1 ; Entry 9).
The versatility of employing UV-light was highlighted in a recent study carried out by Barner-Kowollik
et al. by harnessing different wavelengths for different functionalization purposes.35 Namely, by
synthesising a (co)polymer containing 9-triazolylanthracene units distributed along the polymer chain and
a terminal styrylpyrene unit polymer, authors developed amphiphilic SCNPs. By irradiation with UV light
at λ = 330 nm, P1 was intramolecularly cross-linked. Subsequently, a PEG polymer block was
incorporated by irradiating blue light at λ = 455 nm (Scheme 1.3). The unprecedent selectivity to trigger
different dimerisations arised from the unique set of λ-orthogonal photoligations.
38
Scheme 1.3. Chemical structure of the parent copolymer P1, its photochemically induced folding into SCNP1 and
subsequent ligation to SCNP1-co-PEG.35
1.1.2.1.2 Organometallic bond
In this part, is discussed the possibility to incorporate metal-ions as a means to intramolecularly crosslink
linear chains into SCNPs (summarised in Table 1.2). One should distinguish between two types of
fcnctionalisation that SCNPs can undergo via metal-complexation. Firstly, the externally introduced
metal-ions do not only impart the desired catalytic function to the polymeric architecture, but operate
instead as structure-forming elements. Alternatively, SCNPs can be previously formed and subsequently
loaded with metal ions (Fig.1.2).36 It has to be acknowledged though, that the first case appears the most
promising, as related SCNPs may behave as analogous of metallo-enzymes.36,37
Figure 1.2 (A) The introduction of appropriate ligand functionalities in the polymer chain allowing SCNP folding
and catalytic functionalitisation in one step. (B) Nanoparticle formation via an external trigger and subsequent metal
ion loading.36
39
Organometallic bonds
Entry Before cross-linking Structure of cross-linking Type of Ref
chemistry .
38,3
1 Palladium
9
complexati
on
40
2 Ti
complexati
on
41
3 Iron
complexati
on
40
42
4 Gadolinium
complexati
on
43
5 Nickel
complexati
on
44
6 Copper
complexati
on
Table 1.2 Illustrations of chemical transformations used as well as the structure of the organometallic cross-links
employed in SCNPs.
In order to form organometallic hybrid SCNPs, ligands are generally supported onto the polymeric
structure. Specifically, Kowollik et al. designed a linear copolymer of styrene and 4-
(diphenylphosphino)styrene via nitroxide-mediated polymerization.45 The triarylphosphine ligand
moieties along the backbone allowed for the intramolecular cross-linking of SCNPs via the addition of
[Pt(1,5-cyclooctadiene)Cl2] in diluted conditions. These nanoparticles were developed for catalysis
purpose, and interestingly, embedding Pt ions into the SCNP-structure enabled homogeneous catalytic
conditions as well as full recyclability of the SCNPs (Scheme. 1.4) (Table 1.2; Entry 1).
41
Scheme 1.4. Synthesis of copolymer P1 via NMP of styrene and 4-(diphenylphosphino)styrene. The subsequent
addition of [Pt(cod)Cl2] results in SCNPs formation.45
The ease of preparation of this specific type of ligand-bearing linear polymer precursor has motivated the
incorporation of large number of different metal ions. Namely, the same polymer precursor decorated
with 4-(diphenylphosphino)styrene served as (poly)ligand for both ruthenium46 and palladium.39 Equally
to the example represented in Scheme 1.4, the latter metal-containing SCNPs were used as nanoreactors
for catalysis.
Together with phosphines, several monomers have been derivatized in order to support versatile and
highly efficient ligands, such as chiral saleen moieties for titanium40 (Table 1.2 ; Entry 2) or NHCs for
palladium (Table 1.2 ; Entry 1).38 Of special importance, in the latter example Taton et al.,38 disclosed a
synthetic strategy where no active carbenes were employed for the folding step; instead, a
benzimidazolium chloride ionic liquid was used as non-sensitive ligand. This achievement critically
decreased the complexity of the process enabling an easy handling and storage of both precursors and Pd-
SCNPs.
In most cases, the latter backbone is of (meth)acrylic or styrenic-type. Conversely, Lemcoff et al.
introduced a wide-ranging strategy using the actual polymer backbone for the exploitation of
orgnanometallic bonds to induce SCNPs collapse with a diverse system.47 This was simply achieved by
using a pCOD poly(1,5-cyclooctadiene) obtained by ROMP (ring opening metathesis polymerization) as
(poly)ligand. This provided a straightforward synthetic route to metal-containing SCNPs without the need
42
for a specific monomer to act as ligands (Scheme 1.5). Moreover, the versatility of COD as ligand was
harnessed by serving as support for different metals as rhodium, iridium or nickel.
Scheme 1.5. Schematic illustration of the preparation of the linear poly(COD) by ROMP and subsequent metal
complexation (in this particular case iridium is shown as an example).47
Different to the one-step metal incorporation of metal-ions into polymer supported-ligands, Sawamoto et
al. created amphiphilic SCNPs bearing iron ions via a two-step procedure.41 Briefly, a linear
poly(methyl)methacrylate supported aniline-type motifs was designed . The aniline motifs were post-
functionalised to incorporate bifunctional ligand cavities (i.e. 2,6-pyridine derivative) and then FeBr2 was
incorporated into the core of already cross-linked SCNPs occupying the previously formed ligand cavities.
SCNPs could be recycled after each catalytic cycle thanks to the covalently cross-linked robust structure
which enabled to keep catalytic activity and thus efficient recyclability (Table 1.2; Entry 3).
Another notorious example of a two-step procedure for incorporating a metallic ion was performed by
Odriozola et al.42 In this example, an azide-bearing polyacrylate copolymer was designed and
subsequently cross-linked by a Cu(I)-catalyzed click reaction in presence of short dialkyne molecule. This
covalently bond cross-linker provided with a DTPA (diethylenetriaminepentaacetic acid) then served as
43
chelating units for Gd(III) ions. Interestingly, the obtained nanoparticles showed higher relaxivity
properties for MRI (magnetic resonance imaging) applications than commercially available analogues,
thanks to an enhanced water solubility provided by the polymeric structure, as well as the ease to load
multiple Gd(III) ions (Table 1.2; Entry 4).
He and coworkers developed SCNPs-based metallofoldamers by intramolecular self-folding through Ni-
thiolate coordination within thiol-functionalised linear copolymer.43 These Ni-thiolate cofactors were
employed for catalytic purposes. Interestingly, they were found not only to act as cross-linking bridges
but also acted as a secondary coordination environment to promote photocatalytic activity (Table 1.2;
Entry 5).
Targeting the same mimicry related to metalloenzymes, Pomposo et al. developed an efficient vitamin B9
nanocarriers known as “Michael” nanocarriers, based on Cu(OAc)2 complexes supported all along SCNPs
structure.44 Helped by computational support, these “Michael nanocarriers” were found to resemble
disordered multidomain proteins with semiflexible linkers in solution, whereas they remained collapsed
with globular morphology in dry state (Table 1.2; Entry 6).
1.1.2.1.3 Supramolecular Chemistry
Supramolecular intractions, such as H-bonding and π-π interactions, are the dominant intra-chain linkage
in folded biomacromolecules.5 Monomers employed to this end are typically, functionalized with
hydrogen bonding units that are (photo)protected, in an effort to avoid the formation of premature
aggregates. As summarised in Table 1.3; Entry 1, Palmans, Meijer et al. have carried out studies
involving 2-ureidopyrimidinone (UPy),48–50 a motif that is prone to dimerization by hydrogen bondings.
The deprotection step, occuring under dilute conditions, favors the formation of intra-chain quadruple
hydrogen bonds, promoting the formation of the targeted SCNPs. The authors refer to these SCNPs as
metastable particles, as high temperatures and solvent exchange were found to induce polymer
44
precipitation, as a result of inter-chain interactions. Moreover, Upy dimerization was used to study the
effect of several variables in SCNPs formation and its performance for several applications (Table 1.3;
Entry 2). Briefly, the same group stablished that the rigidity of the polymer backbone, the placement of
additional hydrogen bonding sites in the UPy linker, and the molecular weight of the polymer had little
effect on the ability of a polymer to form supramolecular SCNPs. In contrast, solvent was found to play
an important role in disrupting or facilitating H-bond formation. 51
Supramolecular bonds
Entry Before cross- Structure of cross-linking Type of Ref.
linking chemistry
6,46,52
1 Benzene-
–54
1,3,5-
tricarboxamide
(BTA)
hydrogen
bonding
48,51
2 2-ureido-
4[1H]-
pyrimidinone
(UPy)
45
hydrogen
bonding
55,56
3 Thymine,
diaminopyridi
ne hydrogen
bonding
55,57
4 Hamilton
wedge,
cyanuric acid
hydrogen
bonding
58
5 Dendritic self-
complimentary
hydrogen
bonding
Table 1.3 Illustrations of chemical transformations used as well as the structure of the supramolecular cross-links
employed in SCNPs.
In another report, benzene-1,3,5-tricarboxamide (BTA) instead of UPy was used as H-bonding motif
causing the single chain folding. This also generated a helical self-assembly along the copolymer
46
backbone via hydrogen bonding.59 In one instance, a photoprotected BTA containing motif was used to
prevent aggregation during polymer synthesis.54 In more recent publications, this protection strategy was
no longer necessary, BTA-based monomers being directly polymerized in a solvent capable of disrupting
H-bonds.46,52,53,60,61 Nevertheless, this group developed, in parallel, a polymer in which BTA units could
be attached via azide-alkyne “click” chemistry.62 In a joint effort to combine both different hydrogen
bondings (i.e. helical and quadruple hydrogen bondings), Palmans, Meijer et al. combined UPy and BTA
units in a block copolymer (Scheme 1.6).62 In summary, a polymethacrylate precursor containing BTA
and UPy motifs was readily synthesised using a post-functionalisation approach. The resulting copolymer
was functionalized using the CuAAC and isocyanate conjugation reactions, affording the final precursor
containing distinct self-assembling motifs in a single chain. Interestingly, the obtained linear precursor
could thermally fold into SCNPs through intramolecular self-assembly of the BTAs to form internal
columnar, helical stacks. Upy deprotection using UV light results in a further collapse of the polymers
into more compact conformation via intramolecular UPy association. Well-defined SCNPs with
orthogonally self-assembling domains mimicking an α-helix and a β-sheet were herein successfully
provided.
47
Scheme 1.6 a) SCNPs formation based on a triblock copolymer bearing BTA and UPy motifs, b) chemical
composition of the employed linear copolymeric precursor, c) helical BTA H-bonding driven self-assembly and d)
photoinduced dimerization of UPys via quadrupole H-bonding.62
Another approach related to supramolecular chemistry and enabling for SCNP synthesis uses
cucurbit[n]urils for host-guest complex foramtion (Table 1.3; Entry 2) The Scherman group developed
ternary host-guest complex-based SCNPs using methyl viologen and naphtyl-functionalised polymers as
building blocks., Important aggregation was however observed therefore studies were therefore conducted
at very low concentrations ca. 0.1 mg/mL.63,64
Weck et al. synthesised a triblock copolymer containing styrene and pentafluorostyrene motifs (Scheme
1.7). The quadrupole interacions involving the electron-rich and electron-deficient blocks was studied
under different concentrations in different solvents. Although SCNP formation was favoured at high
dilution (i.e. 1 mg/mL), it was found that intramolecular SCNPs folding occurred in chloroform preferably
48
due to this arene-perfluoroaren quadrupole, whereas in DMF (N-N-dimethyl formamide) larger aggregates
were observed due to intermolecular interactions (Scheme 1.8).65
Scheme 1.7 Schematic representation of the SCNP folding of poly(styrene-co-pentafluorostyrene) block copolymer
in solution.66
In another attempt to make compatible different supramolecular interactions upon the same SCNP
structure, Barner-Kowollik et al. demonstrated that complex supramolecularly cross-linked SCNPs based
on cyanuric acid-Hamilton wedge multiple hydrogen bonding and thymine and diaminopyridine triple
hydrogen bonding interactions could be obtained and isolated (Table 1.3; Entry 3).55 Interestingly, it was
found that the single chain self/folding was dependent on concentration as well as temperature, with single
chain self/folded structures dominating at low temperatures and high dilution regimes.
The effects of solvents and steric hindrance on the self-assembly of the complementary recognition units
(i.e. thymine and diaminopyridine, (Table 1.3; Entry 4)) was studied by Barner-Kowollik et al.56 They
established that the sterically less demanding t-butyl acetyl group leads to a better assembly process.
Moreover, they recognised dichloromethane as the preferred solvent over chloroform, as the nonspecific
interactions between the cyanuric acid protons and the solvent were avoided.
Another important contribution to supramolecular interactions-based SCNPs was brought by S. Kim et
al. with the use of 2-((3,5-bis(4-carbamoyl-3-(trifluoromethyl)phenoxy)benzyloxy)
carbonylamino)ethyl methacrylate units aka SHB (Table 1.3; Entry 5).58 At low levels of SHB
incorporation (> 1.5%), intermolecular interactions predominated in nonpolar solvents resulting in large-
49
scale aggregation, while for high loading levels (ca. 6%), intramolecular hydrogen bonding was favored
in toluene leading to the formation of well-defined and stable nanoparticles.
1.1.2.1.4 Dynamic covalent chemistry
As summarised in Table 4, SCNP synthesis via dynamic covalent bonds proves versatile to achieve
adaptable and responsive nanostructures. This indeed creates reversible bonds that can be kinetically
cleaved or rearranged after applying a stimulus, such as temperature, pH or radiation.5 Inspired by
analogous ocurring redox chemistry in biological systems,67 the utilisation of disulfides has been an area
of interest in the SCNP field.
Specifically, the group of Berda et al. developed the synthesis of anhydride functionalized linear polymer
precursors, where intramolecular disulfide linkages were incorporated by addion of 4-aminophenyl
disulfide, and could be further reversibly cleaved and reformed in dilute solution by treatment with
dithiothreitiol (reducing) and iron(III) (oxidative) agents, respectively (Table 1.4; Entry 1).67
Dynamic covalent
Entry Before cross-linking Structure of cross-linking Type of Re
chemistry f.
67
1 Disulfide
formation
50
69
2 Hydrazon
68
3 Enamine
formation
70
4 Benzophe
none
71,7
5 Diels-
2
Alder
Table 1.4 Illustrations of chemical transformations used as well as the structure of the dynamic covalent cross-
links employed in SCNPs.
Important contribution to SCNP technology has been brought by the group of Fulton. For instance,
acylhydrazone bonds were employed to synthesise SCNPs with a reversible character (Table 1.4; Entry
51
2). Namely, a bis(hydrazide) cross-linker was continuously added to an aldehyde-containing polystyrene
in presence of catalytic amounts of trifluoroacetic acid (TFA). In order to isolate the resulting SCNPs,
TFA was quenched with triethylamine and hence SCNPs would remain intact upon isolation.
Interestingly, no collapse was observed at higher cross-linking densities. The dynamic behavior of the
acylhydrazone bond was confirmed by triggering the exchange with a monohydrazide.69 In a more recent
publication by the same group, oligo(ethylene glycol) side chains were incorporated to a similar system,
imparting response not only to pH variations, but also to temperature changes. In this manner, at low pH,
related SCNPs remained stable in solution, whereas when the system was exposed to acid and heat, the
nanoparticles precipitated followed by hydrogel formation. This process could be reversed by simple
cooling down.32
More recently, in a collaboration with the Pomposo group, Fulton et al. derived β-ketoester functionalized
linear polymers and condensed these precursors with butylamine (Table 1.4; Entry 3). SCNPs were then
acheved by an enamine exchange reaction with ethylene diamine under dilute conditions. The reversibility
of the cross-links was evidenced upon addition of phosphoric acid, and crosslinks could be restored by
adding ethylene diamine. 68
In a contribution brought up by Temel et al., a dynamically covalent photoactive SCNPs were presented.
The linear parent precursor was tailored with chloromethyl styrene moieties. The subsequent addition of
Micheler’s ketone by “Menschutkin click chemistry” led to charged SCNPs. Interestingly, the Michler’s
ketone parts of the nanoparticle proved reactive under photoexcitations to initiate the free-radical
polymerization of MMA (Sheme 1.8) (Table 1.4; Entry 4).. 70
52
Scheme 1.8 Dynamic behaviour of PIL SCNPs by release of radicals after UV-induced homo/heterolytic cleavage
for MMA polymerisation initiation.70
Dynamic covalent chemistry using Diels-Alder chemistry was harnessed by Kowollik et al. Briefly,
hetero-Diels-Alder (HDA) chemistry based on cyanodithioester (CDTE), cyclopentadiene (Cp) and sorbic
alcohol resulting in reversible chain folding was applied (Scheme 1.9) (Table 1.4; Entry 5). Cp-protected
CDTE moieties were supported in a poly(methacrylate) backbone, and subsequent addition of sorbic
derivate bi-linker. Interestingly, the folded structure could return to its linear version by simply adding
sorbic alcohol exploiting the reversible nature of HAD chemistry. 73
53
Scheme 1.9 Overview of the dynamic covalent folding and unfolding of SCNPs using hetero-Diels-Alder (HDA)
chemistry.73
1.1.3 Characterisation of Single Chain Polymer Nanoparticles:
Analytical Techniques
Corroborating the data provided by a variety of analytical techniques is necessary in order to verify the
formation of SCNPs. Most commonly, this approach seeks to identify distinct differences between the
linear polymer and the folded SCNPs following cross-linking, such as the disappeareance of functional
groups or changes in the polymer size/morphology. Probably one limitation is that sensitive techniques
have to be used to establish absence of aggregates that can form during the synthesis/purification of
SCNPs. 5,74,75
Although standard polymer analysis techniques, for example, nuclear magnetic resonance (NMR)
spectroscopy and size exclusion chromatography (SEC), are often used to analyze the prepared polymers,
54
much of the work consists on analysing the morphology, size and stability of the obtained particles, in
comparison to the parent polymer. Common methods for particle analysis include light scattering
techniques and microscopy. However, the combination of different techniques provides a larger and more
accurate information of SCNPs in study.76
1.1.3.1 Size Exclusion Chromatography (SEC)
SEC has been an invaluable tool for characterising folding processes and better understanding SCNPs.
Although the extracted data is based on the hydrodynamic volume of both linear and folded polymers, the
SEC measurements not only provide qualitative information, but can also provide quantitative information
by applying sensitive detectors, such as MALLS (multi-angle laser light scatering) or a viscosimetric
detector.74,76 SEC analyses have evidenced that polymers will show an incrase in retention time and a
decrease in apparent molecular weight, following collapse.
As a representative example, Berda et al. reported a study where intrachain radical homopolymerisation
between stilbene units in a styrenic backbone was performed under dilute conditions. Among different
characterisation techniques, one piece of evidence that folding was effective was provided by SEC. As
illustrated in Fig. 1.3, from the parent polymer to the SCNP, the retention time and molecular weight
increased, while the radius decreased which is result of the coil-to-nanoparticle transition.77
55
Figure 1.3. SEC UV detector traces obtained in THF at 40 °C for reaction of styrene functionalized P1 with AIBN
to yield NP1-0.77
Additionally, a decrease in the dispersity (Đ) is often also observed via SEC when a folded SCNP is
formed from a linear coil. This was studied in more details by Pomposo et al. who developed mathematical
equations to relate the decrease in hydrodynamic radius to corresponding calibration standards.78
Nevertheless, they put the attention on the high sensitivity of PDI (polydispersity index) values to the
presence of high molecular weight tails arising from minor quantities of byproducts generated by
intermolecular secondary reactions.
Related to the diverse nature of polymeric structures, the presence of charged groups, such as those found
in polyelectrolytes, e.g. in PILs, can result in complications and unreliable characterisation data via SEC.
Matyjaszewski et al. proposed a « universal method » to characterise imidazolium-type PIls, by inserting
the non-coordinating anions such as TFSI, tetrafluoroborate (BF4-) or hexafluorophosphate (PF6-) and use
56
10 mM LiTFSI in THF as eluent.79 This technique dramatically decreases the interaction between the
PILs and the SEC stationary phase, providing a more accurate and more representative mass and dispersity
values for the TFSI-modified PILs.20
1.1.3.2 Spectroscopic characterisation of SCNPs
Spectroscopic techniques offer convenient ways of characterising SCNPs. Each technique, in tandem with
others, provides an elaborate picture of SCNPs features such as structure, morphology or size. NMR
spectroscopy has also helped to probe various aspects of macromolecular composition, structure and
dynamics.5–7,76,80
1.1.3.2.1 NMR spectroscopy
Formation of cross-links can be detected by monitoring characteristic signals in NMR spectra, with the
use of 1D 1H NMR spectroscopy regarded as the quickest way of monitoring the conversion of the linear
polymer to cross-linked SCNP.76
A clear example was reported by Berda et al. in a study where they implemented thermal Diels-Alder
chemistry.72 Random copolymers based on poly(methacrylate) bearing furfuryl and maleimide motifs
were employed to achieve internal folding through a thermal Diels-Alder reaction. To prove the efficiency
of this approach, 1H NMR analysis of P1 (Fig. 1.4 blue traces) and NP1 (Fig. 1.4 red traces) was carried
out to proof Diels Alder adduct formation following the decrease in intensity of key signals.
57
Figure 1.4 1H NMR overlay spectrum of polymer (P1) and nanoparticle (NP1) in CDCl3.
Fluorine (19F), phosphorous (31P), boron (11B), nitrogen (15N) and carbon 13C are also very useful in NMR
spectroscopy, being sensitive to any environment change induced by polymer folding.76
Equally, the use of 1D NMR spectroscopy experiments provides valuable insight for the incorporation of
reactive monomer units and the formation of SCNPs. However, it does not provide much information
regarding the particle conformation and structure. One common approach to overcome these limitations
is by 1D NMR experiments at different temperatures, which can allow for better understanding of the
dynamic effects of the polymer, such as ligand exchange.76 Alternatively, 2D NMR-spectroscopy has
emerged as a key tool for probing how SCNPs collapse,5 techniques such as diffusion-ordered
spectroscopy (DOSY) can provide information about Mw or particle diameter, by using equations based
on the polymer/particle diffusion coefficients.81,82 When applied to SCNPs, the intramolecular collapse
of the linear polymer chain leads to an increase in the diffusion coefficient, a complementary evidence of
the formation of collapsed SCNPs.20,83
58
As a supplementary evidence of the conformational change from coil linear polymers to intramolecular
collapsed NPs, Loinaz et al. employed DOSY experiments (Fig. 1.5).18 This enabled to determine the
diffusion coefficient of a polymer in solution, a parameter that is reversely proportional to the
hydrodynamic volume, hence intramolecular collapse should lead to an increase of the diffusion
coefficient, evidencing SCNP formation. For instance, the values of D for the linear precursor and
corresponding SCNP were -8.56 and -8.30, respectively, confirming the reduction of the hydrodynamic
radius after collapse, even if in that particular case the amount of cross-linking was only of 3%.
Linear
precursor
SCNP
Figure 1.5 DOSY spectra of linear precursor and corresponding SCNP CD2Cl2.18
1.1.3.2.2 IR, UV-VIS, CD and Fluorescence Spectroscopy
Other spectroscopic techniques, such as infrared (IR), ultraviolet-visible (UV-VIS), fluoroscence and
circular dichroism (CD) also prove valuable to get an insight into the structure of SCNPs. These methods
are typically used in tandem with other techniques to rationalise the characterisation of SCNPs.76
59
IR spectroscopy has been key to characterise the formation of SCNPs following the disappearance or
appearance of particular signals depending on the system. As an example, Wang et al. resorted to IR
spectroscopy to monitor the disappearance of the azide (2127 cm-1) and formation of the C-N (1200-1450
cm-1) bounds after reacting upon heating. As observed, a new signal corresponding the stretching
vibration of groups of C-N appeared at 1200 cm-1.84 (Fig. 1.6)
Figure 1.6. FTIR spectra of a) linear polymeric precursor and b) corresponding SCNP.84
In a recent study conducted by Kowollik et al. a versatile process for the preparation of fluorescent SCNPs
via two tetrazole chemistry-based mechanism in pure water was introduced.85 In a polyacrylate-based
backbone, tetrazole, alkene and tetraethylene glycol monomethyl ether moieties were incorporated. SCNP
formation was triggered by UV-light and carefully confirmed by various means, among which UV-vis
spectroscopy. Namely, as displayed in Fig. 1.7, the obtained characteristic pyrazoline absorption band at
415 nm demonstrated that the cross-linking was successfully driven for SCNP1. On the other hand,
SCNP2 presented a less intense and blue-shifted band corresponding to the carboxylic acid ligation. In
60
this manner, it was proven SCNPs could present different fluorescence by simply modulating the starting
copolymer composition.
A B C
Figure 1.7 (A) UV-vis absorbance of the polymer precursors (smooth lines) and the corresponding SCNPs (dashed
lines), (B) Emission spectra of the formed SCNPs and (C) photograph of a solution of SCNPs under a hand-held
UV-lamp (λ = 366 nm).85
Meijer et al. designed a triblock copolymer with orthogonally self-assembling motifs, BTA and UPy
helped to be folded into a SCNP structure.62 Different SCNPs compositions were studied, where the
optically active components were varied, and their behavior upon UV-irradiation in water was studied at
20 °C. CD spectra at 20 °C before and after irradiation were identical (Fig. 1.8), confirming that UPy
dimer formation did not interfere with BTA self-assembly. This piece of characterisation revealed the
enhanced robustness of SCNPs against UV-irradiation on time-scale.
61
Figure 1.8 CD spectra of different particles (P1, P2 and P3) at 20 °C during 120 min of 350 nm UV irradiation.62
1.1.3.3 Characterisation of Single Chain

Nanoparticles morphology
One challenging aspect for characterising SCNP is to accurately establish their morphology, which is
dependent on the preparation and analysis conditions. The expected spherical morphology of SCNP is not
always consistent with experimental findings. This could be due to variability in the morphology itself,
which has been found to have a strong dependence on the solvent used, concentration, temperature or pH.
Microscopy and scattering techniques have typically been used to determine the size and shape of folded
SCNPs.
1.1.3.3.1 Morphological
characterisation via TEM
With soft SCNPs, contrasting agents, such as ruthenium oxides or uranyl acetate, are applied for TEM to
increase the contrast between particles and the surface of the TEM grid. This provides an accurate visual
representation of particle size and morphological structure (e.g. spherical particles).5 TEM size
measurements are commonly compared with those obtained from light scattering experiments. Although,
62
the obtained size values remain relatively close, some differences are usually observed, due to differences
between the solid and in-solution state of the SCNPs.61,86
In a recent example, Zimmerman et al. compared sizes obtained in TEM with those observed by DLS for
the same SCNPs, ca. 8-10 nm and 5.8 nm, respectively (see Fig. 1.9). The authors suggested that the
polymeric nanoparticles could be flatten when absorbed on the grid surface and that ammonium
molybdate negative staining could further increase the diameter.87
Figure 1.9. TEM images of SCNPs at different zooms stained with ammonium molybdate.87
Concerning polyelectrolytes, and as mentioned in the section about NMR spectroscopy, their charged
nature can cause the retention of solvent among the charges when casting for sample preparation for TEM
analysis. This effect can lead to an increase in size, due to the « swollen-state » of SCNPs or possible
appearance of aggregated domains in the TEM images.20,38,83
1.1.3.3.2 Morphological characterisation via

AFM
Atomic force microscopy (AFM) is a key technique for the characterisation of SCNPs, as it can provide
3D soft particle images on the nanometer scale. One difference when compared to TEM is that AFM does
63
not (necessarely) require the addition of contrast agents. Based on the interaction between a scanning
cantilever with the particles on a mica or highly oriented pyrolytic graphite (HOPG) surface, AFM enables
the observation of either individual SCNPs or their aggregates. The observed SCNPs size has been found
to be highly dependent on molecular weight and degree of cross-linking,49 but also on the concentration
used for sample preparation.50
Meijer et al. used AFM to illustrate a two-step folding process of supramolecularly cross-linked SCNPs.62
The first folding step involved BTA moieties that self-assembled by decreasing the temperature while the
second step involved dimerization of UPy moieties upon UV-irradiation. In this manner, a sample was
prepared with the partially folded SCNPs involving BTA interactions by cooling down (Fig 1.10 A) and
the same sample was irradiated with UV-light to entail UPy dimerisation (Fig. 1.10 B). AFM images
clearly depict the chain collapse and image the “fully folded” SCNPs. In addition to that, the AFM
measurements provided real snapshots of the compartimentalised SCNPs before and after UV irradiation.
Figure 1.10 AFM height imaged of SCNPs capture of two-steps of the molecular folding process (A) before and
(B) after UV irradiation. The top right insets show magnifications of the framed areas. 62
64
1.1.3.3.3 Morphological characterisation via
scattering (DLS, SAXS, SANS)
The hydrodynamic diameter of SCNPs is obtained by analysing a sample solution illuminated by a single-
wavelength laser. Variations of the Brownian motion detected at a given scattering angle can then be used
to extract information about particle size.76 In DLS measurements, SCNPs are analyzed in solution. SCNP
diameter can then be compared with that of the linear parent polymer,41 or the influence of the SCNPs
under different conditions, such as pH55 or temperature, can be studied.83 DLS also enables to monitor the
folding of the particle over time.88
An example was reported by Kowollik et al. A dual-gated orthogonal SCNP unfolding system based on
benzo-21-crown-7 (B21C7)/secondary ammonium salt (AS) host-guest system was explored in presence
of different solvents or salts. DLS analysis revealed the compaction of the unfolded P6 into a more
compact structure (P6 folded) in DCM/acetonitrile (9/1 v/v) after folding (Fig 1.11 A). Then, a similar
particle composition (P16) was studied under different conditions. Namely, when 20 µL was added to a
solution of SCNPs (P16), Dh (hydrodynamic diameter) increased by almost 2 nm. When KPF6 was added,
Dh increased again by almost 2 nm (Fig. 1.11 B). Interesingly, inverting the order of the added triggers
lead to a similar increase in Dh based on DLS. This was believed to occur due to the disruption of
interactions that kept cross-linked the SCNPs and therefore the addition of different triggers entailed the
orthogonal stepwise unfolding.
65
Figure 1.11 (A) Dynamic light scattering (DLS) data (number distributions) for the folded and unfolded polymer
(P6). (B) DLS data for the folded and unfolded polymer P16 in presence of different solvents/salts. X-ray
scattering is being increasingly used to track the conformational changes from linear polymer precursors
to folded SCNPs based on the change in their diameter. By using this technique, size and morphological
aspects can be determined for SCNPs in solution, but with smaller wavelengths used in small-angle X-
ray scattering (SAXS) and small-angle neutron scattering (SANS). By SAXS, the hydrodynamic diameter
of SCNPs can be obtained in solution by suitable data treatment, by extracting the background solvent
and correlating morphologies to theoretical models such as compact, hollow or cylindric particles.62,83
Pomposo et al. had performed SAXS measurements to determine the form factor w(q) of distinct SCNPs
obtained by two different synthetic protocols (i.e. protocol I and protocol II).89 This form factor allows
calculating the Flory exponent (v) for a given SCNP in a good solvent (THF in this case). This information
provides direct values of degree of chain compaction. Thus, the value obtained of v = 0.52 for SCNPs
following protocol I only presents a modest degree of chain compaction. But instead, SCNPs obtained by
protocol II afford a v = 0.48 revealing a sparse morphology (Fig. 1.12 A). The obtained values were in
good agreement with those obtained from molecular dynamics (MD) simulations in which SCNP
synthesis by protocols I and II were simulated (Fig. 1.12 B). It is worth noting that, though both protocols
66
I and II produced sparse SCNPs (v = 0.5), SCNPs obtained from protocol II were more compact at local
sites, as evidenced by the sharper decay of w (q) after the fractal regime.
Figure 1.12 (A) Form factor from SAXS of precursor (circles) , SCNPs following protocol I (diamonds) and II
(crosses) in THF. (B) Form factor from MD simulations of the precursor (circles) and the SCNPs synthesised
through protocol I (diamonds) and II (crosses).
Conversely, SANS experiments have been used to probe the relationship between the form factor and the
concentration for a non-deuterated SCNP system contrasted by a deuterated solvent, allowing for a
detailed study of the SCNP morphology.89,90
Colmenero et al. investigated conformational properties of SCNPs in crowded macromolecular solutions
by SANS and MD simulations.90 Crowding was induced by two means, namely, by adding either linear
polymer chains or SCNPs. SCNPs were found to collapse when the total concentration of a diluted SCNPs
67
solution reaches the value of the overlapping concentration of the pure SCNP solution (23 mg/mL),
irrespective of the length of the crowders. Moreover, the analysis of the scaling behavior of the different
simulation observables confirmed the trends suggested by the experimental form factors, and suggested
that crumpled globular conformations were adopted by SCNPs in crowded macromolecules solutions.
Both experimentally obtained conclusions were in agreement with MD simulation outcomes, despite
complications airsed from the presences of aggregates.
1.1.4 Applications
Due to their size ranging from 5 to 30 nm, the field of SCNPs is part of nanotechnologies, at the interface
between polymer and material science, biology, physics and chemistry.91 The folding of linear polymeric
precursors into SCNPs is reminiscent of the folding of proteins in nature. Inspired by this phenomenon,
the long-term goal of applications using SCNPs is to construct small soft nano-objects endowed with
useful, autonomous and specific functions.92 Their preparation is expected to affect their subsequent
activity and selectivity in important applications, including sensing, drug-delivery or catalysis (Fig.1.13).
Although promising, SCNPs applicability and viability requires overcoming the synthetic bottleneck of
scaling up the synthetic procedures (usually involving highly dilute solutions), for high value-added
applications.93
68
Figure 1.13 Potential applications of SCNPs.
1.1.4.1 Nanomedicine
A promising field where SCNPs could be of practical use is the design and engineering of nano-systems
to address disease and human health, for instance, for diagnosis, monitoring of pathological processes,
biological systems and therapy.94
1.1.4.1 Drug delivery and imaging
Drug delivery is a widespread discipline searching for the optimisation of efficient drug carriers. In this
light, several examples have sought to use SCNPs based on a number of macromolecular structures, as
controlled drug delivery nanocarriers.94 Specifically, SCNPs have been used as nanocarriers for small-
molecule drugs, e.g. vitamins, sacharides, peptides or chiral-amino acids.91
Paulusse et al. recently reported an innovative study where they intented to replicate naturally occurring
glycoconjugates for both efficient targeting and increased cellular uptake of glycoconjugated polymers.95
In this work, linear and cyclic glucose moieties were tuned with methacrylates via enzymatic synthesis
69
and further used as building blocks to cross-linked single chain glycopolymer nanoparticles (glyco-
SCNPs). C1- and C6-glucose-derived monomers were incorporated in different SCNP structures that were
further studied for HeLa cells uptake. SCNPs with glucose moieties conjugated through the C1 and the
C6 position in their pyranose and in their partly linear form were compared in terms of the HeLa cellular
uptake efficiency by confocal microscopy. The effect of a reducing glucose was less determining in
comparison to the position of the conjugations for an efficient cellular uptake.
Two other synthetic routes to SCNPs were reported by the same group, in both organic and aqueous
environments (Fig. 1.14 A).96 Importantly, the antibiotic rifampicin (Rif) was encapsulated in an organic
medium, and the loaded nanocarriers were rendered water soluble and proceeded to the controlled release
of rifampicin, which was tracked by UV-vis spectroscopy. As depicted in Fig. 1.14 B, a burst release of
Rif was observed in the first 2 h (ca. 40%) and more than 60% after 24 h of the original Rif content.
70
A
Figure 1.14 (A) Dual-pathway synthetic of SCNPs via Thiol-Michael addition following the organic route (yellow)
and aqueous route (blue). (B) Release of Rif from SCNPs by measuring UV-vis absorption at 334 nm.96
SCNPs have also been used to increase detection of internal structures within the body using a number of
techniques, which can be summarised as follows. Soft-nanodevices have been evaluated as fluorescent
probes for confocal laser scanning microscopy (CLSM),97–99 gamma-emitters for single photon emission
computerised tomography (SPECT)100 or the more commonly used image contrast agents for magnetic
resonance imaging (MRI).42,101
71
In an investigation by Odriozola et al. a two-step Gd(III) loading procedure based on CuAAC chemistry
was presented (Fig. 1.15 A).42 The cross-linked SCNPs possessed Gd(III) ion that is paramagnetic and
showing a high relaxivity. However, as these species are not water soluble, they require to be entailed in
a hydrophilic macromolecular structure. When the Gd-SCNPs were compared to the commercially used
Magnevist® (Fig. 1.15 B), the r1 value of 6.78 mM-1 s-1 obtained for the Gd-SCNPs represented already
more than a 4-fold increase over its monometallic counterpart on a per Gd basis, and a 2-fold excess over
Magnevist®. In addition, the molecular relaxivity for Gd-SCNPs was 122 mM-1s-1, representing a 38-fold
increase over the molecular relaxivity of Magnevist.
IMAGING (gadolinium)
Figure 1.15 (A) Formation of SCNPs and loading with Gd(III) following a two-step route for their
incorporation using CuAAC-based chemistry. (B) Relaxivity values for Gd-SCNPs compared to
commercially available reference Magnevist®.
72
1.1.4.2 Nanoreactors for catalysis
SCNPs also represent versatile platforms as catalytically active nano-objects based on enzyme mimicry.
The particular features that SCNPs show compared to other catalytic structures include: large surface-to-
volume ratio, the formation of sparse or globular conformations containing localised pockets, size and
solublity tunability based on solvent change and the dynamic bonding behaviour of SCNPs.36,92 Moreover,
these nanoreactors could show enhanced catalytic efficiency, due to confinement effects, by increasing
the conversion rates or selectivity, or simply affording a polymeric and hence recyclable support.102–105
Catalysis mediated by SCNPs as nanoreactors has been classified by the type of enzyme mimicks, i.e.
reductase, oxidase, aldolase, polymerase or metalloenzyme,37 by the type of process catalyzed, i.e. organic
molecular, macromolecular, nanomaterials92 or by referring to metallo-enzyme mimicry.36 One can also
discriminate different types of catalysts, i.e. whether they are organic, organometallic or biological in
nature.
1.1.4.2.1 Organocatalysts
Organocatalysis refers to an organic (macro)molecule that does not contain a metal in which
substoichometric amounts accelerates a reaction. However, there are a number of challenges associated
with supporting organocatalysts in SCNPs, such as their accessibility within the confined domains, but
also the solubility of the catalyst in an aqueous environment. Hydrophilic polymeric stabilisers, e.g.
polyethyleneglycol (PEG), are generally incorporated within the SCNP structure to impart a water
solubility.106 It has to be acknowledged that SCNPs, as nanoreactors, are also widely used in organic
solvent media. In fact, several studies have used either aqueous, organic or a mixture of both environments
for organocatalysis mediated by SCNPs, as summarised in Table 1.5.
73
Entry Reaction type Catalytic Solvent t (h) T(°C) C(%) Reference
center
107
1 Carbonate Diphenyl H2O/MeCN 10 - -
hydrolysis phosphate
52
2 Aldol reaction L-proline H2O 24 r.t. 99
20,83
3 Benzoin NHC THF 24 80 90
condensation
4 Polymerisation of Michler’s THF 2 r.t. 15 70
(meth)acrylates ketone
5 Reduction of α- B(C6F5)3 CH2Cl2 0.1 r.t. 96 109
diketones
109
6 Polymerisation of B(C6F5)3 CH2Cl2 0.1 r.t. 99
THF
Table 1.5 Summary of reactions catalysed by SCNPs as organocatalysts.
The first attempet to mimic catalytic active sites of enzymes using SCNPs was carried out by Wull et
al.107 Catalytic sites were incorporated following an “imprinted particle” approach, i.e. catalytic entities
were imprinted during the synthesis of SCNPs via a diphenyl phosphate template and subsequently
removed from particles. These SCNPs were subsequently used as nanoreactors for carbonate hydrolysis
presenting Michaelis-Menten kinetics (Table 1.5; Entry 1). The “imprinted particle” route was further
74
adopted by Nikang et al. to prove the enhanced enantioselectivity and binding capacity against chiral
amino acid derivatives of imprinted SCNPs, when compared to analogous micelles.110
Chirality was harnessed by Meijer et al. who developed an approach producing water-soluble
organocatalytic SCNPs containing L-proline catalytic centers in the hydrophobic internal pocket (Fig.
1.16) (Table 1.5; Entry 2).60
Figure 1.16 Chemical structure of L-proline functionalised catalytic polymer and schematic representation of the
unfolded polymer and the formation of the compartimentalised catalytic structure in water.
These organocatalytic SCNPs served as self-supported catalysts for the aldol reaction of cyclohexanone
and p-nitrobenzaldehyde in water, allowing to achieve almost quantitative conversions (99%) and fast
rates (TOF of 8 h-1), with an enantiomeric exces of 94% and an ee% (enantiomeric excess) of 70%.
Conversely, when L-proline decorated BTA moieties were incorporated to a BTA-based SCNPs via
molecular recognition, a higher stereoselectity was observed.111 Further research from the same group
revealed that structural and surface hydration features were relatively similar to those found in natural
75
enzymes, and revealed that retarded surface water diffusivity had a critical impact in SCNPs catalytic
activity.
A similar approach was followed by Taton el al. for the development of catalytically active SCNPs
possessing “hydrophobic cavities” based on NHCs.20 For this purpose, a statistical copolymer based on
styrene, PEG-pendant styrene and antagonist benzimidazole- and chlorobenzyl-based units was
synthesised as SCNP precursor. The intramolecular cross-linking was achieved by quaternization and
followed by an anion exchange to afford thermally latent behavior to the entailed “masked-NHC” units.
In this manner, active compartimentalised NHCs within SCNPs were generated upon heating (80 °C) in
THF thanks to the ability of acetate anions to interact with protons in C2-position of benzimidazolium
rings. Catallytically active NHC-based SCNPs (10 mol%) were tested for the benzoin condensation
obtaining 65% after 24 h (Table 1.5; Entry 3).
SCNPs have been used as bioinspired nanoreactors for the synthesis of several polymers. Temel et al.
used the SCNPs described in Section 1.2.1.1.5, which contained Michler’s ketones as cross-linkers that
could act as a photoinitiators for MMA polymerisation (Table 1.5; Entry 4).70 Despite the lack of control
in the free radical triggered polymerisations (Ð = 3.1), PMMA with molecular weights up to 38 kDa were
obtained.
To this regard, in a pionnering work by Perez-Baena et al., SCNPs were endowed with enzyme-mimetic
activity following a concurrent binding/folding technique (Fig. 1.17). Namely, a selection of appropriate
polymer precursors allowed concurrent catalyst-assisted intramolecular cross-linking and binding of the
catalyst to intramolecular SCNP sites. Enzyme-mimetic SCNPs were for instance generated from
glycidyl-type polymers via B(C6F5)3-assisted intramolecular ring-opening polymerization, and B(C6F5)3
binding to oxygen-containing functional groups (carbonyl, ether) of the SCNPs through B-O interactions.
The catalytic activity resulted from the immobilization of the catalyst used to promote the folding/collapse
76
in compartimentalized internal nanoparticle sites that were accessible to reagents. Parameters such as size,
composition, number and placement of catalytic sites, were found to have an important impact on the
reaction kinetics. Namely, these SCNPs organocatalysed the ring-opening polymerization of THF thanks
to the presence of small amounts of glycidyl phenyl ether (GPE) (Table 1.5; Entry 4). Relatively high
molecular weight (55 to 150 kDa) and relatively high dispersities (Ð = 2.2 to 3.2) poly(THF-co-GPE)
with low content of GPE (ca. 3%) were thus achieved.
Figure 1.17 Schematic illustration of the use of SCNPs as bionspired nanoreactors for the synthesis of polymers
through ring-opening polymerisation.109
1.2.3.1.1 Organometallic catalysts
It is estimated that one-third of known enzymes are metalloproteins,112 where the presence of metal ions
in their structure allows metalloenzymes to perform complex functions (e.g. redox reactions) in
challenging environments.37 Synthetically reproducing these types of naturally occurring systems has
been intensively investigated in SCNP technology; this is summarized in Table 6.
Entry Reaction type Catalytic center Solvent t (h) T(°C) C(%) Reference
77
52
1 Hydrogenation Ru(II) H2O 50 40 98
of ketones (PPh3)3Cl2
106
2 Oxidation of Ru(II) H2O 0.07 r.t. 99
secondary (PPh3)3Cl2
alcohols
113
3 CuAAC Cu(I)-Bimpy PBS 0.2 r.t. 99
113
4 Mono- Pd(II)-Bimpy PBS 5 r.t. 99
depropargylation
113
5 Bis- Pd(II)-Bimpy PBS 25 r.t. 99
depropargylation
116
6 CuAAC Cu(II)-aspartate H2O 24 50 99
114
7 Alkyne Cu(OAc)2 Bulk 8 60 98
dimerisation
117
8 Hydrogenation RuCl2(PPh3)3 H2O 1 60 28
of phenol
40
9 Sulfides Ti(salen) H2O 1 r.t. 99
oxidation
78
47
10 Reduction of [IrCl(COE)2]2 THF 16 r.t. 99
secondary
amines
47
11 Biphenyl [RhCl(COE)2]2 THF 16 80 99
formation
38
12 Suzuki coupling Pd-NHC2 H2O 5 r.t. 99
115
13 Sonogashira Pd(II)- HN(C2H5)2 24 r.t. 99
coupling triarylphosphine
45
14 Amination of Pt(II)- C6D6 24 100 99
allyl alcohol triarylphosphine
43
15 Photoreduction Ni-thiolate DMF, 1 80 99
of CO2 to CO Acetonitrile
41
16 Polymerisation Fe(II)- Toluene 92 60 90
of urea/aniline
(meth)acrylates
118
17 Polymerisation Fe(OAc)2 H2O 5 r.t. -
of PEDOT
Table 1.6 Summary of reactions catalysed by SCNPs as organometallic catalyst.
79
Palmans, Meijer et al. also followed in this domain the aforementioned “hydrophobic cavity” strategy
with several examples.46,52 Firstly, catalytically active SCNPs were prepared through self-folding of an
amphiphilic random copolymer and post-loading of Ru(II) catalyst via ligand exchange with complex.52
The resulting Ru-based SCNPs were evaluated as catalysts for the transfer hydrogenation of ketones using
sodium formate as the hydrogen source, achieving almost quantitative conversion after 2 minutes with a
TOF of 20 h-1 (Table 1.6; Entry 1). Interestingly, the same system was found to be active in the oxidation
of secondary alcohols with t-BuOOH as oxidant, showing quantitative conversions too with TOF values
close to 600 h-1(Table 1.6; Entry 2),106 probably due to a “confinement effect”/”concentrator effect” in
the SCNPs core. This was evidenced as higher selectivity toward more hydrophobic secondary alcohol
was observed, due to the more hydrophobic interior of SCNPs. This was further supported by
implementing the reverse reaction of transfer hydrogenation with the same hydrophobic selectivity. BTA
functional groups that were introduced to produce helical stacked self-assemblies did enable further
improvement in the catalytic performance of these SCNPs (Scheme 1.10).46
Scheme 1.10 Design of catalytically active SCNPs for transfer hydrogenation of ketones in water in a BTA-
supramolecular interactions based nanoreactors.
80
Similar BTA-based amphiphilic SCNPs were applied for catalysis purpose, this time in phosphate buffer
at physiological pH, at low substrate concentrations, and at room temperature.113 These SCNPs featured
different ligands including Bimpy, phenanthroline (Phen), BiPy capable of coordinating to Cu(I) and
Pd(II) metallic centers (Table 1.6; Entry 3-5). The resulting metal-based SCNPs proved to catalyse azide-
alkyne cycloaddition and depropargylation reactions obtaining excellent catalytic performances.
Similarly, Oldfield et al. used Cu(I)-containing organometallic SCNPs for azide-alkyne catalysed
cycloaddition reactions (Table 1.6; Entry 6). The main difference with the previous example comes from
the presence of aspartate-containing polyolefins. Remarkably, these SCNPs showed an excellent catalytic
performance (TOF 16,667 h-1), not only in water, but also in bacteria and mammalian cells
environments.116
Cu(I) was also the metal ion employed by Pomposo et al. for oxidative coupling of mixtures of chemically
related terminal alkyne substrates (Table 1.6; Entry 7).28 Interestingly, this type of reactions could be
achieved by these SCNPs, but not by more classical catalysts like CuCl2, Cu(OAc)2 or Cu(acac)2. This
specificity was attributed to the unique compartimentalised local catalytic sites embedded in methacrylate
units, permitting an optimum transition state stablisation for the preferred substrate. The importance of
tuning the spatial arrangement of catalytic specific sites in metal-containing SCNPs was investigated
using molecular dynamics.89
He et al. recently reported the synthesis of Cu-bearing SCNPs mimicking metalloenzymes for the
hydroxylation of phenols (Table 1.6; Entry 8).117 From a PMMA precursor containing imidazole groups,
SCNP folding was triggered by Cu-imidazole binding following the already mentioned “concurrent
binding/folding technique”. These Cu-SCNPs exhibited high selectivities (ca. 80%) and quantitative
conversions with a TOF of 872 h-1 converting, phenol to cathecol in water using H2O2 as oxidant.
Increasing the Cu content did not enhance the catalytic efficiency, which was explained by the difference
81
in flexibility and adaptability of the folded SCNPs containing less Cu-units, hence less cross-linking
points.
Despite not using Cu-centers for their catalysis, Yin et al. developed titanium-based SCNPs for
waterborne catalysis, exploiting the so-called “hydrophobic cavity” in selective sulfides oxidation
reactions (Table 1.6; Entry 9).40 For this purpose, Ti(salen) moieties were supported in a
thermoresponsive N-isopropyl acrylamide (NIPAm) polymeric platform. It was found that the use of
SCNPs enhanced the performance for methyl aryl and alkyl phenyl sulfides (conversions of 85 - 99% and
ee of 95%), compared to standard chiral Ti(salen) complex (48% conversion and 65% ee). This was
attributed to the site “isolation effect” provided by the shielding of the catalytic sites and the “confiment
effect” that effectively concentrated the substrates within the hydrophobic catalytic core, enhancing both
the reaction selectivity and rate. More interestingly, the intrinsic thermoresponsive behavior of the
NIPAm-based architecture was harnessed by inducing SCNP recovery upon heating, for recycling into
further catalytic runs.
Another rather interesting approach in order to concomit both positive effects of metal catalytic centers
and architectural polymer nature was conducted by Lemcoff et al. (Table 1.6; Entry 10).47 in which the
used polycyclocta-1,5-diene polymer backbone served as actual polyligand. In order to demonstrate the
versatility of this polymer platform, different metals were used, namely, Rh(I), Ir (I) and Ni(0) and further
studied for distinct catalytic reactions. In the case of Ir(I)-based SCNPs reduction of secondary amines
and allylation of benzophenone matched the performance of small-molecule models (Scheme 1.12 A)
(Table 1.6; Entry 10). Cross-coupling reactions between 4-nitrobenzaldehyde and phenyl boronic acid
were catalysed by Rh(I)-based SCNPs, unexpectedly showing the first example of selective homo-
coupling to cross-coupling which was further optimised by the inclusion of NHC ligands (Scheme 1.11
B) (Table 1.6; Entry 11).
82
A B
Scheme 1.11 (A) Reduction of benzyl benzamide using Ir-SCNPs and (B) biphenyl production catalysed by Rh-
SCNPs.47
Taking into account the novelties disclosed by the previous example, Taton et al. developed a water-
soluble styrenic precursor bearing NHC-type ligands which could induce SCNPs folding by simple
exposure to Pd(II) (Table 1.6; Entry 12).38 Their catalytic potential as nanoreactors was confirmed
through the Suzuki coupling reaction, revealing markedly improved catalytic efficacy compared to
Pd(OAc)2, which was attributed to a favorable microenvironment within SCNPs’ pocket.
Pd(II)-based SCNPs were also developed by Kowollik et al. using triarylphosphine ligands supported in
a styrenic polymer backbone (Table 1.6; Entry 13).115 Distinctly to the latter example, their ability to
trigger catalysed reactions was tested in Sonogashira couplings. However, the performance could not
reach the one attained by molecular Pd(PPh3)2Cl2. The same group used the same triarylphosphine ligand-
based precursors to incorporate Pt(II) catalytic entities (Table 1.6; Entry 14).45 The Pt(II) incorporated
as Pt(1,5-cyclooctadiene)Cl2 to be folded into SCNPs. The resulting organometallic nanoreactors were
found to be active in amination of allyl alcohol reactions under homogeneous conditions, obtaining
quantitative conversions after only 16 h with only 0.2 mol% catalyst, which could be further recycled
with no apparent loss of activity (Scheme 1.12).
83
Scheme 1.12 Illustration of a SCNP folding into a Pt-containing nanoreactor employed for the amination of allyl
alcohol which can be further recycled.45
In a more specific enzyme-mimicry attempt, He et al. developed Ni(II)-containing SCNPs via Ni-thiolate
coordination for the photoreduction of CO2 to CO (Table 1.6; Entry 15).43 The reported conditions
included TiO2 as light absorber support and triethanolamine as electron donor agent. Reactions were
conducted at 80 °C leading to TOF values of ca. 2500 h-1 both in DMF and acetonitrile.
As proof of concept, Sawamoto et al. developed a polymerase-like iron-containing SCNPs (Table 1.6;
Entry 16).41 After their synthesis was conducted as described in Section 1.2.1.1.2., living radical
polymerization of various alkyl methacrylate monomers was efficiently catalysed by these nanoreactors.
Well-controlled PMMA’s of relatively narrow molecular weight distribution (Ð = 1.1, high conversions
90%) were obtained in toluene. The catalyst recovery and further recycling was achievable thanks to a
simple washing with an organic solvent of the aqueous reaction medium.

84
More recently, Pomposo et al. used Fe-SCNPs as enzyme-mimic nanoreactors for the synthesis of
polymers (Table 1.6; Entry 17).118 These SCNPs differ from the Sawamoto’s ones described above in
the fact that supported Fe(OAc)2 served as catalytic center to trigger the dispersion polymerization of
poly(3,4-ethylendioxythiophene) : polystyrenesulfonate (PEDOT:PSS) in water conditions. Interestingly,
the obtained dispersion was casted to form films exhibiting conductivity values (σ = 1 x 10-4 S/cm) similar
to those typically obtained with iron-containing proteins.
1.1.4.1.3 Enzymatic catalytic mimics
In nature, different ordered or disordered proteins can be found with functions relating to the binding and
transport of various substances. Interestingly, the form factor of sparse SCNPs was found to be very
similar to that displayed by intrinsically disordered proteins (IDPs).37 The main advantage of this particle
morphology is their capacity to bind several centers, such as ions, small organic molecules, other proteins
and nucleic acids (RNA, DNA). The capacity of SCNPs as enzyme binders has not been widely explored.
119
However, a few studies have started to appear, where either the isolated active site or the protein
(antigen)120 is loaded within the SCNP structure.
A promising example of this was reported by Loinaz et al. The advantageous use of water-dispersible and
biocompatible SCNPs based on dextran as naturally occurring polysaccharidic support was reported as a
Tn-antigen mimetic (Scheme 1.13). 128 The obtained hybrid-SCNPs triggered a series of innate immune
responses human peripheral bloodmononuclear cells (PBMC) like those elicited by naturally ocurring Tn
clusters. This could represent an alternative to immune proteins as well as a unique tool to interrogate the
role and reactions of Tn-like antigens in cell medium.
85
Scheme 1.13 Preparation of dextran-based SCNPs and subsequent incorporation of the Tn-Antigen.120
Use of SCNPs as enzyme binders for enzymatic catalysis is still in its infancy and there is still a lot of
room for improvement, for instance to address issues such as enzyme compatibility or adaptability in a
polymer hybrid structure.
1.1.4.3 Other uses
SCNPs have become a valuable artificial soft nano-objects, which can be efficiently endowed with useful
properties in wide array of applications, such as rheology-improving agents for melts of thermoplastics,121
nanocomposites,122–124 elastomeric polymers,29,125,126 paints,127,128 compartimentalised sensors of metal
ions,53 templates for photoluminiscent carbon nanodots(C-NDs)128 or hydrogels.32,125
86
A diversity of nanomaterials have been synthesised involving the utilization of SCNPs, not only in
catalysis, but for many other applications. In a pionnering work by Qian et al. SCNPs obtained by
Bergman cyclization intramolecular folding were employed to encapsulate quantum dots (QDs) in a one-
pot reaction.97 As a proof of concept, photoluminescent (PL) zinc sulfide (ZnS) quantum dots (QD) were
fabricated and encapsulated in SCNPs of different sizes. The smallest nanoreactors produced a single QD
of 4 nm in diameter and giving a quantum yield (QY) of 17% at 310 nm excitation wavelength, while
bigger nanoreactors trapping multiple QDs presented QY of only 2%. The versatily of SCNPs as QDs
platform, cadmium sulfide (CdS) QDs of 4.7 nm were obtained with QY = 45%.
The same group also developed bright photoluminescent C-NDs with low toxicity as suitable candidates
for in vivo imaging. SCNPs were obtained following the same Bergman cyclization chemistry, but water
solubility was improved by inserting PEG chains.128 In this manner, the optimal emission wavelength of
the C-NDs was found to red-shifted upon decreasing the size of the studied C-NDs probably, due to the
amorphous core architecture (Fig. 1.18), as further evidenced by computational calculations.130
Interestingly, the surface chemistry of the C-NDs was found to affect the QY through aggregate-induced
energy/charge transfer processes, leading to lower QYs.
87
Figure 1.18 Size and size-dependent photoluminescence spectra of CNDs. TEM image and size histogram
of big CND (A) and small ones (B). Photoluminiscent spectra of surface oxidised at 340 nm of small
CND (green line C) and big CND (blue line C) and spectra of reduced surface (green line D and blue line
C, respectively).128
Palmans et al. reported the synthesis of BiPy-BTA pendant polymers by ROMP chemistry.53
Corresponding SCNPs were intramolecularly self-assembled by supramolecular interactions between
BiPy-BTA motifs. Addition of copper to solutions led to binding of the added Cu(II) BiPy units (Scheme
1.14). This binding was probed by fluorescene and UV-vis spectroscopy. Outcome from this study
constrasted with other reported examples utilising other polymers by showing enhanced fluorescence,
presumably due to the abscene of interpolymer interactions amd compartmentalization of the sensor units.
88
Scheme 1.14 Schematic representation of the sensing function of the BiPy-BTA functional polymers.53
1.5 Conclusions and aims of this PhD thesis
Although far from reaching the structural complexity of proteins, SCNP have yet allowed the creation of
functional macromolecular compounds featuring globular, stimuliresponsive structures and, in some
cases, with some compartmentalized functions, such as site isolated catalysts, like in enzymes. Interest in
SCNPs is thus growing due to the different folding strategies available for generating organic-, metallic-
89
or enzyme-polymer hybrid structures.
The success of these structures requires first for the accurate characterisation, to provide the whole picture
of the system to better understanding their ultimate performance in their respective applications.
Associated to the SCNPs synthetic challenges, their characterisation is also a tricky, which in most of the
cases requires the combination of different analytical techniques for better depicting their structure,
morphology or stability. Moreover, the difficulties come often from the need of sensitive characterisation
techniques to detect, even at small concentrations, the presence of the targeted single molecule structure
and discard intermolecularly cross-linked aggregates that may occur during synthesis.
SCNPs technology is advantageous in several areas (e.g. catalysis, sensors or nanomedicine) due in large
part to the small size of the nanoparticles and the ease in which they can specifically tailored. While the
research involving SCNPs has been primarily inspired by nature (i.e. enzymes), other new applications
related to their intrinsic performance have been found (e.g. nanocomposite materials) due to their unique
properties and large variety of opportunities to incorporate selective functions, afford functional chemical
compartimentalised environments or easily modulate their solubility.
In relation to the state-of-the art described in this chapter, the four following chapters presenting the work
of this PhD thesis will deal with the synthesis and the manipulation of new polymer-based structures for
specific catalysis. More specifically, random copolymers based on poly(ionic liquids) will be developed
under different architectures such as single chain nanoparticles (SCNPs) or as (macro)gels. Those
different systems will be employed as N-heterocyclic carbenes (NHCs) precursors to be used as
organocatalysts. The incorporation of relatively basic counteranions in PIL units derived from
imidazolium moieties allows the in situ generation of active NHC species for catalysis. Firstly, a reactive
PIL based (macro)gel will represent the preliminary study to better understand and analyse the catalytic
performance in the macroscale. This study will then permit the identification of suitable model reactions
90
as well as conditions and standards, becoming a reference system all along this thesis. Moreover, this
(macro)gel will also serve as a base for the further development of more sophisticated nanogels known as
single chain nanoparticles (aka SCNPs). These SCNPs will specially be designed based on their PIL
tunability and synthesised by reversible additions fragmentation chain transfer (RAFT) polymerisation.
In first place, the ionic nature of the NHC precatalyst will be exploited by triggering the interaction
between imidazolium derivatives and basic anions supported in the polymer leading to a ionically cross-
linked SCNP. Secondly, the thermolatent properties of NHC precursors will be harnessed by proving the
compatibility of both substrates and precatalyst supported on the same polymer chain and triggering the
folding by condensing the substrates by the simple application of heat. Finally, the intrinsic capacity of
poly(NHC)s to act as poly-ligands will innovatively be demonstrated by forming SCNPs after
organometallic complexation using a silver salt.
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97
Chapter II: Facile Synthesis of Reversibly Crosslinked
Poly(ionic liquid)-type Gels: Recyclable Supports for
Organocatalysis by N-Heterocyclic Carbenes
98
99
Table of Contents
Chapter II: Facile Synthesis of Reversibly Crosslinked Poly(ionic liquid)-type Gels: Recyclable
Supports for Organocatalysis by N-Heterocyclic Carbenes
2.1. Abstract………………………………………………………………….…………101-102
2.2. Introduction………………………………………………………………………..102-104
2.3. Synthesis, characterisation…………………………………………………………105-110
2.4. Manipulation of gel-supported pre-catalyst…………………………..……………110-113
2.5. Organocatalysis from gel-supported NHCs…………………………..……………113-116
2.6. Conclusions……………………………………………………………..…………116-117
2.7. References…………………………………………………………………………117-119
2.8 Experimental section…………………………………………………..…………..120-135
100
2.1 Abstract
Owing to their broad modularity, polymeric versions of ionic liquids, referred to as poly(ionic liquids)
(PILs), have attracted increasing attention as recyclable polymer-supported (pre)catalysts for various
chemical transformations. Herein, an imidazolium-based statistical copolymer based on PIL (= coPIL) is
specifically designed by free-radical copolymerization of styrene and 4-
vinylbenzylethyl(benz)imidazolium chloride. A selective ion-exchange reaction can be subsequently
achieved to incorporate bio-sourced difunctional sebacate-type counter-anions, causing the physical
crosslinking of the coPIL precursor via electrostatic interactions between pendant imidazolium moieties
and sebacate dianions. The as-obtained gel-type precursor exhibits a thermally latent behavior in THF,
proving advantageous for a facile manipulation and practical use for organocatalysis. Upon heating,
typically at 80 ºC, interaction between the sebacate dianion and the proton in C2-position of the
imidazolium moieties generates polymer-supported N-heterocyclic carbene units that act as catalytic
active species towards NHC-organocatalyzed reactions, namely, benzoin condensation, transesterification
and cyanosilylation. The PIL-based gel precursors can be restored, recycled and reused by simply cooling
down, i.e. with no need of an external chemical reagent, due to the shift of the intramolecular equilibrium
towards the formation of imidazolium sebacate-type units. Overall, this novel gel-type copolymeric
platform shows a thermo-responsive behaviour, and proves particularly versatile for heterogeneous
organocatalysis.
101
2.2 Introduction
Polymeric versions of molecular ionic liquids (ILs), namely, poly(ionic liquid)s or polymerized ionic
liquids, abbreviated as PILs, have attracted a great deal of attention as a new class of polyelectrolytes in
the past two decades.1–5 In PILs, cationically or anionically charged monomer units are covalently tethered
to the polymer backbone, while counter-ions generally show high mobility. Typical organic cations of
PILs include imidazolium, pyridinium and phosphonium groups, which can be associated to anions, such
as Cl-, Br-, BF4-, CH3SO3-, (CF3SO2)2N-, CH3CO2-, etc.6,7 A very broad range of PILs with a large number
of functionalities have been designed, either following a chain-growth or a step-growth polymerization
pathway, sometimes involving a post-chemical modification step of a polymer precursor.3 Subsequent
exchange of the counter-ion, referred to as ion metathesis, provides another means to tune PIL properties.1
PILs thus combine essential features of ILs, including a high CO2 solubility and a high ionic conductivity,
with inherent qualities of polymers. These combined properties make PILs highly attractive in various
102
applications, for instance, in analytical chemistry,8 gas separation,9 precursors of porous structures and
nanostructured carbon-based materials,10 as solid ionic conductors for energy storage,11 and for catalysis
as well,3,12 which is the topic of the present contribution.
In the latter case, PILs eventually play two distinct roles. On the one hand, they can serve as efficient
13
polymeric stabilizers of metal nanoparticles (NP), forming PILs@NP nanohybrids in which the
presence of PIL chains allows minimization of metal coalescence, providing efficient electrostatic + steric
(= electrosteric) stabilization.14 On the other hand, PILs can also operate as versatile polymeric supports
of various types of catalysts.15,16 For the general purpose of organocatalysis, PILs featuring sulfonic acid
or proline moieties can for instance be employed as polymer-supported Brønsted acids and Lewis bases,
respectively.3 Furthermore, imidazolium-based PILs are handy precursors of polymer-supported N-
heterocyclic carbenes (= polyNHCs).17–22 Such polyNHCs can either be employed for reference
organocatalyzed reactions of molecular chemistry, or serve as polymer-supported ligands for transition
metals, i.e. forming polyNHC-metal derivatives,19 by analogy with molecular NHC counterparts.23 The
latter polymer-supported metallic complexes have been advantageously employed to catalyze various
organometallic reactions. In many of these catalysis applications, “task specific PILs” have been found to
greatly facilitate separation, recovery and reuse, i.e. recycling of the polymer-supported (pre)catalysts –
most often by simple filtration– and/or to improve stabilization of PILs@NP nanohybrids.13,24
In this context, imidazolium-based PILs featuring anions such as hydrogen carbonate, HCO3-, 20 or acetate,
CH3COO-,21,22 have been shown to serve as efficient air-stable progenitors of polyNHCs. This relates to
the weakly basic character of both counter-anions interacting with the proton in C2-position of pendant
imidazolium rings. Specifically, the imidazolium acetate-containing PILs exhibit a thermally latent
behavior when employed in organocatalyzed reactions, and their catalytic activity can be turned on and
off by a simple temperature increase and decrease.21,25 Furthermore, such precursors can be readily
recycled and reused, with no need of an exogenous chemical reagent, owing to the aforementioned
103
intramolecular and temperature-dependent interaction between the acetate and the imidazolium moiety.21
This convenient way of masking and manipulating polymer-supported NHCs can be further exploited, as
discussed in the present contribution. By incorporating a commercially available and bio-sourced
dicarboxylic acid, namely, sebacic acid, imidazolium-based physically crosslinked PIL gels can be
achieved, and be readily manipulated and recycled for various NHC-organocatalyzed reactions. Here we
describe for the first time the design of gel-supported NHC precursors from imidazolium-based PILs that
are physically crosslinked, i.e. the crosslinking process is reversible, through the formation of a bis-
carboxylate-type reagent. In addition, such gel-supported NHC precursors exhibit a thermally latent
behavior when used in selected organocatalyzed reactions, namely, benzoin condensation,
transesterification and cyanosilylation, which enables the manipulation of the catalytic activity by a
simple temperature change. Overall, this novel polymeric platform is proven to be particularly flexible
for heterogeneous organocatalysis.
104
2.3 Synthesis, characterisation
A statistical copoly(ionic liquid) (coPIL), namely, polystyrene-co-poly(4-vinylbenzylethyl-
(benz)imidazolium chloride), denoted as PS-co-Poly[ViEBIm]Cl (3), was prepared by free-radical
copolymerization of 4-vinylbenzylethylbenzimidazolium chloride (2) and styrene, using AIBN as a
radical source (Scheme 2.1). Benzimidazolium- rather than imidazolium-type units as reported in
previous works 22 were introduced here, owing to their slightly higher proton-acidity in the C2 position. It
was thus expected that the equilibrium could be better shifted towards the formation of the NHC active
species. After 12 h of reaction achieving 50% monomer conversion, the resulting copolymer was
chemically modified into the coPIL 4 possessing non-coordinating anions, namely,
bis(trifluoromethane)sulfonylimide (TFSI) = (CF3SO2)2N-, prior to characterisation by size exclusion
chromatography (SEC) in THF containing 10 mM LiTFSI. This was readily achieved by anion exchange,
as previously reported.26 The as-obtained TFSI-containing coPIL 4 exhibited a unimodal distribution of
molar masses with a dispersity (ĐM) of 1.35. Copolymer 3 then served as precursor for the synthesis of a
physically crosslinked gel via anion metathesis converting 3 into PS-co-Poly[ViEBIm]Seb (5). The
commercially available Amberlite® IRA-400 hydroxy resin was employed for this purpose, providing an
entirely metal-free synthetic route to the imidazolium-based physically crosslinked gel (Scheme 2.1).30
The anion exchange reaction indeed allowed substituting OH- counter-anions for Cl- ones and further
introduction of sebacic acid yielded copolymer 5 and water as side product.31
105
Scheme 2.2. Synthetic route to (PS-co-Poly[ViEBIm]Cl) (3) by free radical copolymerizacion of [ViEBIm]Cl and
styrene in methanol, followed by the synthesis of physically crosslinked (PS-co-Poly[ViEBIm]Seb) (5) by anion
exchange. Synthesis of (PS-co-Poly[ViEBIm]TFSI)-1 (4) is also displayed.
In addition to being a non-fossil bio-based resource, sebacic acid contains two carboxylic acidic groups
with a similar pKa ~4.6 to that of acetic acid, i.e. the conjugated acid of acetate counter-anion that has
been found to efficiently generate polymer-supported NHCs from imidazolium acetate-containing
PILs.[20-21] Interestingly, copolymer 5 could be solubilized in DMSO, facilitating its structural
characterization by NMR spectroscopy, whereas it was not soluble at all in solvents such as THF or
acetonitrile. Near quantitative anion exchange reaction (~95%) was achieved as determined by 1H NMR
spectroscopic analysis (Figs. 2.1 & S2.1, S2.2). Importantly, the characteristic proton of the C2-position
of benzimidazolium units appearing at δ = 10.5 ppm in 3 was shifted downfield to δ = 11.5 ppm, as a
consequence of the insertion of bis-carboxylate anions, while the signal at δ ~12 ppm that resulted from
the resonance of the carboxylic acidic protons of sebacic acid disappeared. This attested to the formation
106
of hydrogen bond-type interactions between C2-protons of the imidazolium moieties and the carboxylate
anions.
Figure 2.1. 1H NMR (DMSO-d6) showing the insertion of the sebacate forming the physical gel (PS-co-
Poly[ViEBIm]Seb) (5) from (PS-co-Poly[ViEBIm]Cl) (3).
Characterization of the two copolymers by 13C NMR spectroscopy (Fig. 2.2, 2.3) confirmed the selective
incorporation of sebacate anions, as evidenced by the presence of sebacate carboxylate single signal at δ
~168 ppm.
107
Figure 2.2. Synthesis of ((PS-co-Poly[ViEBIm]Cl)(3). 13C NMR spectra in DMSO-d6.
Figure 2.3. Synthesis of ((PS-co-Poly[ViEBIm]Seb)(5). 13C NMR spectra in DMSO-d6.
108
This was also confirmed by FTIR spectroscopic analysis of copolymer 5. The presence of a strong band
at 1640 cm-1 (Fig. 2.4) can be assigned to the C=O stretching of carboxylates. Thermogravimetric analysis
also evidenced a significant change in the degradation profile, before and after anion exchange, the
stability of the resulting imidazolium sebacate-containing coPIL 5 (Fig. 2.5) being lower than that of its
parent copolymer 3 (5 wt.% loss observed at 200 and at 300 ºC, respectively; see Fig. S2.3-5). This result
is consistent with previous observations concerning imidazolium-type coPILs featuring acetate counter-
anions.21 This was also reflected in the Tg values, a Tg of 23 ºC being determined for the chloride-
containing precursor 3 (Fig. S2.6, 7), while coPIL 5 did not exhibit any clearly detectable Tg, likely due
to its gel-like behavior.
Figure 2.4. Synthesis of Polystyrene-co-poly(4-vinylbenzylethyl-(benz)imidazolium sebacate) (PS-co-
Poly[ViEBIm]Seb) (5) overlay with starting materials .FTIR spectra.
109
Figure 2.5. (PS-co-Poly[ViEBIm]Cl) (3), (PS-co-Poly[ViEBIm]Seb) (5) and Sebacic Acid plotting with
corresponding proposed degradation steps for each case.
2.4 Manipulation of gel-supported pre-catalysts
Heating coPIL 5 at 80 ºC in THF for 4 h led to an orange swollen gel (see Fig. 2.6). This bathochromic
effect could be due to an increase in electron donating ability from C2-benzimidazolium as a consequence
of basic carboxylate insertion, leading to higher-energy associated HOMO as similarly found in some
carbene metal ligands.32 After drying, this physically crosslinked copolymer exhibited a porous monolith
structure featuring open pores with pore sizes in the range 100 nm-10 µm, as revealed by scanning electron
microscopy (SEM; Fig. 2.7). Such porosity was expected to enhance the interfacial mass and energy
exchange and be beneficial for catalytic performance of the monolith. Unfortunately, this hypothesis could
not be confirmed by analysis of the surface area by Brunauer–Emmett–Teller (BET), owing to the high
heterogeneous porosity.33
110
Figure 2.6. PS-co-Poly[ViEBIm]Seb (5) gelation procedure for heterogeneous supported catalyst synthesis in THF.
Figure 2.7. SEM pictures of polymer 5 as a heterogeneous catalyst support in organocatalysis showing pore sizes
between 100 nm to 10 µm.
Owing to the absence of covalent bonds in the gel deriving from copolymer 5, i.e. to the formation of
physical crosslinking points, this gel could be easily manipulated by further anion exchange, for instance,
by using the non-coordinating TFSI anion.3,4 In this way, the gel could be readily de-crosslinked, restoring
a linear and eventually soluble copolymer (7; see Scheme 2.2). Addition of LiTFSI onto a methanol
solution of gel 5 thus caused its gradual disruption, ultimately yielding a fully dissolved compound after
12 h of stirring. The corresponding 1H NMR spectra of both TFSI-containing copolymers 4 and 7,
111
emanating from the same parent copolymer 3 proved to be identical (Fig. S2.8), validating the de-
crosslinking method by anion exchange.
Scheme 2.2. Two different pathways followed for the synthesis of TFSI anion-containing copolymers (4, 7)
supporting the anion-exchange mediated decrosslinking of the gel.
112
Figure 2.8. 1H NMR spectra overlay (PS-co-Poly[ViEBIm]TFSI)-1 (4) and (PS-co-Poly[ViEBIm]TFSI)-2 (7) in
DMSO-d6.
13 19
This was also evidenced by analysis by C and F NMR spectroscopy of compounds obtained after
anion exchange (see Fig. S2.8-13). In addition, SEC analysis of copolymers 4 and 7 showed
chromatograms that were almost superimposable (Fig. 2.9). In other words, these results did not show
any evidence of degradation or side reactions or aggregation phenomena occurring during the post-
chemical modification of coPIL derivatives.
Figure 2.9. SEC traces corresponding (PS-co-Poly[ViEBIm]TFSI)-1 (4) (in blue) and (PS-co-
Poly[ViEBIm]TFSI)-2 (7) in (red) using 10 mM LiTFSI THF as eluent using a RI detector.
2.5 Organocatalysis from gel-supported NHCs
The ability for coPIL-type gel 5 to in situ generate self-supported NHC units was first demonstrated by
adding a large excess of CS2 as electrophilic reagent.21,34,35 This chemical post-modification step led to
copolymer 6 consisting of polymer-supported NHC-CS2 betaine-type adducts. The 13C NMR spectrum of
the as-obtained red solid compound showed the characteristic signal at δ = 231 ppm due to the dithiolate
group (CS2-; Fig. 2.10). Although this chemical transformation was not quantitative, as observed by
signals corresponding to residual bis-carboxylate in 13C NMR analysis, it provided an indirect proof for
113
the in situ formation of polymer-supported NHCs. NHC-CS2 adduct formation also allowed disrupting
the physically crosslinked copolymer gel, leading to a copolymer-supported betaines soluble in methanol
and corresponding free sebacic acid as by-product.
Figure 2.10. Synthesis of PS- co -poly(4-vinylbenzyl-NHC-CS2 (6) . 13C NMR spectra in DMSO-d6.
Copolymer 5 was then employed as a gel-support of masked NHCs in three distinct benchmark NHC-
organocatalyzed reactions, including benzoin condensation,36 transesterification and cyanosilylation
(Scheme 2.3). Of particular interest, NHC-type active species could be thermally activated with no need
of an exogenous reagent, owing to the dynamic equilibrium between sebacate anions and protons of
imidazolium units, enabling to switch the catalytic activity on and off upon heating and cooling,
respectively. The temperature change also allowed us to easily recycle copolymer 5 and reuse if for
subsequent catalytic cycles.
114
Scheme 2.3. Benzoin condensation, transesterification and cyanosilylation organocatalyzed by NHC-supported
physically crosslinked porous gel under heterogeneous conditions.
Benzoin condensation was first implemented in THF using benzaldehyde as the substrate and 10% mol.
of copolymer 5 referred to imidazolium moieties. For sake of comparison, the TFSI- and chlorine-
containing copolymers, 4 and 3, were also tested under the same conditions. However, no benzoin product
was obtained with the two latter precursors, corroborating the non-innocent role of carboxylate counter-
anions to in situ generate catalytic polymer-supported NHCs. In contrast, conversions were in the range
65-70% after 24 h in five consecutive catalytic cycles when gel 5 was applied (Fig. 2.11). As discussed,
the benzoin product was formed only upon heating at 80 ºC, i.e. no catalytic activity was noted at RT,
presumably owing to the shift of the equilibrium to the formation of inactive imidazolium units. With the
benzoin product being soluble in THF, the coPIL-type gel precursor 5 could be simply recovered by
filtration due to its insoluble character. It could further be stored and handled in air for several weeks,
without apparent degradation. It could also be implemented both in the NHC-organocatalyzed
transesterification and cyanosilylation reactions under heterogeneous conditions in THF (Scheme 2.3).
The former reaction was performed using benzyl alcohol and vinyl acetate as substrates, which in presence
of 10 mol % of 5 as gel-supported pre-catalyst, yielded benzyl acetate with conversions in the range 72-
115
90% during 5 different catalytic cycles (Fig. 2.4). Finally, when treating benzaldehyde with trimethylsilyl
cyanide (TMSCN) in presence of gel 5, α-trimethylsilyloxy-phenylacetronitrile was obtained in near
quantitative yields after 1h (Fig. 2.4). This series of results thus verified that 5 could be readily applied to
a range of organocatalytic reactions and could be readily recycled, without any significant loss of catalytic
activity (see Experimental for details). Overall, catalytic performances of coPIL gel 5 were found similar
to those obtained with the different linear polymer-supported NHCs previously reported.19,21,22,24
Figure 2.11. Different benzoin condensation, transesterification and cyanosililation average conversions obtained
after 5 cycles using 10 mol % amount of catalyst in heterogeneous conditions.
2.6 Conclusion
Air-stable physically crosslinked porous gels swollen in THF were designed for the purpose of
organocatalysis under heterogeneous conditions. This was achieved by free-radical copolymerisation to
obtain a statistical benzimidazolium-based styrenic-type copoly(ionic liquid), followed by a metal-free
anion exchange reaction to incorporate dicarboxylate functions deriving from a biosourced dicarboxylic
116
acid, namely, sebacic acid. Difunctional sebacate anions eventually played a dual role of i) ionic
crosslinker and ii) slightly basic internal counter-anion to in situ deliver catalytically active NHC species
upon heating. The as-obtained gels could be reversibly manipulated to regenerate a linear coPIL by anion
exchange using a monofunctional anion. These distinctive advantages allowed performing standard
molecular heterogeneous NHC-organocatalysed reactions, leading to relatively high conversions in
reaction products. The gel-like catalysts could be readily recycled up to 5 times, without any significant
loss of catalytic activity or leaching. The catalytic performance could be tuned by thermal
activation/deactivation, shifting the equilibrium either towards NHC active species, or to inactive
imidazolium sebacate.
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119
2.8 Experimental section
Instrumentation
1
H NMR, 13C NMR and 19F NMR spectra were recorded on a Bruker AC-400 spectrometer in appropriate
deuterated solvents. All 13C NMR measurements were carried out at 298 K on a Bruker Avance III 400
spectrometer operating at 100.7 MHz and obtained over 6144 scan with a 30º flip angle (90º pulse = 9µs),
an acquisition time of 1.3s, a relaxation delay of 3 s and 65 k data points. All HSQC (heteronuclear single
quantum correlation) measurements were also performed at 298 K on a Bruker Avance III HD 400
spectrometer operating at 400,33 MHz. THF soluble polymers were previously modified inserting TFSI
as counter-anion and their molar masses were determined by size exclusion chromatography (SEC) in
THF in presence of 10mM LiTFSI as eluent (1 mL / min ) at 40 ºC using both refractometric (RI) and UV
detectors (Varian).26 Analyses were performed using a three-column set of TSK gel TOSOH (G4000,
G3000, G2000 with pore sizes 20, 75, 200 Å respectively, connected in series). A Bruker spectrometer
was used for ATR-FTIR analysis. Differential scanning calorimetry (DSC) measurements were carried
out with a Q1000 apparatus from TA Instruments. DSC experiments were performed with aluminum
sealed pans. A constant heating/cooling rate of 10 ºC/min and gas purging (N2) at a flow rate of
100mL/min was used for all experiments. Thermogravimetric analyses (TGA) were performed using a
TA instrument Q50 under a nitrogen atmosphere, from temperature (10 ºC / min) to 800 ºC. The weight
loss was recorded as a function of temperature. The macroporous gel was examined using scanning eletron
microscopy (SEM) in a JEOL JSM-6360 microscope operating at an accelerating voltage of 20kV and
5000/10000 magnification.
Materials
Benzimidazole (≥95%), ethyl bromide (99%), 4-vinylbenzyl chloride (90%), lithium
bis(trifluoromethane)sulfonylimide and Amberlite® IRA400 (hydroxide form) were obtained from

120
Aldrich and cleaned by passing a mixture of water/methanol prior to use. Azobis(2-methylpropionitrile)
(AIBN, 99%) was received from Aldrich and was recrystallized from methanol. Styrene and 4-
vinylbenzylchloride (90%) were dried over CaH2 and distilled prior to use. Sebacic acid (98%) and
potassium hydroxide (KOH) were obtained from Alfa Aesar and benzimidazole (99%) was obtained from
TCI and used as received. Tetrahydrofuran (THF) was distilled over Na/benzophenone. Ethyl acetate,
acetonitrile and methanol (99.7%, Aldrich) were used without further purification. Pre-wetted dialysis
tubing with a cut-off of 10 kDa (Spectra/Por® 6 Standard RC) was obtained from Spectrumlabs.
General Procedures
Synthesis of N-ethylbenzimidazole (1). Benzimidazole (8 g, 67.72 mmol) was dissolved in DMF (45 mL)
and (7.6 g, 135 mmol) of potassium hydroxide were added. The solution was stirred for 1 hour and 5.5
mL (74.5 mmol) of ethyl bromide were added dropwise. After stirring at RT for 24 h, the solution was
diluted in 100 mL of water and extracted with chloroform (3x25 mL). Organic phases were combined,
dried over MgSO4 and evaporated, yielding a yellow viscous oil (yield: 80%; 7.9 g). 1H NMR (DMSO-
d6): δ = 8.25 (s, 1H, N-CH-N), 7.69-7.20 (m, 4H, aromatics), 4.12 (t,2H, N-CH2-CH3), 1.32 (t, 3H, -CH3).
C NMR (DMSO-d6): δ = 144.5, 143.7, 123, 119.8, 110, 43.1, 14.8.

13
Synthesis of 4-vinylbenzylethyl(benz)imidazolium chloride ([ViEBIm]Cl) by quaternization (2).
1-vinyl-4-chloromethylstyrene (8.37 mL, 59.4 mmol) and (7.9 g, 54 mmol) of 1 was dissolved in
acetonitrile (20 mL) and heated to 80 ºC for 24 h. The solvent was evaporated and the resulting powder
was washed with diethyl ether. The product was dried for 8h under vacuum, yielding a white powder
(yield 77%, 12.41 g). 1H NMR (DMSO-d6): δ=9.68 (s, 1H, N-CH-N), 8.12-7.14 (m, 8H, aromatics), 6.72
(dd, 1H, Ph-CH-CH2), 5.95 (s, 2H, Ph-CH2-N), 5,76 (d, 1H, CH=CH2), 5.25 (d, 1H, CH=CH2), 4.15 (dd,
2H, N-CH2-CH3), 1.31 (t, 3H, -CH2-CH3). 13C NMR (DMSO-d6): δ = 142, 136.2, 135, 133.8, 131.5, 128.8,
128.7, 126.5, 126.3, 114.1, 113.5, 58.6, 44.5, 14.9.
121
Synthesis of polystyrene-co-poly(4-vinylbenzylethyl-(benz)imidazolium chloride) (PS-co-
Poly[ViEBIm]Cl) (3) by free-radical copolymerization. 5 g (0.167 mmol) of 2, 3.84 mL (0.335 mmol)
of styrene, 41 mg of AIBN and 20 mL of dry methanol were added in a Schlenk tube. Five freeze-thaw
pump cycles were performed and the solution was stirred at 75 ºC for 12h. The resulting compound was
purified by two dialyses against methanol (10kDa MWCO). (Yield: 38%; final composition: 63% styrene
/ 37% of 2). 1H NMR (DMSO-d6): δ=10.5 (br, 1H, N-CH-N), 8.22-5.68 (br, 16.5, aromatics), 5.9-5.5 (br,
2H, Ph-CH2-N), 4.6-4.4 (br, 2H, -CH2-CH3), 2.1-0.9 (br, 12.7H, CH-CH2 backbone, CH3 ethyl chain).
Synthesis of Polystyrene-co-poly(4-vinylbenzylethyl-(benz)imidazolium sebacate) (PS-co-
Poly[ViEBIm]Seb)(5) by anion metathesis using Amberlite resin. 4 g of Amberlite® IRA 400 OH- were
taken in a round bottom flask and agitated for 12 h in a 50:50 MeOH:H2O solution. Finally, the resin was
filtered and air-dried. The resin was suspended in 15mL of MeOH and 1g of polymer 3 was added to the
solution and stirred for 10 minutes. Sequential addition of 0.215 g (0.106 mmol) of sebacic acid were
added to the solution and stirred for 15 minutes. Note that addition in sequence was preferred owing to
the instability known to OH- anions in imidazolium derivatives that can lead to hydrolysis.27–29 The
solution was filtered and dried under vacuum to yield a yellowish powder (yield 94%). 1H NMR (DMSO-
d6): δ=11.4 (br, 1H, N-CH-N), 8.22-5.68 (br, 16.5, aromatics), 6-5.5 (br, 2H, Ph-CH2-N), 4.6-4.4 (br, 2H,
-CH2-CH3), 2.2-0.9 (br, 12.7H, CH-CH2 backbone, CH3 ethyl chain, CH2-CH2 sebacate, CH2-CH3
sebacate).
Synthesis of gel-supported precatalysts. 0.251 g of 5 were dried by azeotropic distillation in dry THF
(3x5 mL) in a Schlenk tube. After, polymer 5 powder was suspended in THF (0.5 M) and heated at 80 ºC
for 4 hours, yielding a physically-crosslinked insoluble orange gel (yield 99%).
Synthesis of PS- co -poly(4-vinylbenzyl-NHC-CS2 ) (6). In a Schlenk tube, 41 mg of gelled 5 were
suspended in 5 mL of dry MeOH. 0.5 mL (8.3mmol) of CS2 were then added and the mixture was stirred
122
at 80 ºC for 48h when the formed 6 became soluble in the solvent (MeOH) dissolving the gel. The solvent
and the excess of CS2 were evaporated, forming a reddish powder (PS-co-Poly[ViEBIm]CS2). 1H NMR
(DMSO-d6): δ= 12.3-11.8 (br, 1H, -COOH) 8.22-5.98 (br, 16.5, aromatics), 6-5.5 (br, 2H, Ph-CH2-N),
4.6-4.4 (br, 2H, -CH2-CH3), 3-0.8 (br, 12.7H, CH-CH2 backbone, CH3 ethyl chain, CH2-CH2 sebacic acid,
CH2-CH3 sebacic acid) 21
Benzoin Condensation. In a typical experiment, 0.251 g (0.446 mmol) of gelled 5, a portion of 4 mL of
THF was added and 0.455 mL (4.46 mmol) of benzaldehyde was added in a Schlenk tube. The reaction
mixture was stirred for 24 h at 80 ºC. The mixture was allowed to cool down to room temperature, and
the liquid phase removed and analysed. This phase was analysed by 1H NMR in DMSO-d6. Benzoin
conversion was determined by 1H NMR in DMSO-d6 by comparing the integral value of the aldehyde
signal of benzaldehyde (d, 10ppm) with the one of the –CH- benzoin signal (d, 6 ppm) (Fig. S14). The
swollen gel was dried and cleaned with dry THF at 40 ºC twice. Finally, the same quantity of dry THF
was added enabling the next run of catalysis. Note that every cycle the polymer-supported catalyst was
weight and no loss of catalyst was observed.
Transesterification. In a typical experiment, 0.170 g (0.3 mmol) of 5 were previously gelled and a portion
of 4 mL of THF was added. Then 0.32 mL (3 mmol) of benzyl alcohol and 0.30 mL (3.27 mmol) vinyl
acetate were added. The mixture was stirred for 2 h at 80 ºC. After cooling down to room temperature,
the liquid phase was retired and analyzed by 1H NMR in DMSO-d6 and conversion calculated comparing
the integral value of the –CH2- benzyl alcohol signal (4.5 ppm) to that of the –CH2- benzyl acetate signal
(d, 5ppm) (Fig. S2.15). The swollen gel was dried and cleaned with dry THF at 40 ºC two times. Finally,
the same quantity of dry THF was added to perform next catalytic run using the same catalyst.
Cyanosilylation. In a typical experiment, 0.1 g (0.176 mmol) of 5 were previously gelled in THF as
explained in Fig. 2.2., a portion of 4mL THF was included and then 0.18 mL (1.76 mmol) of benzaldehyde
123
and 0.24 mL (1.9 mmol) trimethylsilyl cyanide (TMSCN) were added. The mixture was stirred for 1 h at
80 ºC. After cooling down to room temperature, the liquid phase was retired and analyzed by 1H NMR in
DMSO-d6 and conversion of α-trimethylsilyloxy-phenylacetronitrile calculated comparing the integral
value of aldehyde signal (10 ppm) to that of the –CH- cyanide product (d, 5.5 ppm). The swollen gel was
dried and cleaned with dry THF at 40 ºC twice. The same amount of dry THF was added to proceed to
next catalytic run. (See Fig. S2.16).
Procedure for reversibility of gels. 0.1g (0.176mmol) of 5 previously gelled in THF was dried
under vacuum. Gel 5 was suspended in methanol afterwards and heated at 40 ºC. Then, 0.505 g (1.76
mmol) of LiTFSI were added and let stir overnight. The polymer ((PS-co-Poly[ViEBIm]TFSI)-2 (7)
became insoluble after the anion metathesis. The excess of methanol and LiTFSI was removed and the
precipitated polymer washed with water and ((PS-co-Poly[ViEBIm]TFSI)-2 (7) recovered (yield 71%).
The same procedure was applied to (PS-co-Poly[ViEBIm]Cl) (3) in order to obtain the (PS-co-
Poly[ViEBIm]TFSI)-1 (4) as well (yield 80%).
124
Related spectra
Figure S2.1. Synthesis of Polystyrene-co-poly(4-vinylbenzylethyl-(benz)imidazolium
chloride) (PS-co-Poly[ViEBIm]Cl) (3) . 1H NMR spectra in DMSO-d6.
125
Figure S2.2. Synthesis of Polystyrene-co-poly(4-vinylbenzylethyl-(benz)imidazolium
sebacate) (PS-co-Poly[ViEBIm]Seb)(5) . 1H NMR spectra in DMSO-d6.
Figure S2.3. TGA plot of (PS-co-Poly[ViEBIm]Cl) (3).
126
Figure S2.4. TGA plot of (PS-co-Poly[ViEBIm]Seb) (5).
127
Figure S2.5. TGA plot of Sebacic Acid.
Figure S2.6. DSC plot of (PS-co-Poly[ViEBIm]Cl) (3).
128
Figure S2.7. DSC plot of (PS-co-Poly[ViEBIm]Seb) (5)
129
Figure S2.8. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-1 (4). 1H NMR spectra in DMSO-d6
Figure S2.9. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-2 (7) .1H NMR spectra in DMSO-d6.
130
Figure S2.10. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-1 (4). 19F NMR spectra in DMSO-d6.
Figure S2.11. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-2 (7). 19F NMR spectra in DMSO-d6.
131
Figure S2.12. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-1 (4). 13C NMR spectra in DMSO-
d6.
132
Figure S2.13. Synthesis of ((PS-co-Poly[ViEBIm]TFSI)-2 (7). 13C NMR spectra in DMSO-d6.
133
Figure S2.14. Benzoin Condensation Conversion. 1H NMR spectra in DMSO-d6.
134
Figure S2.15. Transesterification Conversion 1H NMR spectra in DMSO-d6.
Figure S2.16. Cyanosililation Conversion 1H NMR spectra in DMSO-d6.
135
Chapter III: Reversible Ionically-crosslinked Single
Chain Nanoparticles as Bioinspired and Recyclable
Nanoreactors for N-Heterocyclic Carbene
Organocatalysis
136
137
Table of Contents
Chapter III: Reversible Ionically-crosslinked Single Chain Nanoparticles as Bioinspired
and Recyclable Nanoreactors for N-Heterocyclic Carbene Organocatalysis
3.1. Abstract…………………………………………………………………………………139
3.2. Introduction………………………………………………………………………..140-142
3.3. Synthesis of catalytically active SCNPs……………………………………………143-148
3.4. Benzoin condensation catalyzed by SCNP 5………………………………………148-152
3.5. Conclusions……………………………………………………………..………………153
3.6. References…………………………………………………………………………153-157
3.7 Experimental section………………………………………………………………158-169
138
3.1 Abstract
The intrinsic advantages of poly(ionic liquid)s (PILs), based on their high chemical activity and
flexible structure, have been harnessed by exploring their applicability as catalytic single chain
nanoparticles (SCNPs). A non-covalent bioinspired approach has been established to ionically
crosslink an imidazolium-based poly(ionic liquid) to form a folded SCNPs. An amphiphilic
styrenic-type coPIL was synthesized by reversible addition fragmentation chain transfer
(RAFT) to include hydrophilic stabilizers units, hydrophobic spacers and two antagonist
functionalities randomly distributed through the polymer backbone. The antagonist
functionalities were then intramolecularly and ionically-crosslinked using a simple anion
metathesis reaction, which resulted in folding to form the SCNPs under mild conditions. The
folding process enabled the protection of the N-heterocyclic carbene (NHC) functionality,
through the benzoate-imidazolium interaction between antagonist monomer units. Upon the
application of heat, free NHCs could be generated within the confined SCNPs, which could be
further utilized in benzoin catalysis. Most importantly, the reversible nature of the crosslinking
and reversible generation of the active functionality allowed for utilization of the SCNPs as a
recyclable catalytic support.
139
3.2 Introduction
Single-chain polymer nanoparticles (SCNPs) have recently attracted increasing interest due to
their exceptional and unique properties in an array of applications in nanomedicine, catalysis
and information storage.1–6 SCNPs are based on self-collapsed individual chains that mimic the
structure of folded biomacromolecules, such as (poly)peptides or enzymes.7 Particularly in
catalysis, these biomacromolecules serve as source of inspiration for the construction of
artificial nano-objects (i.e. nanoreactors) trying to emulate such precision pathways towards
functionality, specificity and efficiency.7,8 The strategy followed is based on folding individual
synthetic polymer chains through intramolecular crosslinking to obtain SCNPs containing
confined catalytic entities.9–11 Whilst the majority of work has been particularly focused on the
use of covalent intramolecular interactions for the synthesis of robust SCNPs, it is increasing
the number of approaches based on reversible intramolecular interactions for the development
of stimuli-responsive SCNPs.6,12,13 Reversibly bonded SCNPs synthesis was first achieved via
non-covalent interactions through hydrogen-bonding.14 Subsequently, many other
folding/collapsing routes have been investigated, based on hydrogen-bonding,15–19 host-guest
interactions,20–22 dynamic covalent bonds,6 disulfide bridges,23 redox/pH/UV-responsive
SCNPs 24–26 or metal complexation.9,27–31 All of these SCNPs can be disassembled by applying
different stimuli (e.g. pH/temperature/redox change, solvent polarity variation, include host
competitors). The formation of reversible SCNPs linkages that rely on dynamic configuration
processes represent probably the most promising pathway towards enzyme biomimicry since
the nature of these non-covalent bonds could determine the function and performance of
synthetic SCNPs as it occurs in certain proteins.6 As a new type of non-covalent bonding in
SCNPs technology, ionic-liquids (ILs or PILs in the polymerized version) display a solvent-
independent ionization state and have found unusually broad potential applications such as
catalysis, due to their negligible vapor pressure, high thermal stability and powerful solvation
capability.32–34 Moreover, the freedom to choose the cation and anion and their tunable
miscibility with numerous organic compounds/solvents make (P)ILs potential candidates as
new type of non-covalent bond based SCNPs for catalysis. To this purpose, imidazolium-based
(P)ILs have been found to serve as a latent source of catalytically active N-heterocyclic carbenes
(NHCs), which are readily generated through a temperature-dependent acid-base
equilibrium.35,36 These masked-NHCs have been widely implemented in both molecular or
supported macromolecular structures using a variety of different imidazolium precatalysts.
Interestingly, supported imidazolium-based masked-NHCs were previously decorated in our
140
group with different basic counter anions in wide array of different polymeric structures such
as with HCO3- (in linear polymers),37,38 acetate (in both linear polymers and folded SCNP) ,39,40
or sebacate (in gels) ,41 by simple anion exchange. Inspired by such a concept, supporting on
the one hand the imidazolium cationic moieties (NHC source) and on the other hand the basic
counter anions (thermally latent trigger) on the same single polymeric chain should enable the
creation of a confined SCNP pocket, based on electrostatic interactions. This would facilitate
the creation of thermally latent NHC based catalytic centers, which could then potentially be
utilized as catalytic nanoreactors. In this context, a new methodology for the collapse of a linear
imidazolium-based coPIL precursor, into an ionically-crosslinked SCNP, using a simple anion
exchange has been explored. The folding procedure has then been carried out under mild
conditions, through deprotonation of carboxylic acid functionality. The resulting carboxylate
then has the dual role of physically crosslinking the SCNPs, whilst generating the masked-NHC
precatalyst. These SCNPs were further used as a thermally latent homogeneous catalyst for the
benzoin condensation and could be easily recycled for a number of cycles without any
significant loss of activity (Scheme 3.1). Functionalization of the SCNPs with carbon disulfide
141
evidenced generation of the active NHC and resulted in unfolding of the ionically crosslinked
SCNPs.
Scheme 3.1. Design of catalytically active SCNPs for benzoin condensation reaction.
142
3.3 Synthesis of catalytically active SCNPs
Amphiphilic copolymer 4 was synthesized by reversible addition fragmentation chain transfer

(RAFT) polymerization in methanol at 80 °C, in the presence of 2-cyano-2-propyl
benzodithioate as a chain transfer agent and AIBN as an initiator. Copolymers were prepared
by randomly copolymerizing the commercially available monomers 4-vinyl benzoic acid and
styrene as well as the synthesized vinyl ethyl benzimidazolium chloride (2) and PEG16-styrene
(3). Note that monomer 2 was polymerized in its chloride form, which enabled the use of
methanol as the copolymerization solvent (Scheme 3.2).
Scheme 3.2. Synthetic route to the parent linear copolymer 4 by RAFT copolymerization of 2, 3, 4-
vinylbenzoic acid and styrene, followed by a folding step caused by anion-metathesis leading to the
formation of SCNP 5. Unfolded copolymer, 6 could be obtained by irreversibly post-functionalizing
SCNP 5 with CS2.
To obtain SCNPs with comparable size and similar amphiphilic character to those reported in
literature,28,41 the total theoretical degree of copolymerization of different styrenic monomers
143
was kept around 80. The copolymerization was not carried out to full conversion (instead to ca.
40 %) to avoid side reactions which might have led to a loss of key functionality or to an
increase in dispersity. Consequently, the molar mass distribution (ĐM) was narrow (1.2) for all
of the copolymerizations. The conversion of the monomers was quantified via 1H NMR
spectroscopy by both the disappearance of the vinyl peaks and the broadening of the C2- proton
during copolymerization. The almost identical consumption of the four different styrenic
monomers, together with the moderate conversion, indicated that a statistical copolymer
distribution was achieved. The composition of benzoic acid, styrene, 2 and 3 in copolymer 4
was then found to be 0.15/0.55/0.15/0.15, respectively, as identified by 1H NMR spectroscopy
(Fig. 3.1A).
In previous work from our group, SCNP-supported NHCs were generated upon heating to a
temperature of 80 °C involving a post-functionalization approach to confer the thermally latent
behavior to NHC precatalyst moieties.40,41 As a more facile and scalable alternative, we apply
here an anion-exchange method enabling to trigger the self-folding of the RAFT-derived
copolymer precursor. This provides, on the one hand, a three-dimensional robust SCNPs
structure and, on the other hand, a basic counter anion for the benzimidazolium moieties, hence
enabling their utility as a latent NHC-source upon thermal triggering. Indeed, the ionic nature
of the crosslinking requires only mild conditions for the triggering of SCNPs folding and also
confers reversibility in this process. In detail, linear copolymer precursor 4 was subjected to an
anion metathesis reaction under diluted conditions (1 mg/mL), replacing the chloride anions
(present in benzimidazolium moieties) by carboxylate ones (present in benzoic acid moieties)
in the presence of triethylamine (TEA) to afford SCNP 5.
This folding process, in which a carboxylate counter anion ionically interacts with the
benzimidazolium cation, was evidenced using a range of analysis methods, including 1H, 13C
NMR spectroscopy, diffusion ordered spectroscopy (DOSY), Fourier transform infrared
spectroscopy (FTIR), size exclusion chromatography (SEC), dynamic light scattering (DLS),
transmission electron microscopy (TEM), and small-angle X-ray scattering (SAXS). In
particular, the 1H NMR spectroscopy revealed the disappearance of the acidic –OH proton
signal, as well as the shift of the benzimidazolium C2-proton signal from 10.5 to 11.4 ppm (Fig.
3.1). The FTIR confirmed the disappearance of the acidic –OH vibration signal around 3300
cm-1, and the presence of the acetate symmetric and asymmetric vibrations in the 1500-1600
cm-1 (specifically at 1590 cm-1) region (Fig. 3.2).
144
Figure 3.1: 1H NMR spectrum in DMSO-d6 of linear precursor 4 (A) and SCNP 5 (B) after folding.
Figure 3.2: Attenuated total reflection Fourier transform infrared (ATR-FTIR) analysis for linear
starting copolymeric precursor 4 (red) and folded SCNP 5 (blue).
It is known that PILs supporting polycations and polyanions in the same backbone are difficult
to characterize by SEC analysis due to electrostatic interactions with the stationary phase.42,43
Thus, after testing a number of different solvents, the use of DMF containing 10 mM
ammonium tetrafluoroborate at 50 °C was found to be optimal. An increase in the retention
145
time for SCNP 5 compared to linear precursor 4 was observed, which was attributed to the
decrease in hydrodynamic volume, confirming successful folding of the co(PILs) (Fig. 3.3.A).
Dynamic light scattering (DLS) experiments were performed to confirm the single chain folding
of the prepared copolymers. The folded SCNP 5 was analyzed at a concentration of 5 mg/mL
and showed a single peak around 12 nm for hydrodynamic diameter (distribution in volume) at
room temperature. However, we were also interested in the particle size at catalysis temperature
(i.e. 80 °C in THF) and hence variable temperature DLS analysis was performed, as
summarized in Fig. 3.3.B. (see Fig. 3.4 for 20-80 °C range). This analysis confirmed a relatively
homogeneous diameter of the SCNPs from room temperature (rt) to catalytic conditions. Dry
state TEM, stained with uranyl acetate, revealed particle diameters of 7-10 nm, confirming
results obtained by DLS analysis (Fig. 3.3.C).
To further confirm the change in size upon folding, the linear and folded co(PILs) were
characterized by DOSY NMR spectroscopy in DMSO-d6. This characterization technique
confirmed the faster diffusion coefficient for the SCNP 5 (D = 3.14 x 10-11 m/s2) compared to
the linear precursor 4 (D = 2.39 x 10-11 m2/s) and also allowed for the calculation of the
hydrodynamic diameter of the SCNPs (of ~7 nm) using the Stokes-Einstein-equation (Fig.
S3.1). Furthermore, despite the suggested presence of some larger aggregates, SAXS
measurements (fitted to a compact particle model) unambiguously revealed a compaction from
9.4 nm to 5.3 nm calculated from the Porod region in the Kratky plot (Fig. 3.1.D). All of these
characterization methods afforded similar values for SCNPs diameter (with variations
attributable to the difference measurement conditions, solvents etc.) and confirmed successful
folding of the linear coPIL 4 to form the SCNP 5.
146
Figure 3.3. A) SEC responses (in DMF in presence of 10 mM NH4BF4; RI detector) of SCNP 5 (red
line) obtained via cross-linking of copolymer precursor 4 (blue line) by anion exchange. B) DLS analysis
of SCNP 5 at rt (solid red line) and at catalysis temperature (solid black line) distributed by volume in
THF (conc. = 5 mg/mL). C) TEM images of SCNP 5 (conc. = 1 mg/mL in methanol) stained with uranyl
acetate; scale bar = 50 nm. D) Kratky Log-Log plot from SAXS analysis of precursor 4 (solid red line)
and folded 5 (solid blue line) in THF (conc. = 1 mg/mL; fitted to compact particle model).
147
Figure 3.4. Multi-T DLS analysis of SCNP 5 from 20 to 80 °C in THF with volume (black line) and
number (red line) distributions (Conc: 5 mg/mL).
3.4 Benzoin condensation catalysed by SCNP 5

This particular folding technique was of interest as it provided a method for the generation of a
thermally latent NHC-precatalyst, which could be activated upon thermal cleavage of the
intrachain crosslinks. To prove that an active NHC species was generated upon heating SCNP
5, an NHC-CS2 adduct forming reaction was carried out (copolymer 6; Scheme 3.2).40 Upon
addition of CS2 irreversible and selective “trapping” of the generated active NHCs in the
SCNPs was expected. This was confirmed by identifying the characteristic signals of the NHC-
13
CS2 betaine (223.9 ppm, corresponding to the dithiolate group in C NMR spectrum; Fig.
3.5).44 Masked carbenes in their active form are known for their versatility and capability of
acting as (organo)catalysts in a wide array of (macro)molecular reactions.35,36,45,46 Since the
folding step afforded a 3D conformational NHC-masked precatalyst, no further post-
functionalization was required prior to catalysis. We hypothesized that the active NHC species
could be generated upon heating as previously proven by NHC-CS2 selective formation,
resulting in the generation of a thermally latent catalyst, which could be utilized in an organic
transformation.
148
Figure 3.5. 1H NMR (A) 13C NMR (B) spectra of CS2 post-functionalization reaction in SCNP 6 in
DMSO-d6.
Benzoin condensation was chosen as model reaction because it is almost exclusively catalysed
by carbenes,47 and hence would permit to evaluate the catalytic performance of our system.
Therefore, this reaction was first implemented in THF using benzaldehyde as the substrate and
10 mol.% of SCNP 5 (reference concentration: 20 mg/mL) relative to benzimidazolium
moieties. In the first catalyst run using these conditions, 71% of benzaldehyde units were
converted into benzoin after 24 h (Run 1; Table 3.1) and no higher conversions were observed
when prolonging experiment time up to 48 h (Run 2). Interestingly, owing to both the
incorporated side oligo-PEG in the polymeric structure and thermo-latent behavior of SCNPs,
the increased solubility allowed polymer-supported catalyst recycling after catalyst
deactivation, namely, by dialysis against methanol (see experimental). Conversions remained
around 70% after 24 h reaction time, and after three consecutive catalytic cycles when SCNP 5
was applied. This highlights the robust and reversible nature of our latently crosslinking
approach (Runs 3 and 4).
The role of confined space, where the reagents are able to efficiently interact with the thermally
latent NHC, was then explored. The amount of SCNP 5 catalyst was thus decreased from 10
mol.% to 1 mol.%. Interestingly, conversions increased from 71% to 85%, passing upon
reducing the mol.% of the SCNP 5 ten-fold (Runs 5 and 6). However, when the catalyst amount
was dropped further to 0.1 mol.% (Run 7), the conversion did not increase, suggesting a product
inhibition effect in the catalytic pocket of SCNP 5, which has been observed before in similar
149
confined systems.48 More specifically, we hypothesized that this inhibition effect could come
from the generated –OH moieties in benzoin molecules that would inhibit the NHC catalyst as
similarly occurred in other masked-NHC catalytic systems.37–39,49
To examine the relationship between the confinement effect and inhibition provoked by the
catalysed benzoin product, SCNP 5 was compared with a linear polymeric model, i.e. only
bearing NHC precatalyst and spacer moieties, and a molecular model based on an active
benzimidazolium monomer. Both molecular and macromolecular models were assessed for the
benzoin condensation reaction under the same catalysis conditions as SCNP 5. No appreciable
confinement effect was found when the molecular model was used, showing a progressive
decrease from 74% to 45% conversion when dropping the catalytic amount from 10 to 0.1
mol.% (Run 8-12). The lower catalytic performance of the molecular model compared to SCNP
5 could be due to the poor solubility of benzimidazolium benzoate and subsequent aggregation
in the solvent used (i.e. THF). Conversely, the linear copolymeric model based on styrenic
benzimidazolium benzoate moieties showed higher solubility compared to the molecular
model, but led to a lower catalytic activity than both the molecular model and, more
importantly, SCNP 5. In fact, only 61% conversion was obtained when using 10 mol.% of the
linear copolymer, which dropped up to 50% when decreased down to 0.1 mol.% catalyst
loading (Runs 13-16). The observed plateau of 50% conversion when using either 1 and 0.1
mol.% catalyst (Runs 15 and 16, respectively), suggested that the inhibition effect was probably
more apparent in the linear model, since the catalytic sites were more exposed to the obtained
product (i.e. benzoin), and hence, more prone to inhibition than SCNP 5. This is proposed to be
due to the confinement effect on SCNP 5, leading to an energy-free driven catalytic nanoreactor
system based on the osmotic gradient between the SCNP pocket and the external solution.48,50–
52
Otherwise, for comparison, the chlorine-containing monomer 2 and the linear parent coPIL 4
were also tested under the same conditions (Runs 17 and 18). However, no benzoin product
was obtained, providing further evidence for the role of benzoate counter-anions to generate in
situ catalytic SCNP-supported NHCs. Finally, control experiments were performed in order to
successfully discard any catalytic activity of SCNP 5 in H2O (Run 19) or spontaneously
generated benzoin without catalyst under previously used conditions (Run 20). It is also worth
mentioning that no benzoin conversion was observed when the experiments were run at room
150
temperature, in good agreement with previously reported studies of our group reporting similar
systems.39–41
This non-covalently crosslinked SCNPs approach illustrates the importance of having the
normally ionic catalyst tethered to the SCNPs scaffold for efficient catalysis of generated
soluble products which may entail inhibition in relatively apolar solvent conditions.
Table 3.1. Benzoin condensation reactions of benzaldehyde under different conditions using
NHC-containing SCNPs and control experiments.
151
Run Catalyst Cat. (mol%) Cycle Time (h) Conv(a) (%)
1 SCNP 5 10 1st 24 71
2 SCNP 5 10 1st 48 71
3 SCNP 5 10 2nd 24 69
4 SCNP 5 10 3rd 24 68
5 SCNP 5 5 1st 24 76
6 SCNP 5 1 1st 24 85
7 SCNP 5 0.1 1st 24 80
8 Molecular 10 1st 24 74
model(c)
10 Molecular model 5 1st 24 62
11 Molecular model 1 1st 24 61
12 Molecular model 0.1 1st 24 45
13 Linear model(d) 10 1st 48 61
14 Linear model 5 1st 24 61
15 Linear model 1 1st 24 50
16 Linear model 0.1 1st 24 50
17 2 10 1st 24 0
a
Conversions were calculated by 1H NMR spectroscopy (Fig. S3.8); b
THF was dried under
Na/benzophenone prior to use in each catalytic run except from Run 19) c Active monomer based
d e
molecular model; Linear model containing randomly ordered spacers and active monomer units.
Entry 19 the catalysis reaction was run in water. The reference catalyst concentration used was 20
mg/mL and temperature set at 80 ˚C. In all catalytic experiments, no enantiomeric selectivity was
observed.
152
3.5 Conclusions
In summary, a novel type of non-covalently bonded SCNPs obtained by RAFT

copolymerization is reported. Exploiting the PIL nature of the parent linear precursor,
amphiphilic SCNPs folding was triggered by a mild anion-metathesis intramolecular reaction.
The collapse was confirmed by different characterization methods (1H/13C NMR
spectroscopy, SEC, DLS, SAXS, TEM and FTIR). These SCNPs contain latent NHC-type
active species which could be thermally activated without the need for an exogenous reagent.
The relatively high-conversions (~70%) in the benzoin condensation reactions could be
maintained up to 3 catalytic cycles. Interestingly, the conversions could be enhanced up to 85%
when 1 mol.% catalyst was used, as a result of the confinement in the catalytic environment in
THF. The latter was further evidenced when comparing SCNPs to both molecular and
polymeric models, showing higher catalytic efficiency, probably due to less catalyst inhibition
effect in SCNPs catalytic pocket. Finally, post-modification of SCNPs by CS2 insertion
confirms the NHC active species generation, as well as providing a simple SCNPs unfolding
route. Although synthetically challenging, opening SCNPs chemistry to an entirely new terrain
based on non-covalent interactions using PILs structures can answer to major organocatalysis
challenges.
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157
3.7 Experimental Section
Synthesis of different monomers
Synthesis of N-ethylbenzimidazole (1). Benzimidazole (5 g, 42.32 mmol) was dissolved in

DMF (20 mL) and 4.75 g of potassium hydroxide was added (2.5 eq., 106 mmol). The solution
was stirred for 15 minutes and 3.45 mL (5.07 g, 46.55 mmol) of ethyl bromide was then added
drop-wise. After stirring at room temperature for 24h, the solution was diluted with 50 mL of
water and extracted with dichloromethane (4 x 25 mL). The organic phases were combined,
dried over MgSO4 and evaporated, yielding a yellow viscous oil (4.93 g, 33.8 mmol, yield =
80%) 1H NMR (DMSO-d6): δ = 8.25 (s, 1H, N-CH-N), 7.69-7.20 (m, 4H, aromatics), 4.12 (t,
2H, N-CH2-CH3), 1.32 (t, 3H, -CH3). 13
C NMR (DMSO-d6): δ = 144.5, 143.7, 123, 119.8,
110.0, 43.1, 14.8.
Synthesis of 4-vinylbenzylethylbenzimidazolium chloride ([ViEBIm]Cl) (2). N-

ethylbenzimidazole 1 (4.82 g, 33 mmol) was dissolved in 25 mL of acetonitrile and 4.65 mL (1
eq. 5.03 g) of 4-vinylbenzylchloride were added into a schlenk tube. After stirring 24 h at 80
°C, the monomer was precipitated in EtOAc and dried under vacuum to remove the solvent
leading to a white powder (8.87 g, 42 mmol, yield = 91%). . 1H NMR (DMSO-d6): δ = 9.68 (s,
1H, N-CH-N), 8.12-7.14 (m, 8H, aromatics), 6.72 (dd, 1H, Ph-CH-CH2), 5.95 (s, 2H, Ph-CH2-
N), 5,76 (d, 2H, CH=CH2), 5.25 (d, 1H, CH=CH2), 4.15 (dd, 2H, N-CH2-CH3),1.31 (t, 3H, -
CH2-CH3). 13C NMR (DMSO-d6): δ = 142, 136.2, 135, 133.8, 131.5, 128.8, 128.7, 126.5, 126.3,
114.1, 113.5, 58.6, 44.5, 14.9.
Synthesis of 4-vinylbenzyl-PEO16 (3). The hydroxy-containing polyoligo(ethylene oxide)

monomethylester (CH3O-PEO16-OH, 750 g.mol-1) (11.87 g, 15.82 mmol) was dissolved in THF
(40 mL) and an excess of NaH (0.8 g, 40 mmol) was added slowly. After 1 hour stirring, 2.9
mL (3.14 g, 23.73 mmol) of 4- vinylbenzylchloride were added drop-wise. The reaction was
stirred at rt for 24h. The excess NaH was quenched with water. After filtration an extraction
with chloroform was performed. The chloroform was then removed under vacuum and the
monomer purified by precipitation in cold heptane. The pure product was recovered as a yellow
viscous oil (7.3 g, 8.31 mmol, yield = 70%) . 1H NMR (DMSO-d6): δ = 7.4 ( m, 4H, aromatics),
6.7 (dd, 1H, Ph-CH-CH2), 5.5 (d, 2H, CH=CH2), 4.5 (s, 2H, Ph-CH2-O), 3.5 (m, 64H, O-CH2-
158
CH2-O-), 3.22 (s, 3H, O-CH3). 13C NMR (DMSO-d6): δ = 137.2, 137.0, 129.6, 128.2, 114.5,
73.1, 71.5, 70.3, 70, 59.1.
Synthesis of linear copolymer 4 CTA (15 mg, 0.067 mmol), styrene (0.86 mL, 7.53 mmol),
monomer 2 (570 mg, 1.89 mmol), 4-vinylbenzoic acid (280 mg, 1.89 mmol) and monomer 3
(1.8 g, 2.02 mmol) were placed in a 20 mL glass tube. Methanol (10 mL) was added into the
tube and the solution was stirred. AIBN (11.1 mg, 0.067 mmol) was added under dry argon at
room temperature. Immediately after mixing, the polymerization mixture was placed in an oil
bath at 80 °C for 24 h. After reaching 40% conversion measured by 1H NMR spectroscopy, the
reaction was terminated by cooling the mixture to room temperature. The conversion was
determined from the concentration of residual monomer detected by 1H NMR spectroscopy.
The quenched reaction solution was purified by dialysis against MeOH (1 L) using a 3.5 kDa
dialysis membrane and finally evaporated to dryness and subsequently dried overnight under
vacuum at room temperature. Yield = 33%. 1H NMR (DMSO-d6): δ (ppm) = 13.2-12.1 (br, 1H,
HOOC-Ar), 10.9-10.5 (br, 1H, N-CH=N), 8.3-6 (br, 34.3H, Ar-H), 5.9-5.5 (br, 2H, Ar-CH2-N),
4.7-4.1 (br, 4H, N-CH2-CH3, O-CH2-Ar), 4.1-3.1 (br, 67H, O-CH2-CH2, CH3-CH2-O), 2.3-0.9
(br, 13H, CH2-CH- (backbone) , N-CH2-CH3) (Fig, 3.1A); 13C NMR (DMSO-d6): 166.4, 164.9,
150.2, 145.5, 142.7, 141.3-126.2, 113.1, 72.1, 70.3, 68.7, 52.1, 50.9, 13.2 ppm (Fig. S3.3A);
IR: ʋ 3422.7 (OH), 1719.6 (C=O), cm-1 (Fig. 3.2 in red).
Synthesis of SCNP 5. Linear copolymer 4 (1 g) was dissolved in 1 L of MeOH at a

concentration of 1 mg/mL in a 1 L round bottom flask. A large excess of TEA (10 eq.) was
added dropwise to the methanolic solution. The resulting mixture was stirred at room
temperature for 24 h until the anion-exchange was complete, as evidenced by 1H NMR
spectroscopy. The SCNP 5 solution was concentrated in vacuo and dialyzed (3.5 kDa MWCO
against MeOH (1 L) to remove the liberated salt and the excess TEA. The purified SCNP 5 was
dried under reduced pressure to yield a viscous oil. Yield: 89% 1H NMR (DMSO-d6): δ (ppm)
= 11.6-10.9 (br, 1H, N-CH=N), 8.3-6.05 (br, 34.3, Ar-H), 6-5.55 (br, 2H, Ar-CH2-N), 4.83-4.05
(broad, 4H, N-CH2-CH3, Ar-CH2-O), 4.1-3.1 (br, 67H, O-CH2-CH2, CH3-CH2-O), 2.3-0.8 (br,
13
13H CH2-CH-(backbone), N-CH2-CH3) (Fig. 3.1B); C NMR (DMSO-d6): 166.8, 150.4,
145.4, 132.4-127.3, 113.1, 72.1, 70.3, 51.9, 13.2 ppm (Fig. S3.3B); IR: ʋ 1715.6 (C=O), 1619.7,
1536.7 (COO-) cm-1 (Fig. 3.2 in blue).
159
Synthesis of unfolded copolymer 6. In a 10 mL glass tube, folded SCNP 5 (155 mg) was
azeotropically dried using distilled THF. Then 2 mL of dry THF was added and the solution
stirred. CS2 (0.4 mL) was then added at room temperature under argon. The solution was stirred
at 80 °C for 24 h and the color change from colorless to red was observed, this being indicative
of NHC-CS2 formation. After cooling, the excess of CS2 and solvent were removed under
reduced pressure. Yield = >95% 1H NMR (DMSO-d6): δ (ppm) = 13.2-12.9 (br, 1H, HOOC-
Ar), 8.2-6 (br, 34.3H, Ar-H), 5.9-5.3 (br, 2H, Ar-CH2-N), 4.8-4.1 (br, 4H, N-CH2-CH3, O-CH2-
Ar), 4.1-3.1 (br, 67H, O-CH2-CH2, CH3-CH2-O), 2.3-0.9 (br, 13H, CH2-CH-(backbone), N-
CH2-CH3) (Fig. S3); 13C NMR (DMSO-d6): 223.9, 167.2, 166.6, 152.7, 150.4, 145.2, 132.6-
124.3, 113.1, 72.1, 69.7, 52.3, 43.2, 13.8 ppm (Fig. 3.5).
Synthesis of molecular model. Monomer 2 (0.5 g, 1.67 mmol) was solubilized in methanol (2
mL). Potassium acetate (0.18 g, 2 mmol) was added and the reaction carried out at rt under
stirring for 16 h. The solution was filtered to remove the formed KCl and dried under reduced
pressure. Yield > 95%. 1H NMR (DMSO-d6): δ (ppm) = 10.6 (s, 1H, N-CH=N), 8.15-7.4 (m,
8H, Ar-H), 6.78-6.6 (dd, 1H, CH2-CH-Ar), 5.85 (d, 2H, CH2-CH-), 5.79 (s, 2H, Ar-CH2-N),
5.3 (d, 2H, CH2-CH-), 4.5 (m, 2H, N-CH2-CH3), 1.6 (s, 3H, -OOC-CH3), 1.5 (t, 3H, CH2-CH3)
(Fig. S3.4).
Synthesis of linear model polymer. 2-cyano-2-propyl benzodithioate CTA (30 mg, 0.13
mmol), styrene (2.64 mL, 23 mmol) and monomer 2 (1.21 g, 4 mmol) were placed in a 20 mL
glass tube. Methanol (10 mL) was added and the suspension allowed stirring for 5 min until a
solution was obtained. AIBN (27 mg, 0.11 mmol) was then added to the methanolic solution
under dry argon at room temperature. After mixing, the glass tube was placed at 80 °C in an oil
bath for 17 h. 46% conversion was reached as evidenced by 1H NMR spectroscopy. The
reaction was quenched by cooling the solution to room temperature. The crude copolymer was
then purified by dialysis against methanol (1 L x 2 every 24 h) using 3.5 kDa MWCO dialysis
membranes. The obtained copolymer (1 g) was solubilized in methanol and subjected to anion-
exchange by adding potassium acetate (0.7 g, 10 eq.) to the solution, this was then left overnight
under stirring. The reaction was then cooled, filtered, and dried under reduced pressure. Yield=
39%. 1H NMR (DMSO-d6): δ (ppm) = 11.5-10.5 (br, 1H, N-CH=N), 8.2-6.05 (br, Ar-H), 6-
5.55 (br, 2H, Ar-CH2-N), 4.6-4.4 (br, 2H, N-CH2-CH3), 2.3-0.9 (br, 9H, -OOC-CH3, N-CH2-
CH3, -CH2-CH- (backbone)) (Fig. S3.5). SEC analysis «Đ» = 1.18; Mn = 14.8 kDa (Fig. S3.6).
160
General procedure for benzoin condensation reaction. In a 10 mL glass tube, different
catalysts were first azeotropically dried using distilled THF. Then, dry THF was added keeping
a reference catalyst concentration of 20 mg/mL. The solution was stirred, and previously
distilled benzaldehyde (10 eq.) was added under argon. The resulting mixture was stirred under
argon at 80 °C for 24 h. After cooling, an aliquot was immediately taken and analyzed by 1H
NMR spectroscopy to determine the conversion by comparing the integral value of the aldehyde
signal of the benzaldehyde starting material (s, 1H, 10 ppm) with that of the -CH- benzoin
product signal (s, 1H, 6 ppm) (Fig. S3.7-9).
General catalyst recycling procedure
After the previous catalytic cycle was performed, the resulting mixture was cooled down,
significantly diluted in methanol and purified by dialysis (3.5 kDa MWCO) against MeOH (1L
x 2 every 24 h) in order to remove unconverted benzaldehyde, formed benzoin and THF. The
catalyst was dried under vacuum and the azeotropically dried again once using THF before the
next catalytic run.
Diffusion Ordered Spectroscopy
Molecules are distinguished according to their diffusion, which correlates with their
hydrodynamic radius. Samples of polymer 4 as well as the SCNP 5, were analyzed in DMSO-
d6 employing the conditions displayed in experimental part. Calculation of the diameter,
applying the Stokes-Einstein-Equation.
Stokes-Einstein-Equation:
𝑘𝑇
𝐷=
6𝜋𝜂𝑟
k = 1.38x10−23 J.K-1
D = 3.14.10-11 m2/s
T = 298 K
𝛈 DMSO viscosity = 1.99. 10-3 Pa.s
R = 3.5 nm D =7 nm (SCNP 5)
161
.
Figure S3.1. Original figure of DOSY measurements of the precursor copolymer 4 and SCNP 5,
recorded in DMSO-d6.
162
Figure S3.2: 13C NMR spectrum in DMSO-d6 of linear precursor 4 (A) and SCNP 5 (B) after folding.
163
Figure S3.3: 1H NMR (A) 13C NMR (B) spectra of CS2 post-functionalization reaction in SCNP 6 in
DMSO-d6.
Synthesis of model catalysts
164
Scheme S3.1. Synthetic route to prepare molecular catalyst model based on the active monomer and
linear catalyst model.
Figure S3.4. 1H NMR spectrum of molecular model catalyst in DMSO-d6.
165
Figure S3.5. 1H NMR spectrum of catalyst linear copolymer model in DMSO-d6.
Figure S3.6. SEC traces of Linear Copolymer model (in Cl- amion form) in DMF (10 mM ammonium
tetrafluoroborate) with RI detector («Đ= 1.18; Mn = 14.8 kDa: Universal calibration).
166
Figure S3.7. Reaction of benzoin condensation with benzaldehyde catalyzed by SCNP 5 and conversion
obtained 1H NMR spectroscopy in DMSO-d6.
167
Figure S3.8. Reaction of benzoin condensation with benzaldehyde catalyzed by molecular model and
conversion obtained 1H NMR spectroscopy in DMSO-d6.
Figure S3.9. Reaction of benzoin condensation with benzaldehyde catalyzed by linear copolymer model
and conversion obtained 1H NMR spectroscopy in DMSO-d6.
Waterborne catalysis conditions
PEG-based side-oligopolymers were incorporated along the (co)polymer chain to render this
system soluble in water. When a 1H NMR analysis experiment was performed using D2O as
deuterated solvent, only the PEG side chains were observed due to the external conformation
of the SCNP 5 (Fig. S10).
168
Figure S3.10. 1H NMR spectra of the SCNP 5 in D2O.
169
Chapter IV: Self-catalysed folding of single chain
nanoparticles (SCNPs) by NHC-mediated
intramolecular benzoin condensation
170
171
Table of Contents
Chapter IV: Self-catalysed folding of single chain nanoparticles (SCNPs) by NHC-

mediated intramolecular benzoin condensation
4.1. Abstract.........................................................................................................................173
4.2. Introduction..............................................................................................................174-176
4.3. Synthesis of catalytically active SCNPs..................................................................176-182
4.4. Transesterification reaction catalysed by SCNP 5.....................................................182-186
4.5 Conclusions..............................................................................................................186-187
4.6. References................................................................................................................187-189
4.7. Experimental section................................................................................................190-209
172
4.1 Abstract
A self-catalysed folding strategy to form single chain nanoparticles (SCNPs) was developed
via an intramolecular N-heterocyclic carbene (NHC)-mediated benzoin condensation.
Benzaldehyde, styrene and benzimidazolium chloride units were randomly incorporated into a
poly(ionic liquid)-based (PIL) copolymer precursor by reversible addition–fragmentation chain
transfer (RAFT) copolymerisation. Post-chemical modification of this linear precursor by
insertion of a non-innocent acetate counter-anion into the benzimidazolium moieties conferred
thermolatent catalytic behaviour owing to the equilibrium between benzimidazolium acetate
units and corresponding NHC ones. Upon heating, catalytically active NHCs allowed the
formation of benzoin-type intramolecular cross-links, thus folding linear chains into SCNPs.
NHC moieties became deactivated after cooling to room temperature, which enabled easy
isolation and purification of the covalently and intramolecularly cross-linked SCNPs.
Importantly, the latent NHC moieties were proven to retain their catalytic activity when
arranged into SCNPs as evidenced through their reactivation by simple heating. The catalytic
activity of these SCNPs was further confirmed by implementing another NHC-organocatalysed
reaction, namely, transesterification reaction between vinyl acetate and benzyl alcohol. This
work represents the first example of catalysis by a parent linear precursor which drives its own
folding and remains catalytically active.
Reactive
Functionality Spacer Self-catalysed
SCNPs Folding
Intramolecular
Thermolatent NHC Catalyst cross-linking
173
4.2 Introduction
Single-chain nanoparticles (SCNPs) have recently emerged as versatile soft nano-objects with
unique characteristics, that make them suitable in an array of applications, such as
nanomedicine,1,2 bioapplications (bioimaging, drug delivery),3,4 or catalysis.5–7 SCNPs consist
of single polymer chains that are cross-linked through intramolecular bonding, in an attempt to
mimic the unique properties of natural biomacromolecules (e.g. polypeptides, DNA,
enzymes).8–13 In this context, synthetic enzymatic mimics that utilise polymer backbones
present a number of opportunities for preparing efficient catalysts, by controlling key properties
such as polymer solubility,14 increased accessibility to a larger library of substrates,15 increased
turnover frequency (TOF),16 recycling,17–19 or supporting organic/metallic catalysts on a soluble
polymeric support.20–24 The most common strategy to prepare SCNPs is based on the design of
a linear single chain precursor that features pendant functionalities to facilitate folding through
the formation of intramolecular cross-links following exposure to an external stimuli (e.g.
temperature, solvent, UV-irradiation), or addition of external reagents.13,25–27 After covalent
and/or non-covalent cross-linking, the SCNPs may be used as nanoreactors. However, the
catalytic ability of the parent linear precursor has not been so far exploited as a driving force
for its own folding. Here, new insight is brought to this field through immobilisation of both
the reactive functionality and the catalyst onto the same linear copolymer precursor, enabling
triggering through a self-catalysed folding as a novel route to SCNPs (Scheme 4.1).
174
A. Classic route for SCNPs folding
External reagent
+
Reactive functionality Intramolecular
cross-linking
B. This work: Self-catalysed SCNPs folding
Catalyst (thermolatent NHC)
Reactive functionality Benzoin condensation as

Intramolecular cross-linking
Scheme 4.2. Strategies to conduct SCNP synthesis for use as catalytic nanoreactors. A) Classic route
involving the addition of external reagents to induce chain folding. B) Self-catalysed SCNPs folding
mediated by supported thermally latent NHC precatalysts.
One possible obstacle to the folding process lies in the orthogonality between reactive
functionalities and the catalyst. We therefore turned to the use of a copoly(ionic liquid) (coPIL)
precursor, PILs representing modular polymeric platforms where different orthogonal
functionalities can be introduced, thanks to the broad selection of monomeric ionic liquids.28–
30
In particular imidazolium-based ILs are known as versatile precursors of N-heterocyclic
carbenes (NHCs), which can be activated in situ for instance by means of solvent change or
upon heating among other triggers. More specifically, imidazolium-based precursors featuring
a slightly basic counter-anion, e.g. hydrogen carbonate,31 acetate,32 sebacate33 or benzoate,19
can autonomously generate NHCs, i.e. without the need for any external reagent, owing to the
deprotonation of the C2-position by the basic anion. Installation of the latter is straightforward
175
as it can be achieved one step by simple anion-metathesis (= anion exchange reaction).
Synthesis of imidazolium-type coPILs bearing such anions provides a convenient strategy to
immobilize latent NHCs onto a polymeric support, which can be catalytically turned on and off
simply three decades, not only as ligands for transition metals, but also as true organocatalysts
for numerous molecular and macromolecular transformations.34–37 The so-called benzoin
condensation is an emblematic NHC-catalysed carbon-carbon bond-forming reaction occurring
by self-condensation of two aldehyde substrates forming a β-keto alcohol with no by-
product.38,39 By introducing both latent aldehyde-type units and benzimidazolium acetate units
as site-isolated latent NHCs into the same copolymer chain, we reasoned that intramolecular
benzoin condensation of supported benzaldehydes could be triggered by simple heating under
dilute solution, causing the single copolymer chain to fold through the formation of benzoin-
type crosslinks. This inherent thermal-latency would be further harnessed by
cooling/deactivating the masked supported NHCs after folding, to isolate the resulting SCNPs.
These could be further used as nanoreactors to mediate another NHC-catalysed reaction,
namely, transesterification between benzyl alcohol and vinyl acetate. Herein, we thus report a
novel self-catalysed folding strategy to SCNPs, forming intramolecular covalent cross-links of
benzoin-type. Of particular interest, the resulting SCNPs remains catalytically active. By
immobilizing for the first time both the catalytic species and the substrates onto the same single
copolymer chain, the synthetic strategy we describe here further expands the scope of SCNPs.
4.3 Synthesis of catalytically active SCNPs
The linear statistical single chain precursor was devised to be constituted of three distinct
monomer units, namely, deriving from benzaldehyde, benzimidazolium and styrene
functionalities (Scheme 4.2). As emphasised above, benzimidazolium chloride moieties served
as NHC precursors, benzaldehyde as reactive substrate both being immobilised onto the coPIL
backbone, while styrene units would play the role as spacers to facilitate easier accessibility of
the NHC catalyst to the reactive functionalities, also conferring some hydrophobicity to the
copolymer backbone. As depicted in Scheme 4.2, the IL monomer, namely, 4-
vinyilbenzylethylbenzimidazolium chloride 1 was synthesised following an established
proceedure.14,19,33 Copolymerisation of 1 with 3-vinylbenzaldehyde and styrene was achieved
via the reversible addition fragmentation chain transfer (RAFT) process in DMF, using AIBN
176
as a radical source and 2-cyano-2-propyl benzodithioate as the RAFT agent. A
[Monomer(s)]/[CTA]/[AIBN] ratio of 98/1/1 was targeted. The reaction was carried out for 12
h at 80 °C, reaching ca. 40% conversion. The structure of the resulting linear coPIL 2 was
authenticated by 1H NMR spectroscopy. In particular, the proportion of the different monomer
units within the backbone structure could be determined by relative integration of the
characteristic signals of each monomer obtained by 1H NMR spectroscopy (Fig. 4.1). Briefly,
the intensity of signals corresponding to the aldehyde proton was compared to the N-alkylated
moieties of benzimidazolium chloride, i.e. benzyl-CH2-N at 5.4 ppm and br. N-CH2-CH3 at 4.6
ppm, and the aromatic region at 6-8 ppm, corresponding to the number of styrene units. This
calculation gave an average composition of 48 styrene units, 8 units of 1 and 24 units of
benzaldehyde. Therefore, the calculated molecular weight for copolymer 2 was found equal to
~10.5 kg mol-1, that was, slightly smaller than the value delivered by SEC in DMF of 11.9 kg
mol-1.
177
Scheme 4.2. Synthetic route to functional linear copolymer 3 and subsequent self-catalysed folding step
leading to catalytically active SCNP 5. The NHC-CS2 functionalised versions of both linear precursor
(4) and obtained SCNP (6) as well as corresponding active NHC intermediates are also represented.
178
Figure 4.1. 1H NMR spectrum of copolymer 2 in DMSO-d6.
The benzimidazolium chloride functionality was then subjected to an anion exchange,

substituting the acetate anion for the chloride in one step and thus affording a latent NHC pre-
catalyst.40 This metathesis reaction was carried out at room temperature in dry methanol in
presence of KOAc, yielding copolymer 3 (Fig.S4.2, S4.3). This was confirmed first by the
appearance of a new signal corresponding to acetate -CH3 protons at ca. 1 ppm in 1H NMR
13
analysis and the presence of the same acetate carbonyl signal at 176.6 ppm in C NMR
spectroscopy. This strategy enables the easy handling and storage of the coPIL precursor 3 in
an inactive state at low temperature.21,32,41,42
We first examined the latent NHC-like behaviour of coPIL 3 via a simple chemical
postmodification consisting in the reaction between benzimidazolium acetate units with an
excess of carbon disulfide (CS2). Upon heating in THF this reaction mixture for 24 h, polymer-
supported NHCs thus released NHCs from 3 are trapped, forming a red solution characteristic
of a NHC-CS2 adduct (= copolybetaine 4). This was evidenced by the appearance of diagnostic
signals in the 13C NMR spectrum at 224.1 ppm and 153.1 ppm corresponding to C2imi and CS2-
, respectively (Fig. 4.2).31,43
179
Figure 4.2. 13C NMR spectrum of copolymer 4 in DMSO-d6.
This reaction test thus allowed us, to confirm the crucial role of acetate anion in supplying
copoly(NHC)s from the linear coPIL precursor 3 upon heating. The self-catalysed folding based
on the intramolecular benzoin condensation of benzaldehyde units could then be investigated.
To this end, a solution of coPIL 3 was heated to 80 °C in THF at 1 mg mL-1 concentration for
48 h. The folding process generating SCNP 5 constituted of benzoin covalent cross-links was
evaluated by 1H and 13C NMR spectroscopy, size exclusion chromatography (SEC), dynamic
light scattering (DLS), transmission electron microscopy (TEM), diffusion-ordered
spectroscopy (DOSY) NMR and Fourier-transform infrared spectroscopy (FTIR).
Characteristic signals corresponding to the newly formed benzoin moieties were clearly
detected in the 1H NMR spectrum, namely, at 5.4 ppm (H from the chiral benzoin carbon) and
at 4.2 ppm (-OH from the same chiral carbon; Fig. S4.4). 13C NMR analysis also revealed the
presence of both a newly formed carbonyl signal at 179.3 ppm and the -CH- benzoin carbon at
80.7 ppm (Fig. S4.5). Formation of benzoin-type crosslinks was further evidenced by HSQC
spectroscopy (Fig. S4.6) correlating the -CH- of benzoin moieties to the corresponding chiral
carbon atom. Furthermore, FT-IR spectroscopy showed both the appearance of the benzoin –
OH group at 3300 cm-1, as well as the broadening of the carbonyl vibration signal at 1700 cm-
1
, due to the presence of the acetate (counter-anion), ketone (benzoin) and residual aldehyde
(Fig. S4.7). Self-folding was also demonstrated by a decrease in the hydrodynamic diameter of
180
the as-obtained SCNPs, according to different analytical techniques, as summarised in Figure
4.3. Firstly, a decrease in the apparent molecular weight was noted by SEC, compared to the
linear precursor 2 (Fig. 4.3A) due to compaction by intramolecular crosslinking upon forming
SCNP 5. DLS performed in THF at 20 °C revealed a slight decrease in hydrodynamic diameter
(DH), from 7.5 nm to 6.1 nm (Fig. 4.3B; see Fig. 4.4 for the range 20-80 °C). In addition, dry-
state TEM analysis confirmed the presence of spherical nanoparticles corresponding to SCNP
5 with an average diameter of c.a. 4.5 nm (Fig. 4.3C). Finally, DOSY NMR spectroscopy in
DMSO-d6 showed a reduction in diameter after the self-catalysed benzoin condensation step,
with a diameter of 2.3 nm calculated for SCNP 5, whilst a value of 6.6 nm was obtained for the
linear precursor 2 (Fig. S4.8). All these results are consistent with a compaction due to self-
catalysed folding step formation benzoin-type crosslinks.
A B C
Figure 4.3. A) SEC traces (in DMF with 10 mM NH4BF4) of SCNP 5 (blue line) obtained via
intramolecular cross-linking of coPIL 2 (red line) by self-catalysis (UV detector). B) DLS analysis of
coPIL 2 (red line) and SCNP 5 (blue line) diameters at 20 °C distributed by volume in THF (conc. 1 mg
mL-1). C) TEM images of SCNP 5 (conc. 1 mg mL-1 in methanol) stained with uranyl acetate. Scale bar
= 20 nm.
181
Figure 4.4. Hydrodynamic diameter-temperature correlation obtained for SCNP 5 by variable
temperature dynamic light scattering (DLS) in THF (Conc.: 1 mg mL-1; 173° back-scattering detector;
average value of 4 runs is reported along with the error corresponding to the standard deviation in the
measurements; solid red line corresponds to values obtained for the volume distribution, whilst the solid
black refers to the number distribution).
4.4 Transesterification reaction catalysed by SCNP 5
As SCNPs 5 thus formed still contains benzimidazolium acetate units, they were in turn
evaluated as masked NHCs. This was first achieved through their post-functionalisation by
insertion of CS2, generating polybetaine 6. Thus, the reaction mixture in THF turned orange
upon heating 5 in the presence of CS2 after 24 h. The characteristic signal of functionalised C2imi
13
at 153.1 ppm (Fig. S4.9) was again present in the C NMR spectrum of 6, although it was
hardly detected likely because of the confined environment provided by SCNP 6. In contrast,
the COOH proton of the acetic acid by-product released during the functionalisation step was
detected in the 1H NMR spectrum, appearing at 12.5 ppm (Fig. S4.10). Formation of
polybetaine 6 was further confirmed by FT-IR spectroscopy with the appearance of the
asymmetric vibration of CS2- at 1030 cm-1 (Fig. 4.5). These results highlight that thermally
latent NHC units remain active after the folding step.
Figure 4.5. FTIR spectrum of SCNP 5 (in red) and NHC-CS2 functionalised SCNP 6 (in blue) showing
the appearance of the characteristic vibrational signal of CS2- (at ~1030 cm-1) when forming the betaine.
The activity of SCNPs 5 was next tested in another NHC-mediated organocatalysis application,
namely, the transesterification reaction between vinyl acetate and benzyl alcohol. This was first
182
achieved in THF using 1 eq. of benzyl alcohol and a slight excess of vinyl acetate (1.2 eq.) as,
in presence of 1 mol.% of SCNP-supported masked NHCs 5. Under such conditions, only 6%
of benzyl alcohol was converted into benzyl acetate after 2 h (run 1; Table 4.1). Further
optimisation using a loading of the catalytic SCNP 6 equal to 5 and 10 mol.%, whilst
maintaining the concentration of reagents, allowed us to increase the conversion to 43% and up
to 69% respectively (run 2 and 3). For a comparison purpose, SCNP 5 was compared to a linear
statistical coPIL analogue 7 constituted of benzimidazolium acetate and styrene units, i.e.
poly(styrene-co-4-vinylbenzylethylbenzimidazolium acetate) and to the 4-vinylbenzimidazole
ethylimidazolium acetate monomer 8, serving as molecular model. Both the molecular and
macromolecular models were assessed for the transesterification reaction under the same
catalysis conditions as SCNP 5. Faster catalysis kinetics was observed from coPIL 7 compared
to SCNP 5 (Fig. 4.6B), providing faster kinetics and higher conversions upon increasing the
pre-catalyst loading (almost quantitative conversion was noted for 5 and 10 mol.% vs. 42% for
1 mol.% runs 5 and 6 and run 4, respectively). In comparison, almost quantitative conversions
were obtained using 1, 5 and 10 mol.% catalyst loading of the molecular model after only 2 h
(runs 7-9).
Table 4.1. Transesterification between benzyl alcohol and vinyl acetate under different reaction
conditions using masked NHC-containing SCNPs and control experiments.
183
Run Catalyst Cat. (mol.%) Conv(a) (%)
1 SCNP 5(b) 1 6
2 SCNP 5 5 43
3 SCNP 5 10 69(c)
4 7(d) 1 42
5 7 5 97
6 7 10 >99
7 8(e) 1 96
8 8 5 93
9 8 10 >99
10 SCNP 5(f) 10 0
11 Copolymer 2 10 0
12 Potassium Acetate 10 <2
13 -(g) 0 0
a
The reaction was run for 2 h and conversions were calculated by 1H NMR spectroscopy comparing
conversion by comparing the integral value of the -CH2- benzyl alcohol signal (d, 2H, 4.5 ppm) to that
of the -CH2- benzyl acetate signal (d, 2H, 5 ppm) by 1H NMR spectroscopy in DMSO-d6 (Fig. S4.13-
24). b THF was used as solvent and dried under Na/benzophenone prior to use in each catalytic run being
0.015 mmol mL-1 reference catalyst concentration referred to benzimidazolium at 10 mol.%. c
The
conversion barely increased duplicating the reaction time up to 4 h of reaction obtaining ca.70%
conversion. d Linear model 7 containing randomly ordered spacers and active monomer units in a 84/16
ratio. e Active monomer based molecular model 8. f The same conditions as in run 1 were used running
the experiment at rt instead of 80 °C. g This reaction was performed only using benzyl alcohol (1 eq.)
and vinyl acetate (1.2 eq.) for 2 h at 80 °C. The results correspond to the average value obtained after
two different runs for each reaction.
184
A
Figure 4.6. Kinetics for transesterification reaction at 1 mol.% (blue line), 5 mol.% (red line)
and 10 mol.% (black line) using A) SCNP 5, B) 7 and C) 8 as catalysts.
185
In light of these comparative investigations of the three different catalytic systems (SCNP 5 vs.
coPIL 7 and monomer 8), higher conversions and faster rates observed with both the molecular
and the linear coPIL models suggest that the microenvironment provided by SCNP 5 somehow
restricts the catalytic activity of supported-NHCs relatively to both the linear and molecular
models. 5,44–47 As expected, no organocatalytic activity was noted at room temperature, while
the transesterified reaction product formed upon heating, demonstrating the thermal latency of
SCNP 5 (run 3 vs. run 10). Despite the fact that SCNP 5 did not improve the catalytic
performance of the transesterification reaction, it has been shown that the catalytic activity of
the NHC is retained within the compact core of the 3D-SCNP.
4.5 Conclusions
In this work, the modularity of PIL chemistry has been further exploited to design individual
linear copolymer chains by RAFT, combining thermally latent and autonomous NHC
behaviour, i.e. in absence of any external reagent, and the capability to self-catalyse some
substrate units immobilized on these chains. These unique features can be exploited to achieve
SCNPs by self-NHC-organocatalysed folding of the individual chains, as evidenced by
different analytical techniques, including SEC, TEM, DLS and DOSY NMR. To this end, 3-
vinylbenzaldehyde, styrene and 4-vinylbenzylethylbenzimidazolium chloride were randomly
copolymerised using the RAFT process, resulting in a well-defined but catalytically inactive
coPIL support. Installation of a slightly basic acetate counterion by anion metathesis imparts
the catalytic activity and thermally latent behaviour to the coPIL precursor. The self-catalysed
folding process lead to the formation of SCNPs occurs by the formation of covalent cross-links
through the benzoin condensation of benzaldehyde moieties. The as-obtained SCNPs retain
their NHC behaviour, as demonstrated not only through the trapping of CS2, but also by the
possibility to further catalyse the transesterification reaction between vinyl acetate and benzyl
alcohol. Comparison with both a molecular and a linear coPIL catalyst homologues show
however that the confined environment provided by the SCNPs does not improve the
organocatalytic performance. Efforts to tune the catalytic environment of the SCNPs, by
varying the cross-linking density, is currently in progress. Overall, this study highlights the
186
versatility of thermally-latent NHC catalysts, demonstrating their use as a novel trigger for the
folding of catalytically active SCNP nanoreactors.
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189
Synthesis of monomer 1: Synthesis of 4-vinylbenzylethylbenzimidazolium chloride

([ViEBIm]Cl). N-Ethylbenzimidazole was synthesised according to the previously reported
procedure from Taton, O’Reilly et al.19,33 Benzimidazole (5 g, 42.32 mmol, 1 eq.) was first
dissolved in DMF (20 mL), potassium hydroxide was then added (4.75 g, 106 mmol, 2.5 eq.).
The solution was stirred for 30 minutes before the drop-wise addition of ethyl bromide (3.45
mL, 46.55 mmol). After stirring at room temperature for 24 h, the reaction mixture was diluted
using H2O (50 mL), the aqueous phase was then extracted with dichloromethane (4 x 25 mL).
The organic phases were combined, dried over MgSO4 and evaporated, yielding N-
ethylbenzimidazole as a viscous yellow oil (4.93 g, 33.8 mmol, 80% yield) 1H NMR (DMSO-
d6): δ = 8.25 (s, 1H, N-CH-N), 7.69-7.20 (m, 4H, aromatics), 4.12 (t, 2H, N-CH2-CH3), 1.32 (t,
3H, -CH3).
A portion of N-ethylbenzimidazole (4.65 mL, 31.8 mmol, 1 eq.) was then dissolved in
acetonitrile (20 mL) within a Schlenk tube, this was immediately followed by the addition of
4-vinylbenzylchloride (4.82 g, 31.8 mmol, 1 eq.) After stirring for 24 h at 80 °C, the crude
reaction mixture was precipitated into ethyl acetate (20 mL) and dried under vacuum to remove
the solvent, yielding the target monomer 4-vinylbenzylethylbenzimidazolium chloride as a
white powder (8.64 g, 28.9 mmol, yield = 91%). 1H NMR (DMSO-d6): δ = 9.7 (s, 1H, N-CH-
N), 8.12-7.1 (m, 8H, aromatics), 6.7 (dd, 1H, Ph-CH-CH2), 5.9 (s, 2H, Ph-CH2-N), 5.8 (d, 1H,
CH=CH2), 5.2 (d, 1H, CH=CH2), 4.2 (dd, 2H, N-CH2-CH3), 1.3 (t, 3H, -CH2-CH3).
Characterisation matches that previously reported in the literature.19,33
Synthesis of linear copolymer 2. 2-Cyano-2-propyl benzodithioate (43 mg, 0.19 mmol) as a

chain transfer agent (CTA), styrene (2.4 mL, 23.6 mmol), 4-vinylbenzylethylbenzimidazolium
chloride (1.18 g, 3.93 mmol), 3-vinylbenzaldehyde (1.5 mL, 11.8 mmol) and AIBN (31 mg,
0.19 mmol) were dissolved in 12 mL of DMF. The solution was purged with nitrogen for 30
min and stirred for 12 h at 80 °C. The as-obtained copolymer was purified by dialysis against
methanol (1 L x 2 every 24 h, MWCO 3.5 kDa membrane) and the solvent was removed under
reduced pressure, yielding copolymer 2 as a pink powder (1.6 g, yield = 31%). 1H NMR
(DMSO-d6): δ = 10.9-10.1 (br, 1H, N=CH-N), 9.9-9.6 (br, 3H, H-CO-), 8.2-6.1 (br, 53.1 H, Ar-
), 5.9-5.5 (br, 2H, Ar-CH2-N), 4.7-4.5 (br, 2H, N-CH2-CH3, 2.2-0.9 (br, 30.2 H, backbone, CH2-
190
CH3) (Fig. 4.1). 13C NMR (DMSO-d6): δ = 193.1, 147.6-143.9, 142.7, 136.6-124.8, 114.2, 80.1,
42.9, 14.4 (Fig. S4.1). SEC analysis: ĐM = 1.2; Mn = 11.9 kDa.
Synthesis of linear copolymer 3. Copolymer 2 (1 g, 0.095 mmol) was dissolved in 12 mL of

methanol and 3 mL of chloroform in a round-bottom flask. Potassium acetate (0.15 g, 1.15
mmol) was added and the reaction mixture was stirred overnight at room temperature. The
solution was filtered and purified by dialysis against methanol/ethanol (75:25, 1 L x 2 every 24
h, MWCO 3.5 kDa membrane). The solvent was removed under reduced pressure, yielding
copolymer 3 as a yellow powder (0.93 g, yield = 92%). 1H NMR (DMSO-d6): δ = 10.5-9.6 (br,
4H, H-CO-, N=CH-N), 8.2-6.1 (br, 53.1 H, Ar-), 5.8-5.5 (br, 2H, Ar-CH2-N), 4.7-4.5 (br, 2H,
13
N-CH2-CH3, 2.2-0.9 (br, 36.4 H, backbone, O=C-CH3, CH2-CH3) (Fig. S4.2). C NMR
(DMSO-d6): δ =193.1, 176.6, 147.6-143.9, 143.7, 136.6-124.8, 114.2, 80.1, 59.8, 42.9, 24.4,
14.4 (Fig. S4.3).
Synthesis of linear copolymer 4. Copolymer 3 (80 mg, 0.008 mmol) was first azeotropically
dried in THF. The sample was then heated at 80 °C for 24 h in THF (3 mL) in presence of CS2
(0.6 mL). The solvent and excess of CS2 were removed under reduced pressure, yielding
copolymer 4 as a red viscous oil. (Yield >95%). 1H NMR (DMSO-d6): δ = 12.2-12.0 (br, 0.5
H, -COOH), 10.5-9.6 (br, 1H, H-CO-), 8.2-6.1 (br, 34.2 H, Ar-H), 5.8-5.4 (br, 2H, Ar-CH2-N),
4.4-4.2 (br, 2H, N-CH2-CH3, 2.2-0.2 (br, 32.6 H, backbone, HOOC-CH3, -CH2-CH3) (Fig.
S4.25). 13C NMR (DMSO-d6): δ = 224.1, 193.1, 174.4, 153.1, 147.6-143.9, 141.3, 136.6-124.8,
114.2, 110.1, 71.1, 52.3, 24.4, 13.7 (Fig.4.2).
Synthesis of SCNP 5. Copolymer 3 (150 mg, 0.015 mol) was dissolved in 150 mL of dry THF
and heated to 80 °C in a 1 L Schlenk flask for 48 h. The solvent was removed under reduced
pressure and the resulting material was dialysed against methanol (1 L x 2 every 24 h, MWCO
3.5 kDa membrane) producing SCNP 5 (130 mg, yield = 87%). 1H NMR (DMSO-d6): δ = 12.0-
11.8 (br, 1H, N=CH-N), 10.1-9.7 (br, 1.2 H, O=C-H), 8.3-5.8 (br, 47.5 H, Ar-H), 5.4 (s, 0.3 H,
O=C-CHOH-Ar), 4.2 (s, 0.25 H, O=C-CHOH-Ar), 4.05 (s, 0.15 H, N-CH2-CH3), 2.2-0.2 (br,
50.2 H, backbone, O=C-CH3, -CH2-CH3) (Fig. S4.4). 13C NMR (DMSO-d6): δ = 179.3, 172.6,
153.1 147.6-143.9, 140.0, 132.1-122.6, 97.6, 80.7, 67.9, 53.3, 42.9, 24.4, 14.4 (Fig. S4.5). SEC
analysis: ĐM = 1.2; Mn =10.8 kDa.
191
Synthesis of SCNP 6. SCNP 5 (35 mg, 0.003 mmol) was dissolved in THF (2 mL) in presence
of a large excess of CS2 (0.4 mL) in a Schlenk tube for 24 h at 80 °C. Yield > 95%. 1H NMR
(DMSO-d6): δ = 12.9-12.3 (br, 0.4 H, -COOH), 10.4-9.6 (br, 1H, H-CO-), 8.3-5.9 (br, 40.8 H,
Ar-H),5.4 (s, 0.2 H, , O=C-CHOH-Ar), 5.2-5.0 (br, 0.5 H, Ar-CH2-N), 4.4-4.2 (br, 0.4 H, O=C-
CHOH-Ar) 2.3-0.2 (br, 51.2 H, backbone, HOOC-CH3, -CH2-CH3) (Fig. S4.10). 13C NMR
(DMSO-d6): δ = 193.3, 168.8, 153.1, 152.0, 147.6-143.9, 139.9, 135.1-122.6, 109.6, 97.6, 80.7,
67.9, 42.9, 24.4, 19.4 (Fig. S4.9).
Synthesis of the model polymer 7. 2-Cyano-2-propyl benzodithioate CTA (30 mg, 0.13
mmol), styrene (2.34 mL, 20.4 mmol) and monomer 1 (0.68 g, 2.26 mmol) were added to a 20
mL glass tube. Methanol (12 mL) was added and the suspension was allowed to stir for 10 min
until a homogenous solution was obtained. AIBN (27 mg, 0.11 mmol) was added to the
methanolic solution under dry nitrogen at room temperature. After mixing and purging the
solution with dry nitrogen, the glass tube was sealed and placed at 80 °C in an oil bath for 16
h. After this time, 52% conversion was reached, as evidenced by 1H NMR spectroscopy. The
reaction was then quenched by cooling the solution to room temperature. The crude copolymer
was purified by dialysis against methanol (1 L x 2 every 24 h, MWCO 3.5 kDa membrane).
The obtained copolymer (0.9 g) was solubilised in methanol and subjected to anion exchange
by adding potassium acetate (0.65 g, 10 eq.) to the solution and then further dialysed against
methanol (1 L x 2 every 24 h) using a 3.5 kDa MWCO dialysis membrane. Yield = 40%. 1H
NMR (DMSO-d6): δ = 11.5-10.2 (br, 1H, N=CH-N), 8.2-6.1 (br, 30.1 H, Ar-), 5.9-5.5 (br, 2H,
Ar-CH2-N), 4.7-4.5 (br, 2H, N-CH2-CH3), 2.2-0.9 (br, 10.6 H, backbone, O=C-CH3, CH2-CH3)
(Fig. S4.11). SEC analysis: ĐM = 1.1; Mn =12.7 kDa (Fig. S4.12).
Synthesis of molecular model 8. Monomer 1 (0.25 g, 0.83 mmol, 1 eq.) was first solubilised
in methanol (2 mL). Potassium acetate (0.1 g, 1 mmol, 1.2 eq.) was then added and the reaction
carried out at room temperature with stirring for 16 h. The solution was then filtered to remove
1
the KCl side-product and the filtrate dried under reduced pressure. Yield >95%. H NMR
(DMSO- d6): δ = 10.9-10.1 (br, 1H, N=CH-N), 9.9-9.6 (br, 3H, H-CO-), 8.2-6.1 (br, 53.1 H,
Ar-), 5.9-5.5 (br, 2H, Ar-CH2-N), 4.7-4.5 (br, 2H, N-CH2-CH3, 2.2-0.9 (br, 30.2 H, backbone,
CH2-CH3). Characterisation matches that reported in the literature.3
General procedure for the transesterification reaction. In a 10 mL glass tube, different

catalysts were first azeotropically dried using distilled THF. Dry THF was then added,
192
maintaining a reference catalyst concentration of 0.015 mmol mL-1 referred to benzimidazolium
moieties. The solution was stirred, and previously distilled benzyl alcohol (1 eq.) and vinyl
acetate (1.2 eq.) were added under nitrogen. The resulting mixture was stirred under nitrogen
at 80 °C for 2 h. The reaction kinetics were monitored by extracting aliquots every 15 min and
calculating the conversion by comparing the integral value of the signal due to the -CH2- group
of benzyl alcohol (d, 2H, 4.5 ppm) to that of the -CH2- benzyl acetate signal (d, 2H, 5 ppm) by
1
H NMR spectroscopy in DMSO-d6 (Fig. S4.13-S4.24).
Figure S4.1. 13C NMR spectrum of copolymer 2 in DMSO-d6.
193
Figure S4.2. 1H NMR spectrum of copolymer 3 in DMSO-d6
Figure S4.3. 13C NMR spectrum of copolymer 3 in DMSO-d6.
194
Figure S4.4. 1H NMR spectrum of SCNP 5 in DMSO-d6.
Figure S4.5. 13C NMR spectrum of coPIL 5 in DMSO-d6.
The multiplicity-edited HSQC NMR spectrum was used to confirm the incorporation of the
benzoin moiety into SCNP 5, with a clear coupling observed between the signal at ~5.4 ppm
and the tertiary carbon corresponding to the –CH– of the benzoin bridge.
195
Figure S4.6. Representative multiplicity-edited HSQC spectrum of SCNP 5 in DMSO-d6, with
tertiary and primary carbons identified in blue, and quaternary and secondary carbons identified
in red.
Figure S4.7. Representative FTIR spectrum of SCNP 5 (in black), linear polymer 3 (in red) and
linear polymer 2 (in blue).
Diffusion Ordered Spectroscopy (DOSY). The folded SCNP and the linear copolymer were
distinguished according to their diffusion coefficients as determined by DOSY NMR
spectroscopy, which correlates their hydrodynamic radius to their relative rates of diffusion
through DMSO-d6. Full details for the experimental conditions used for DOSY NMR
spectroscopy can be found within the experimental of the main article. Calculation of the
196
hydrodynamic radius and therefore the diameter was done so by applying the Stokes-Einstein
equation.
Stokes-Einstein equation:
𝑘𝑇
𝐷=
6𝜋𝜂𝑟
k = 1.38.10−23 J K-1
D = 3.14.10-11 m2 s-1
T = 298 K
𝛈 DMSO viscosity = 1.99. 10-3 Pa s
R (polymer 5) = 1.15 nm; D = 2.3 nm
R (polymer 2) = 3.3 nm; D = 6.6 nm
[m2/s*1e-9]
A
Sol vent
0.5
tra ces
1.0
-11 2 -1
DD==3.34
3.34xx 10
10-11 m s
m2/s D = 9.57 x 1
10 8 6 4 2 ppm 10
B
[m2/s*1e-9]
[m2/s*1e-9]
0.5
0.5
Sol vent
tra ces
1.0
1.0
-11 m
DD==9.57
9.57 x 10
10-11 m22s/s-1
2 ppm 10 8 6 4 2 ppm
197
Figure S4.8. DOSY NMR spectroscopy in DMSO-d6 for linear precursor 2 (A) and folded
SCNP 5 (B).
Figure S4.9. 13C NMR spectrum of SCNP 6 in DMSO-d6.
Figure S4.10. 1H NMR spectrum of SCNP 6 in DMSO-d6.
198
ab
Ar Ar
c f g
d g
Ar e
e
Ar MeOH DMSO
c
d MeOH a, b
f
Figure S4.11. 1H NMR spectrum of linear model 7 in DMSO-d6.
Figure S4.12. SEC trace corresponding to (bis(trifluoromethane)sulfonimide) TFSI-decorated

linear model 7 in DMF (10 mM NH4+BF4-; UV detector; SEC analysis: ĐM = 1.1; Mn =12.7
kDa).
199
Transesterification reaction
a g
Ar b de Ar h
c f i
t = 120 min
t = 105 min
t = 90 min
t = 75 min
t = 60 min
t = 45 min
t = 30 min
g t = 15 min
i h
a THF t=0h
Ar e b dc f THF
Figure S4.13. Reaction kinetics for run 1 (Table 4.1) monitored by 1H NMR spectroscopy in
DMSO-d6.
a g
Ar b de Ar h
c f i
t = 120 min
t = 105 min
t = 90 min
t = 75 min
t = 60 min
t = 45 min
t = 30 min
i g h t = 15 min
Ar e a THF f THF t=0h

b dc
200
DMSO-d6.
a g
Ar b de Ar h
c f i
t = 120 min
t = 105 min
t = 90 min
t = 75 min
t = 60 min
t = 45 min
t = 30 min
g h t = 15 min
i
Ar e d c a THF f THF t=0h

b
DMSO-d6.
201
a g
Ar b de Ar h
c f i
t = 120 min
t = 105 min
t = 90 min
t = 75 min
t = 60 min
t = 45 min
t = 30 min
i g h t = 15 min
a THF THF t=0h

Ar e b dc f
DMSO-d6.
202
a g
Ar b de Ar h
c f i
t = 120 min
t = 105 min
t = 90 min
t = 75 min
t = 60 min
t = 45 min
t = 30 min
g t = 15 min
i h
a THF THF
Ar e b dc f t=0h
DMSO-d6.
203
a g
Ar b de Ar h
c f i
t = 120 min
t = 105 min
t = 90 min
t = 75 min
t = 60 min
t = 45 min
t = 30 min
g t = 15 min
i h
a THF THF
Ar e b dc f t=0h
DMSO-d6.
204
a g
Ar b de Ar h
c f i
t = 120 min
t = 105 min
t = 90 min
t = 75 min
t = 60 min
t = 45 min
t = 30 min
g
i h t = 15 min
Ar e dc a THF f THF t=0h

b
DMSO-d6.
205
a g
Ar b de Ar h
c f i
t = 120 min
t = 105 min
t = 90 min
t = 75 min
t = 60 min
t = 45 min
t = 30 min
g
i h t = 15 min
Ar e dc a THF f THF t=0h

b
DMSO-d6.
a g
Ar b de Ar h
c f i
t = 120 min
t = 105 min
t = 90 min
t = 75 min
t = 60 min
t = 45 min
t = 30 min
i g h t = 15 min
a THF
Ar e b d c f THF
t=0h
206
DMSO-d6.
a g
Ar b de Ar h
c f i
b d c
Ar
a THF f
THF
e b d c H2O DMSO
DMSO-d6.
207
a g
Ar b de Ar h
c f i
a
d c
b
g
Ar f THF
THF H2O
a
e b d c DMSO
DMSO-d6.
a g
Ar b de Ar h
c f i
d c
b
H2O
THF
Ar f
a THF DMSO
c
e b d
DMSO-d6.
208
Figure S4.25. 1H NMR spectrum of copolymer 4 in DMSO-d6.
209
Chapter V: Catalytically Active N-Heterocyclic
Carbene Release from Single-Chain Nanoparticles
following a Thermolysis-driven Unfolding Strategy
210
211
Table of Contents
Chapter V: Catalytically Active N-Heterocyclic Carbene Release from Single-Chain

Nanoparticles following a Thermolysis-driven Unfolding Strategy
5.1. Abstract……………………………………………………………………..…………..213
5.2. Introduction………………………………………………………………..………214-215
5.3. Synthesis of catalytically-active SCNPs…………………………………...………216-220
5.4. NHC-mediated benzoin condensation reaction………………………….…...……220-223
5.5. Conclusions…………………………………………………………..…………………223
5.6 References…………………………………………………………...………..…….224-227
5.7. Experimental Section…………………………………………...………………….228-239
212
5.1 Abstract
The need for efficient, tailor-made catalysts has inspired chemists to design synthetic
macromolecular architectures for selective catalysis. To this purpose, we report herein the
synthesis and in-depth characterization of Ag(I)-crosslinked single-chain nanoparticles
(SCNPs) and demonstrate their application as catalysts. Specifically, a copolymer of styrenic
benzimidazolium chloride was synthesized as a linear precursor via RAFT polymerisation.
Metalation of the benzimidazolium moieties by Ag(I) resulted in the intramolecular cross-
linking of single chains via the formation of Ag-NHC (silver-N-heterocyclic carbene) linkages
under dilute conditions. The successful formation of well-defined, robust SCNPs was evidenced
by size-exclusion chromatography, dynamic light scattering, nuclear magnetic resonance, and
transmission electron microscopy. Finally, we demonstrate that our Ag-SCNPs can be used as
NHC pre-catalysts, by firstly indirectly evidencing the formation of the corresponding unfolded
NHC-CS2 polybetaine and then organocatalysing a benzoin condensation reaction.
Ag2O
-H2O
213
5.2 Introduction
Stable N-heterocyclic carbenes (NHCs) have become an fascinating area of research since their
discovery by Arduengo in 1991.1 Specifically, their peculiar electronic and steric properties
make them powerful ligands of transition metals,2–6 while their inherent nucleophilicity7 and
Brønsted-basicity8 account for their efficient performance as organocatalysts for both
molecular9 and macromolecular transformations.10–12 To overcome their air and moisture
sensitivity, a variety of masked NHCs, including NHC-CO2 adducts, NHC-2-alkoxy adducts or
NHC-Ag have been developed.11–17 Interestingly, silver complexes represent a versatile class
of labile NHC metal complexes because of the relative weakness of the C2-Ag bond.18 The most
popular route to obtain Ag(I)-NHC compounds uses Ag2O, allowing the direct conversion of
imidazolium salts (ionic liquids; ILs) into the corresponding metal complexes by
transmetalation reaction. Thus, in comparison to the approaches used to produce Zn- and Sn-
NHC complexes,19 the free carbenes do not interfere with the synthesis of Ag(I)-NHC, allowing
to achieve good yields using standard laboratory techniques.6,11,13,20,21
Moreover, thanks to the easy accessibility and high versatility of NHCs, several functionalized
architectures can be achieved from Ag(I)-NHC complexes for different applications, such as
antibacterial agents 18,22 or catalysis.23–26 In particular, a promising synthetic strategy inspired
by nature has emerged to prepare unimolecular versatile nano-objects referred to as single-chain
nanoparticles (SCNPs).27–31 Indeed, these folded/collapsed soft nanostructures have gained
increasing attention for the development of functional materials in the fields of nanomedicine,
protein mimicry, and catalysis.30–34 In the catalysis field, the design of supported organometallic
catalysts aims to emulate the unique features of (metallo)enzymes, such as structural
complexity, compartmentalized functions, and site isolation.33,35–39 Previous work in the area
has typically focused on the formation of SCNPs by hydrogen or covalent bonding between
supported orthogonal functions.34 More recently, coordination chemistry, where metals act as
cross-linkers inducing the single-chain particle formation, has been developed.33,40–44,44
Surprisingly, the ability of Ag to trigger the single-chain folding of catalytically active SCNPs
remains unexploited despite the potential of Ag(I)-NHC complexes to generate free NHCs and
undergo transmetalation.30
Herein, we report for the first time the formation of Ag-SCNPs obtained by cross-linking
benzimidazolium moieties using Ag(I) as metalation agent. Upon heating, the free carbene can
214
be released from the Ag-NHC precursors, thus enabling free NHC to catalyse the benzoin
condensation in THF. The generation of NHC-CS2 betaine resulting from the reaction between
Ag-SCNPs and CS2 provided indirect evidence of free NHC formation upon thermal-triggered
unfolding of SCNPs. Therefore, our Ag-SCNPs combine the unique properties of Ag-NHC
complexes with the SCNP technology to create versatile and functional nanoparticles for
catalytic applications.
Ag2O THF , 80 C
CH2Cl2 r.t. -2AgCl
Scheme 5.1. Folding of a single-chain polymer into a nanoparticle structure via addition of a metal ion
source (i.e. Ag2O). These SCNPs are then employed as sources of free NHC upon thermal
decomposition of the organometallic Ag-NHC bond in the nanoreactor to form an active catalyst species.
215
5.3 Synthesis of catalytically-active SCNP
The 4-vinylbenzylethylbenzimidazolium chloride (1) ionic liquid monomer was prepared

following a two-step synthesis (Scheme 5.2), as previously reported in the literature.45–48 A
random copolymer of monomer 1 and styrene units was then obtained via reversible addition-
fragmentation chain-transfer (RAFT) polymerisation, using 2-cyano-2-propyl dodecyl
trithiocarbonate as chain transfer agent (CTA) and azobisisobutyronitrile (AIBN) as radical
source in methanol to yield copolymer 2. The monomer conversion was quantified via 1H NMR
spectroscopy by following the disappearance of the C(H) signals of styrene and 1, as well as
the broadening of CHimi in the polymer. Moreover, the consumption of styrene and 1 in similar
ratio indicates that the imidazolium functional groups were homogenously distributed
throughout the chains. The final structure of 2 corresponded to a styrene/benzimidazolium ratio
of ~5, as confirmed by 1H NMR spectroscopy (Fig. S5.1), which was selected to increase the
solubility of 2 and its derivatives (i.e. 3, 4 and 5) in relatively apolar solvents, such as THF.
Scheme 5.2. Synthesis of copolymer 2 via RAFT polymerization of styrene and 1 in methanol. The
subsequent addition of Ag2O results in the formation of 3 as SCNPs. Further anion exchange was
performed by inserting a non-coordinating anion (NTf2-) into 3 to confer less dynamic behavior (4).
216
In contrast to previous works where the preparation of imidazolium-based SCNPs involved
harsh reaction conditions45 and tedious purification steps,52 our approach affords robust NHC-
loaded SCNPs under relatively mild conditions. The controlled intramolecular formation of
SCNPs (4) was achieved by simply adding Ag2O to a solution of copolymer 3 (1 mg.mL-1) in
dichloromethane at rt. Trapping the produced H2O with molecular sieves (4 Å) afforded a better
yield of 3.26 Interestingly, the insolubility of Ag2O in dichloromethane provided a means of
monitoring the reaction progress by observing its gradual disappearance, as a consequence of
its incorporation in the copolymer structure. The folding of 2 was thus monitored through the
disappearance of the C2H signal corresponding to the benzimidazolium ( = 10.2 ppm), as well
as the broadening of the N-ethyl signals ( = 4.55 ppm) by 1H NMR spectroscopy (Fig. 5.1A).
After 72 h, full conversion to the Ag-NHC moieties ( = 10.7-10.1) was also confirmed by 13C
NMR spectroscopy with the complete disappearance of the C2H signal from benzimidazolium
at  = 146.7 ppm, and the observation of a new signal at  = 188.8 ppm corresponding to C-Ag
(Fig. 5.2 and S5.4). In addition, SEC characterization was used to further confirm the folding
of 2 into well-defined SCNPs (3). Specifically, in comparison to 2 (Mn = 18,000 g mol-1, ĐM =
1.2), the SEC trace of 3 shifted towards a smaller apparent molecular weight (Fig. 5.1B, Mn =
17,600 g mol-1, ĐM = 1.2), which is indicative of the formation of a more compact structure
with a smaller hydrodynamic radius, compared to the linear polymer. As a consequence of the
poor solubility of 2 in THF (with added salt for SEC analysis), it was not possible to directly
compare the apparent molecular weight in the same solvent as catalysis is performed. Finally,
mean hydrodynamic diameters of 4.5 ± 0.4 nm (number-weighted size distribution) and 4.8 ±
0.7 nm (volume-weighted size distribution at a concentration of 1 mg mL-1 of polymer sample)
were determined by DLS for 3 (Fig. S5.11), in excellent agreement with the size (ca. 5 ± 1.5
nm) observed by transmission electron microscopy (TEM) (Fig. 5.1C).
In order to confirm the thermolability of the Ag-NHC crosslinking bridges present in 3, the
variation in size distribution of the SCNPs with temperature was monitored by DLS analysis.
Interestingly, the size of SCNPs 3 increased notably, from 15 nm to 70 nm, at ~ 40 ºC
(Fig.5.1D), likely as a consequence of intermolecular rearrangements into larger aggregates
after disassembly.20 In fact, the silver-carbene bond, which is the weakest among the noble
metals (i.e. gold > copper > silver), is subjected to dynamic exchange, especially when the steric
hindrance is less pronounced.6 Furthermore, in Ag-NHC complexes, both the nature of the
azolium anion and the solvent also play an important role in the bond strength, as coordinating
217
anions, such as halides (e.g. Cl-, Br-, I-), form stronger hydrogen bonds compared to non-
coordinating anions (e.g. BF4-, NTf2-).53–55 However, halides usually facilitate the dynamic
exchange in the resulting complexes via their reversible binding to the silver center, whereas
non-coordinating anions prevent such dynamic behavior, which leads exclusively to the
formation of cationic bis(NHC) complexes, i.e. crosslinked SCNPs.6 Hence, such dynamic
exchange behavior allows halide Ag-NHC complexes to generate free NHCs by thermolysis.
Conversely, the enhanced stability of Ag-NHC complexes with non-coordinating anions
prevents such dynamic process.6,56
218
A)
Ar
Ag2O
a b a
c
Ar
c
t=0h
2 3
t = 24 h
t = 72 h
b
5 4.5
Ar
11 10
c
a
b
11 10 9 8 7 6 5 [ppm]
B)
Linear Copolymer 3
SCNP 4
SCNP 5
13 14 15 16
Retention time (min-1)
C) D)
Diameter (nm)
Temperature (°C)
Figure 5.1. A) Ag-NHC complexation reaction monitored by 1H NMR spectroscopy (400 MHz; 298 K;
DMSO-d6) at different time points (t0 = blue line, 24 h = red line, 72 h = green line). B) SEC curves (in
219
DMF with 10 mM NH4BF4) of 2 (red line), 3 (blue line) and 4 (black line) using RI detector polystyrene
standard. C) TEM micrograph of SCNPs 4 (scale bar = 50 nm). D) Hydrodynamic mean diameter of
SCNPs 4 (blue line volume distribution; red line number distribution) using multi-temperature DLS
analysis from 20 ºC to 80 ºC in THF (Conc. 5 mg mL-1).
In addition to 3 which is stabilized by coordinatingAgCl2- anions, the more stable Ag-NHC

complex 4 bearing non-coordinating NTf2- anions, was prepared by applying a mild anion-
exchange to 3 using an excess of LiNTf2 salt that provided an efficient driving force to displace
Cl-, precipitating AgCl as a byproduct. SEC analysis of the resulting polymer showed a decrease
in apparent molecular weight (Fig. 5.1B, Mn = 17,300 g mol-1, ĐM = 1.2) which is most likely
a consequence of the strong preference of the NTf2— containing SCNPs to be retained as a
dimeric NHCAg complex and hence presenting a more compact hydrodynamic volume during
analysis.
5.4 NHC-mediated benzoin condensation reaction
Before investigating 3 as a catalyst for the carbene-mediated benzoin condensation reaction,57,58

we first examined whether active carbene species could be generated upon thermal
decomposition of the poly(bis-NHC)-silver complex in 3. For that purpose, 3 was heated at 80
ºC in THF in the presence of carbon disulfide (CS2; Scheme 5.3). After 24 h, the solution turned
red-brown, which was indicative of the formation of copolybetaine 5, as it was further
confirmed by 13
C NMR spectroscopy ( = 151.8 and 219.9 ppm corresponding to C2(imi) and
CS2- respectively; Fig. 5.2).20,21
A) Active NHC: B) Ag-NHC SCNP C) Organocatalysis:

NHC-CS2 formation Precatalyst Benzoin Condensation
Active NHC
220
Scheme 5.3. Application of SCNPs 3 as a catalytic platform (B) for the benzoin condensation reaction
by exposing active NHC upon heating (C) Indirect evidence of the formation of active NHC
intermediate (A).
Ar Ar
a
b
Ar a
b
Ar Ar b
Ar a Ar
b a
Ar Ar
Ar a Ar
a
a Ar Ar
a
Ar
[ppm] 220 200 180 160 140 120
Figure 5.2. 13C NMR spectra (100.7 MHz; 298 K; DMSO-d6) of 2 (blue), SCNP 3 (red), SCNP 4 (green),
and copolybetaine 5 (yellow).
Since the benzoin condensation is specifically catalyzed by carbenes,57,58 3 was evaluated as

pre-catalyst for this reaction (Scheme 5.3). Firstly, we tested the catalyst system at ambient
temperature which displayed no activity and hence confirms that no NHC catalyst (SCNP 3)
was delivered at room temperature (Run 1; Table 5.1). Therefore, although the thermolysis of
Ag-bis(NHC) complexes can occur at temperatures as low as 40 ºC,20 the temperature was set
at 80 ºC to increase the release of free NHCs. As summarized in Table 5.1, the conversion
increased from 13 to 32% by increasing the catalyst loading from 1 to 10 mol%, under otherwise
identical conditions (i.e. THF at 80 ºC for 24 h; Runs 2-4). However, increasing the reaction
time up to 48 h (Run 5) did not afford any improvement, suggesting the likely decomposition
of the catalyst at this temperature for longer than 24 h, as previously reported.6 This premature
deactivation also prevented the recycling of SCNP 3, as no catalytic activity was observed in
the subsequent run (6).
221
In order to introduce a control system, a small molecule model with benzylic N-substituents on
the NHC moieties, 6, (see ESI) was used to catalyze the benzoin condensation reaction under
similar conditions (Runs 7-9). This experiment showed higher catalytic activity, reaching up to
51% conversion of benzaldehyde after 24 h, probably because of the easier access to the
catalytic site (Run 7). Similarly, no further increase in conversion was observed after 48 h (Run
8), while the non-recyclability of the molecular model became further evident in the subsequent
run (9). It has to be acknowledged however, that both Ag-(bis)NHC based molecular and
macromolecular systems show lower catalytic performance for this reaction compared to our
previously reported masked-NHC based SCNPs.47,52
Finally, in good agreement with our initial hypothesis, the presence of non-coordinating
counteranions (i.e. NTf2-) in 4 hindered the formation of active carbenes, precluding the
formation of active catalytic species and thus preventing the synthesis of benzoin (Run 10).
Hence, the nature of the counteranion significantly influences the robustness and thermolability
of Ag-SCNPs to deliver catalytically active NHC in a suitable environment, hence highlighting
the potential to employ the anion exchange reaction as a successful strategy to switch on and
off the catalytic activity of this system.
Table 5.1. Condensation reaction of benzaldehyde under different conditions using Ag-NHC SCNPs
and a small molecule model as catalysts.
Run Catalyst Loading Cycle Solvent Temperature Time Conv

mol (%)a (ºC) (h) (%)b
1 SCNP 3 10 1 THFc 80 24 0
2 SCNP 3 1 1 THF 80 24 13
3 SCNP 3 5 1 THF 80 24 21
4 SCNP 3 10d 1 THF 80 24 32
5 SCNP 3 10 1 THF 80 48 32
6 SCNP 3 10 2e THF 80 24 0
7 6f 10 1 THF 80 24 51
8 6 10 1 THF 80 48 51
9 6 10 2g THF 80 24 0
222
10 SCNP 4 10 1 THF 80 24 0
a
Mol% calculated relative to the benzimidazolium moieties; b conversion was calculated by 1H NMR spectroscopy
(Fig. S5.10); c THF was dried over Na/Benzophenone before distillation; d a 20 mg mL-1concentration of catalyst
was used as reference; e 3 purified by dialysis against MeOH; f synthesis and characterization of the molecular
model used in this reaction is included in the ESI. ; g molecular catalyst was recovered by precipitation into cold
MeOH.
5.5 Conclusion
The formation of SCNPs crosslinked by Ag-NHC bridges has been achieved for the first time.
Ag was used as metalation agent to trigger the folding of a linear styrene-benzimidazolium
copolymer into 5 nm SCNPs under relatively mild conditions. These nanoreactors were able to
respond to external increase in temperature and unfold to release free NHC, which was then
able to catalyse the benzoin condensation reaction in the same pot, although in modest yield.
Furthermore, by simply changing the counterion, the catalytic activity can be switched off. In
conclusion, Ag-NHC SCNPs can be envisaged as a valuable nanoplatform for transmetalation
reactions.
223
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Materials
Methanol, benzimidazole (˃95%), 4-vinylbenzyl chloride (90%), ethyl bromide (99%), 2-

cyano-2-propyl benzodithioate (˃97%), potassium hydroxide (pellets), and benzyl chloride (97
%) were obtained from Aldrich and used as received. Dichloromethane (99.7%), carbon
disulfide (CS2), 2-Cyano-2-propyl dodecyl trithiocarbonate and (CTA) lithium
bis(trifluoromethane)sulfonylimide (LiTFSI) were obtained from Aldrich and used as received.
Azobis(2-methylpropionitrile) (AIBN, 99%) was received from Aldrich and was purified by
recrystallization (2x) from methanol. The synthesis of 4-vinylbenzylethylbenzimidazolium
chloride (1) was performed as previously described.45–48 The synthesis of 1,3-dibenzyl-1H-
benzimidazol-3-ium chloride was performed as described elsewhere.49,50 Tetrahydrofuran
(THF) was distilled over Na/benzophenone. Styrene and benzaldehyde were dried over CaH2
and distilled prior to use. All synthesized polymers were purified by dialysis against methanol
using “Standard Grade Regenerated Cellulose Dialysis Membranes (Spectra/Por6) Pre-wetted
RC tubing” (SpectrumLab) with a molecular weight cut off (MWCO) of 3.5 kDa. All polymers
were azeotropically dried using previously distilled THF before performing catalysis.
Polymerization, catalyst loadings, and catalysis experiments were carried out by the syringe
technique under dry argon in baked glass tubes equipped with a two-way stopcock.
Characterisation
1
H, 13C and 19F NMR spectra were recorded on a Bruker AC-400 spectrometer in appropriate
deuterated solvents. All 13C measurements were performed at 298 K on a Bruker Avance III
400 spectrometer operating at 400, 376.5 and 100 MHz and equipped with a 5 mm Bruker
multinuclear direct cryo-probe. Dimethyl formamide (10 mM ammonium tetrafluoroborate)
soluble polymers were first solubilized in concentrations of 1 mg mL-1, and their masses were
determined by size exclusion chromatography (SEC) in DMF at 20 °C using refractometric (RI)
detector (Varian) and polystyrene calibration as standards. Analyses were performed using a
three-column set of TSK gel TOSOH (G4000, G3000, G2000 with pore sizes 20, 75, and 200
Å, respectively, connected in series). Hydrodynamic diameters (Dh) and size distributions of
SCNPs were determined by dynamic light scattering (DLS) on a Malvern Zetasizer Nano ZS
operating at 20 °C with a 4 Mw He-Ne 633 nm laser module. Samples were filtered through a
0.22 µm PTFE filter prior to measurement, and quartz cuvettes were used. Measurements were
228
made at a detection angle of 173° (back scattering), and the data were analysed with Malvern
DTS 6.20 software, using the multiple narrow modes setting. All measurements were performed
in triplicate, with 10 runs per measurement. TEM analyses were performed on a JEOL 2011
(LaB6) microscope operating at 200 KeV, equipped with a GATAN UltraScan 1000 digital
camera. Conventional bright field conditions were lacey carbon-coated copper grids (Agar
Scientific, 400 mesh, S116-4). SCNP solutions were diluted to 1 mg mL-1 in MeOH before 4
µL of each sample were drop-deposited onto the graphene oxide coated grids and allowed to
air dry. Subsequent staining was applied using uranyl acetate (1 mg mL-1, 7 µL) to enhance the
contrast.51 Images were analyzed using Image J software, and 50 particles were measured to
produce a mean and standard deviation for the particle size (Dav).
Synthesis
Synthesis of 4-vinylbenzylethylbenzimidazolium chloride ([ViEBIm]Cl) (1)
Benzimidazole (5 g, 42 mmol, 1 eq.) was first dissolved in N,N-dimethylformamide (20 mL).

Potassium hydroxide (4.75 g, 106 mmol, 2.5 eq.) was then added and the solution stirred for 15
minutes before the drop-wise addition of ethyl bromide (3.45 mL, 46 mmol, 1.1 eq.). After
stirring at room temperature for 24 hours, the solution was diluted with water (50 mL) and
extracted with dichloromethane (4 × 25 mL). The organic phases were then combined, dried
over magnesium sulfate, and concentrated under reduced pressure, yielding N-
ethylbenzimidazole as a yellow viscous oil (yield: 80%, 4.93 g). 1H NMR (400 MHz; 298 K;
DMSO-d6): δ = 8.25 (s, 1H, N-CH-N), 7.69–7.20 (m, 4H, aromatics), 4.12 (t, 2H, N-CH2-CH3),
1.32 (t, 3H, -CH3).
A portion of N-ethylbenzimidazole (4.82 g, 33 mmol) was first dissolved in acetonitrile (25

mL) in a Schlenk tube, this was then followed by the addition of 4-vinylbenzylchloride (4.65
mL, 33 mmol, 1 eq.). After stirring for 24 hours at 80 °C, the crude reaction mixture was
precipitated into ethyl acetate and the resulting solid dried under reduced pressure, yielding the
monomer 1 (4-vinylbenzylethylbenzimidazolium chloride) as a white powder (yield: 91%, 8.87
g). 1
H NMR (400 MHz; 298 K; DMSO-d6): δ = 9.68 (s, 1H, N-CH-N), 8.12–7.14 (m, 8H,
aromatics), 6.72 (dd, 1H, Ph-CH-CH2), 5.95 (s, 2H, Ph-CH2-N), 5.76 (d, 1H, CH=CH2), 5.25
(d, 2H, CH=CH2), 4.15 (dd, 2H, N-CH2-CH3), 1.31 (t, 3H, -CH2-CH3). Characterisation is
consistent with that previously reported within the literature.45–48
Synthesis of copolymeric linear precursor 2.

229
2-Cyano-2-propyl dodecyl trithiocarbonate (60 mg, 0.17 mmol), styrene (3.1 mL, 30 mmol) 4-
vinylbenzylethylbenzimidazolium chloride 1 (1.57 g, 5.21 mmol), AIBN (27 mg, 0.17 mmol)
were dissolved in dry methanol in a 10 mL glass tube. The solution was degassed by five
successive freeze-pump cycles and stirred for 16 h at 80 °C. The as-obtained copolymer (2) was
purified by dialysis against methanol (3.5 kDa MWCO) and obtained as a pink powder (yield:
51%, 2.05 g). 1H NMR (400MHz; 298 K; DMSO-d6): 10.7-10.1 (br, 1H, N-CH=N), 8.2-6.1 (br,
32.8H, Ar-H), 5.9-5.5 (br, 2H, Ar-CH2-N), 4.6-4.4 (br, 2H, N-CH2-CH3), 2.1-0.9 (br, 27.5H,
13
backbone: CH and CH2, CH2-CH3) (Fig. S5.1); C NMR (100.7 MHz; 298 K; DMSO-d6):
146.7, 142.3, 132.9, 129.1-126.6, 114.1, 62.9, 50.8, 42.6, 14.3 (Fig. S5.2). SEC analysis: Mn =
18,000 g mol-1, Mw = 21,600 g mol-1, ĐM = 1.2
Synthesis of SCNP 3
Linear copolymer 2 (350 mg; 0.44 mmol referred to benzimidazolium) was dissolved in 350
mL of dry dichloromethane at a concentration of 1 mg mL-1 in a 1 L round bottom flask. Then,
Ag2O (60 mg; 0.26 mmol) was added by previously preparing a dispersion in dichloromethane
in order to ease the dropwise addition into the flask. Molecular sieves (4 Å) were added in order
to trap the generated water, shifting the equilibrium towards the bis-NHC-Ag moiety. The red
colored solution was stirred for 72 h, during which time the solution turned transparent, and
filtered twice to remove the excess of Ag2O. The solvent was finally removed under reduced
pressure, and 3 was obtained as a viscous liquid (yield: 82%, 322.1 mg). 1H NMR (400 MHz;
298 K; DMSO-d6) = 8.2-6.0 (br, 34.1, Ar-H), 5.9-5.4 (br, 2H, Ar-CH2-N), 4.6-4.3 (br, 2H, N-
CH2-CH3), 2.2-0.9 (br, backbone: CH and CH2, CH2-CH3) (Fig. S5.3); 13C NMR (100.7 MHz;
298 K; DMSO-d6): 188.8, 147.3, 134.0, 129.9-123.7, 113.5, 52.8, 47.7, 44.1, 17.9 (Fig. S5.4).
SEC analysis: Mn = 17,600 g mol-1, Mw = 21,100 g mol-1, ĐM = 1.2
Synthesis of SCNP 4
SCNP 3 (150 mg; 0.19 mmol) was solubilized in a glass flask containing 35 mL of methanol
and 80 mg (0.29 mmol) of LiTFSI previously dissolved in 35 mL methanol. The solution was
stirred at rt (room temperature) until SCNP 4 precipitated. The precipitate was then washed
with methanol (5 mL x 2) (yield: 48%, 77.8 mg).1H NMR (400 MHz; 298 K; DMSO-d6) = 8.3-
6.0 (m, broad, Ar-H), 6.0-5.5 (s, broad, Ar-CH2-N), 4.9-4.4 (d, broad, N-CH2-CH3), 2.3-0.9 (m,
broad, backbone: CH and CH2, CH2-CH3) (Fig. S5.5); 13C NMR (100.7 MHz; 298 K; DMSO-
d6): 179.8, 145.5, 132.3, 129.9-123.7, 121.5, 119.1, 112.4, 51.9, 43.8, 41.2, 17.8 (Fig. S5.6);
230
19
F NMR (376.5 MHz; 298 K; DMSO-d6): -79.9 (Fig. S5.7). SEC analysis: Mn = 17,300 g mol-
1
, Mw = 20,700 g mol-1, ĐM = 1.2
Synthesis of copolymer 5
SCNP 3 (30 mg; 0.04 mmol) was solubilized in dry THF (1 mL) in a glass tube and CS2 (0.3
mL; 2.6 mmol) was added at rt under argon. The colorless solution was stirred at 80 ºC for 24
h, during which time a color change to red was observed, indicative of NHC-CS2 formation.
After cooling, the excess of CS2 and solvent were removed under reduced pressure, obtaining
5 as a viscous liquid (yield: >95%, 27.3 mg). 1H NMR (400 MHz; 298 K; DMSO-d6) = 8.2-6.1
(m, broad, Ar-H), 5.9-5.5 (s, broad, Ar-CH2-N), 4.8-4.4 (d, broad, N-CH2-CH3), 2.5-0.9 (m,
broad, backbone: CH and CH2, CH2-CH3) (Fig. S5.8); 13C NMR (100.7 MHz; 298 K; DMSO-
d6): 219.9, 151.8, 145.4, 131.3-124.6, 112.8, 48.2, 43.2, 14.8 (Fig. S5.9).
Synthesis of molecular model 6
Benzimidazole (1 g, 8.5 mmol, 1 eq.) was first dissolved in N,N-dimethylformamide (5 mL).

Pottassium hydroxide (1.19 g, 21 mmol, 2.5 eq.) was then added and the solution allowed to
stir for 30 minutes before the drop-wise addition of benzyl chloride (1.1 mL, 9.4 mmol, [Add]
eq.). After stirring for 18 hours at room temperature, the solution was diluted with water (2 ×
10 mL) and extracted with dichloromethane (3 × 20 mL). The organic phases were combined,
dried over magnesium sulfate, and the solvent removed under reduced pressure, yielding N-
benzylbenzimidazole as yellow viscous oil (yield: 82%, 1.45 g). 1H NMR (400 MHz; 298 K;
DMSO-d6): δ = 8.2 (s, 1H, N=CH-N), 8.7–7.14 (m, 9H, aromatics), 5.5 (s, 2H, Ph-CH2-N)
A portion of N-benzylbenzimidazole (1 g, 4.8 mmol, 1 eq.) was first dissolved acetonitrile (5

mL) in a Schlenk tube, this was then followed by the addition of benzyl chloride (0.66 mL, 5.8
mmol, 1.2 eq.). After stirring for 24 hours at reflux, the crude reaction mixture was precipitated
into cold diethyl ether and the resulting solid dried under reduced pressure, yielding N,N-
bisbenzylbenzimidazolium chloride as a white crystals (yield: 94%, 1.45 g). 1H NMR (400
MHz; 298 K; DMSO-d6): δ = 9.8 (s, 1H, N=CH-N), 7.9–7.14 (m, 14H, aromatics), 5.6 (s, 4H,
Ph-CH2-N). 13C NMR (100.7 MHz; 298 K; DMSO-d6): 138.4, 136.7, 134.3, 131.5, 129.5,
128.1, 125.6, 114.2, 52.7.
N,N-Bisbenzylbenzimidazolium chloride (0.25 g, 0.75 mmol, 1 eq.) and silver(I) oxide (20 mg,
0.8 mmol, 1 eq.) were dissolved in dichloromethane (3 mL) and allowed to stir at room
temperature for 24 hours. The solution was cooled down and filtered, yielding the molecular
231
model as an insoluble white powder (yield: 40%, 0.13 g). 1H NMR (400 MHz; 298 K; DMSO-
d6): δ = 7.9–7.14 (m, 14H, aromatics), 5.6 (s, 4H, Ph-CH2-N). 13C NMR (100.7 MHz; 298 K;
DMSO-d6): 136.7, 134.3, 131.5, 129.5, 128.1, 125.6, 114.2, 52.7. Characterisation is consistent
with that previously reported within the literature .49,50
General procedure for benzoin condensation reaction
In a typical experiment, 10 mol% of catalyst (61 mg; 0.07 mmol) was suspended in dry THF (3
mL; catalyst concentration 20 mg mL-1) in a 10 mL Schlenk tube, to which 0.07 mL of
benzaldehyde (0.7 mmol) was added under argon. The reaction mixture was stirred for 24 h at
80 ºC. The mixture was allowed to cool down to rt, and an aliquot was withdrawn for 1H NMR
spectroscopy characteritzation. Benzoin conversion was determined by 1H NMR spectroscopy
in DMSO-d6 by comparing the integral value of the aldehyde signal of benzaldehyde (s,1 H, 10
ppm) with the one of the –CH- benzoin signal (s, 1H, 6 ppm) (Fig. S5.10). For the experiments
with variable quantity of catalyst, the volume of solvent and substrate were kept constant.
e
e
Ar Ar
a b
c
Ar d
d
*1 * 2 *3
Ar e
c
a
b
Fig. S5.1. 1H NMR spectrum of linear precursor 2 (400 MHz; 298 K; DMSO-d6; *1 methanol;
*2 water and *3 DMSO)
232
e
e
Ar Ar
a b
c
Ar d
Ar
* 1 *2
Ar e
Ar b a c d
13C NMR analysis of 4 in dmso-d6
Fig.S5.2. 13C NMR spectrum of linear precursor 2 (100.7 MHz; 298 K; DMSO-d6; *1 methanol
and *2 DMSO).
Analysis of folded SCNP 3
d
d
Ar Ar
a
Ar b
c
c
Ar *1 *2 *3
d
a b
Fig. S5.3. 1H NMR spectrum of SCNP 3 (400 MHz; 298 K; DMSO-d6; *1 dichloromethane;
*2 water and *3 DMSO).
233
d
d
Ar Ar
a
e
Ar b
c
Ar
Ar *1 *2
Ar Ar
c
e a d
b
Fig. S5.4. 13C NMR spectrum of SCNP 3 (100.7 MHz; 298 K; DMSO-d6; *1 dichloromethane
and *2 DMSO).
Analysis of modified SCNP 4
d
d
Ar Ar
a
Ar b
c
Ar *1 *2 * 3
c
d
a b
Fig. S5.5. 1H NMR spectrum of SCNP 4 (400 MHz; 298 K; DMSO-d6; *1 methanol; *2 water
and *3 DMSO).
234
f
f
Ar Ar
a
d
Ar b
e
c
Ar
*1 *2
Ar e Ar bf
c
d a
Fig. S5.6. 13C NMR spectrum of SCNP 4 (100.7 MHz; 298 K; DMSO-d6; *1 methanol and *2
DMSO).
Fig. S5.7. 19F NMR spectrum of SCNP 4 (376.5 MHz; 298 K; DMSO-d6).
235
Analysis of polybetaine 5
d
d
Ar Ar
Ar b
c
Ar *1 *2 *3 *1
c
a b d
Fig. S5.8. 1H NMR spectrum of SCNP 5 (400 MHz; 298 K; DMSO-d6; *1 tetrahydrofuran; *2
water and *3 DMSO).
d
d
Ar Ar
a
d
e
Ar b
c
Ar
*1 *2 *1
Ar
e d Ar c
a b
236
Fig. S5.9. 13C NMR spectrum of SCNP 5 (100.7 MHz; 298 K; DMSO-d6; *1 tetrahydrofuran
and *2 DMSO).
Catalysis using SCNPs
Ar
Ar Ar
Ar
a
*1 *1
*2
b c
Fig. S5.10. 1H NMR spectrum of benzoin condensation catalysis using 10 mol% of catalyst 2
(400 MHz; 298 K; DMSO-d6; *1 tetrahydrofuran; *2 DMSO).
Particle Characterisation
237
Fig. S5.11. Mean hydrodynamic diameter of SCNP 3 by volume (black line), number
distribution (blue line) and by intensity (red line) obtained by DLS in THF. Concentration 1 mg
mL-1 analysis was performed at room temperature.
Fig. S5.12. Correlation function of SCNP 3 obtained by DLS in THF. Concentration 1 mg mL-
1
analysis was performed at room temperature.
238
Fig. S5.13. Mean hydrodynamic diameter of linear precursor 2 by volume (black line), number
distribution (blue line) and by intensity (red line) obtained by DLS in THF. Concentration 1
mg mL-1 analysis was performed at room temperature.
Fig. S5.14. Correlation function of linear precursor 2 obtained by DLS in THF. Concentration
1mg mL-1 analysis was performed at room temperature.
239
Chapter VI: Summary and outlook
240
241
Table of Contents
Chapter VI: Summary, principal conclusions and outlook
6.1. Summary……………………………………………………………..…………………243
6.2. Principal conclusions………………………………………...…………………………243
6.2.1. Importing PILs to SCNPs technology………………...…………………243-244
6.2.2. Different SCNPs folding techniques………………….…………………244-245
6.2.3 SCNPs as catalytically active nanoreactors………………..……………245-246
6.3. Outlook…………………………………………………….……………………….246-247
242
6.1 Summary
The main focus of this thesis has been the applicability of poly(ionic liquid)s (PILs) in single
chain nanoparticles as catalytically active nanoreactors. In particular, interest has been placed
on the development of a range of thermolatent N-heterocyclic carbenes derived from ionic
liquids in confined polymeric environments. Both the preparation of these SCNPs supported
catalysts of controlled dimensions and their application as catalytically active nanostructures
has been investigated, showing the ease of use and versatility of the folding linear precursors
into SCNPs and the potential utility as synthetic enzymes.
6.2 Principal conclusions
6.2.1 Importing PILs to SCNPs technology
The theme of poly(ionic liquids) (PILs) is prevalent throughout this work and is utilised
repeatedly to develop supported N-heterocyclic carbenes (NHC) (pre)catalysts. Largely, this is
due to the discovery of the formation of active NHC from imidazolium carboxylate derivatives
by applying heat. This work has demonstrated not only the ease of preparing such materials,
but the tunability of different parts of PILs structures to thermally promote the generation of
NHCs.
The large variety of different modulability options present in PILs technology allowed first to
tune the solubility of a macrogel by inserting a biscarboxylate which ionically cross-linked the
polymeric support and served as basic counter anion to in situ deprotonate the benzimidazolium
moiety affording active NHCs.
Having developed the expertise in ionically cross-linked PILs, they were first imported to
SCNPs domain by supporting polycations and polyanions in the same linear polymeric
precursor which was subsequently folded into a nanoparticle via anion-exchange. This not only
provided a NHC catalyst precursor, but also proved that PILs could adopt more sophisticated
architectures/morphologies.
Interestingly, the particular ability of imidazolium-based PILs to act as metal ions poly(ligands)
was further exploited using silver (I) as cross-linker. Similarly to previous examples, this
organometallic bridges represent labile cross-linking points which could be broken delivering
organic poly(NHC)s catalysts upon heating.
243
More commonly, PILs structures are usually based on (co)polymers which present ionic
moieties and other non-ionic monomers. The capability of combining different monomers
was harnessed by supporting benzoin cross-linker moieties and NHC-precursor
(benzimidazolium acetate) into the same polymeric structure.
The versatility of PILs to act as NHC precursors by different means and based on different
architectures permitted transitioning from less sophisticated linear or macroscopic gels to
SCNPs based catalytically active nanoreactors.
6.2.2. Different SCNPs folding techniques
A wide variety of different synthetic approaches have been implemented for the formation of
SCNPs. The most common utilised route is based on the post-functionalisation of linear
copolymers under dilute conditions to favour intra-chain over inter-chain cross-linking. Many
of the followed approaches are inspired by biomacromolecules in nature exploiting different
orthogonal non-covalent interactions (e.g. hydrogen bonding or van der Waals), covalent
interactions (e.g. disulfides) or dynamic covalent interactions (e.g. reversible acetal formation).
In fact, the cross-linking nature is crucial not only in determining the SCNPs functionality and
performance but also to establish a criterion for classification. Namely, SCNPs are commonly
classified depending on the reversible or irreversible nature of cross-linkings present in the
structure.
Inspired by such phenomena, PILs afforded new answers to the existing challenges in different
SCNPs folding techniques. In fact, exploiting ionic nature intrinsic to IL moieties allowed the
development of an unexplored and reversible folding technique based on ionically cross-linked
SCNPs. More interestingly, these types of ionic interactions could be triggered by a simple
anion exchange under mild conditions. The ease of preparation and lack of hazardous conditions
permits an easy scale up which represents on of the major challenges to circumvent in SCNPs
technology.
The use of PILs in SCNPs technology does not necessarily mean that they must be ionically
cross-linked. Interestingly, PILs could be combined with covalently cross-linked different
moieties. In this manner, ILs could have certain mobility and accessibility in a covalently -
244
hence more robustly- cross-linked SCNPs. These types of systems are known for presenting
enhanced properties such as stability comparing to their purely non-covalently cross-linked
SCNPs counterparts, in catalysis for instance.
Imidazolium based ILs are known for being used as ligands for wide array of different metal
ions. These versatile proligands can be polymerised in a controlled fashion into linear
polymers without side reactions and subsequently post-functionalised by inserting metal ions
(e.g. Ag(I)) which cross-link SCNPs. Particularly, in the case of NHC precursors, the metal ion
has to be bound at least to two ligands to promote the intramolecular folding. Therefore,
imidazolium based PILs can act as poly(NHC)s ligands affording large number of possibilities
depending on the inserted metal ion.
Imidazolium-type linear polymeric precursors have been found to be versatile starting platforms
to trigger the intramolecular folding into SCNPs following different routes based on the
attractive properties almost exclusive to imidazolium ILs.
6.2.3. SCNPs as catalytically active nanoreactors
With the ultimate goal of mimicking the natural occurring enzymatic catalysis reactions, SCNPs
arise as the synthetic alternative to emulate this phenomenon. Few of the most important
motivations for emulating enzymes as catalytic reactors are reaching their high specificity,
selectivity, rate and/or tolerance to different environments. Following the bioinspired approach,
the organocatalyst used throughout this thesis was the NHC, which finds its biological
analogue in the vitamin B1 in its thiazole form.
Indeed, all the NHC-based SCNPs used in this study were activated upon heating. This
thermolatency permitted to easily handle and store these nanoreactors
The presence of the catalytic moieties in the SCNPs pocket was found to have a dramatic impact
in the catalytic performance due to a favourable effect of the confinement effect avoiding
product inhibition. Moreover, the incorporation of side PEG-stabilisers enabled an easy
recyclability without any loss of activity.
245
The versatility of NHCs to mediate different organic reactions was proved by organocatalysing
first the intramolecular benzoin condensation to promote the SCNPs folding and then use the
obtained nanoreactors to organocatalyse transesterification reactions.
Metalloenzymes were also used as source of bioinspiration by developing an organometallic

SCNPs cross-linked by Ag-NHC bridges. Although, Ag-NHC can act as a metal catalytic
center, or even as transmetallation agent, in this study the organometallic bridges were
thermolysed delivering active poly(NHC)s.
6.3 Outlook
As the most prominent theme of this work, poly(ionic liquid) based single chain nanoparticles
have been investigated for the formation of catalytically active nanoreactors. In particular, given
the high interest in the sophisticated supported organocatalysts, the ability to readily access and
control the assembly of polymers into SCNPs through intramolecular cross-linking process
provides a platform to develop a range of new nanomaterials.
Further research, especially for imidazolium-based PILs copolymers, will investigate the
incorporation of functional counter-anions which have multiple roles. This approach should
allow for the thermolatent generation of active NHCs but also incorporating cocatalysts, chiral
information, stabilisers or even polymerisation control agents.
It is also expected that future work in the area of SCNPs will target the catalytic activity in the
nanoscale, allowing for intramolecular folding of linear polymer nanostructures to create even
more complex catalytically active functional materials. Such an approach will not only allow
to use imidazolium ILs moieties as genuine organocatalysts but also as ligands for the
incorporation of wide array of metal centers. Potential research in this area may seek to exploit
the ability of imidazolium ILs to act as ligands which can bind metal ions to form different
metal-NHC complexes. It is predicted that mild conditions or intermediate transmetallation
complexes (e.g. Ag-NHC) could be used to easily scale up the production of organometallic
nanoreactors.
Finally, the underlying theme of this work is providing a transition from molecular or less
sophisticated supported NHC-based catalyst to more optimised and functional NHC containing
SCNPs-based nanoreactors. To this purpose, these nanoreactors could mediate molecular but
246
also macromolecular reactions as their molecular homologues for instance. In this manner,
SCNPs could act as synthetic polymerases but also as hydrolases for depolymerisation
processes in confined environments. However, the ultimate challenge for approaching natural
enzyme performance, in the case of NHC-based SCNPs as nanoreactors, is retaining catalytic
activity in biological conditions (i.e. water).
247
7.1 Sommaire
L'objectif principal de cette thèse a été l'applicabilité des poly (liquides ioniques) (PILs) dans
des nanoparticules à chaîne unique en tant que nanoréacteurs catalytiquement actifs. En
particulier, un intérêt a été porté au développement d'une gamme de carbènes N-hétérocycliques
thermolatents dérivés de liquides ioniques dans des environnements polymériques confinés. La
préparation de ces catalyseurs SCNP supportés de dimensions contrôlées et leur application en
tant que nanostructures catalytiquement actives ont été étudiées, montrant la facilité d'utilisation
et la polyvalence des précurseurs linéaires repliables en SCNP et l'utilité potentielle en tant
qu'enzymes synthétiques.
7.2 Conclusions principales
7.2.1 Importacion de PILs dans la technologie SCNPs
Le thème des poly (liquides ioniques) (PILs) est répandu tout au long de ce travail et est utilisé
à plusieurs reprises pour développer des catalyseurs (pré) catalyseurs N-hétérocycliques (NHC)
supportés. Cela est dû en grande partie à la découverte de la formation de NHC actif à partir de
dérivés de carboxylate d'imidazolium par application de chaleur. Ce travail a démontré non
seulement la facilité de préparation de tels matériaux, mais aussi l'accordabilité de différentes
parties des structures de PILs pour favoriser thermiquement la génération de NHC.
La grande variété d'options de modulabilité différentes présentes dans la technologie PILs a

permis d'abord de régler la solubilité d'un macrogel en insérant un biscarboxylate qui a réticulé
ioniquement le support polymère et a servi de contre-anion de base pour déprotoner in situ la
fraction benzimidazolium offrant des NHC actifs.
Ayant développé l'expertise dans les PILs réticulés ioniquement, ils ont d'abord été importés
dans le domaine SCNPs en supportant des polycations et des polyanions dans le même
précurseur polymère linéaire qui a ensuite été plié en une nanoparticule via un échange d'anions.
Cela a non seulement fourni un précurseur de catalyseur NHC, mais a également prouvé que
les PILs pouvaient adopter des architectures / morphologies plus sophistiquées.
Fait intéressant, la capacité particulière des PILs à base d'imidazolium à agir comme poly
(ligands) d'ions métalliques a été davantage exploitée en utilisant de l'argent (I) comme agent
248
de réticulation. De la même manière que dans les exemples précédents, ces ponts
organométalliques représentent des points de réticulation labiles qui pourraient être rompus en
délivrant des catalyseurs organiques poly (NHC) lors du chauffage.
Plus communément, les structures PILs sont généralement basées sur des (co) polymères qui
présentent des fragments ioniques et d'autres monomères non ioniques. La capacité de combiner
différents monomères a été exploitée en soutenant des fragments de réticulant de benjoin et un
précurseur de NHC (acétate de benzimidazolium) dans la même structure polymère.
La polyvalence des PIL pour agir en tant que précurseurs de NHC par différents moyens et sur
la base de différentes architectures a permis de passer de gels linéaires ou macroscopiques
moins sophistiqués à des nanoréacteurs catalytiquement actifs à base de SCNPs.
7.2.2. Différentes techniques de pliage SCNPs
Une grande variété d'approches synthétiques différentes a été mises en œuvre pour la formation
de SCNPs. La voie utilisée la plus courante est basée sur la post-fonctionnalisation des
copolymères linéaires dans des conditions diluées pour favoriser la réticulation intra-chaîne
plutôt qu'inter-chaîne. Bon nombre des approches suivies sont inspirées par des
biomacromolécules dans la nature exploitant différentes interactions orthogonales non
covalentes (par exemple, liaison hydrogène ou van der Waals), des interactions covalentes (par
exemple disulfures) ou des interactions covalentes dynamiques (par exemple formation acétal
réversible). En fait, la nature de la réticulation est cruciale non seulement pour déterminer la
fonctionnalité et les performances des SCNPs, mais aussi pour établir un critère de
classification. À savoir, les SCNPs sont généralement classés en fonction de la nature réversible
ou irréversible des réticulations présentes dans la structure.
Inspirés par de tels phénomènes, les PILs ont apporté de nouvelles réponses aux défis existants
dans les différentes techniques de pliage des SCNPs. En fait, l'exploitation de la nature ionique
intrinsèque aux fractions IL a permis le développement d'une technique de repliement
inexplorée et réversible basée sur des SCNP réticulés ioniquement. Plus intéressant, ces types
d'interactions ioniques pourraient être déclenchés par un simple échange d'anions dans des
conditions douces. La facilité de préparation et l'absence de conditions dangereuses permettent
249
une mise à l'échelle facile qui représente l'un des principaux défis à contourner dans la
technologie SCNPs.
L'utilisation de PILs dans la technologie SCNPs ne signifie pas nécessairement qu'ils doivent
être réticulés ioniquement. Fait intéressant, les PIL pourraient être combinés avec des fragments
différents réticulés de manière covalente. De cette manière, les ILs pourraient avoir une certaine
mobilité et accessibilité dans un SCNPs réticulé de manière covalente-donc plus robuste. Ces
types de systèmes sont connus pour présenter des propriétés améliorées telles que la stabilité
par rapport à leurs homologues SCNPs réticulés de manière non covalente, en catalyse par
exemple.
Les ILs à base d'imidazolium sont connus pour être utilisés comme ligands pour un large
éventail d'ions métalliques différents. Ces proligands polyvalents peuvent être polymérisés de
manière contrôlée en polymères linéaires sans réactions secondaires et post-fonctionnalisés par
la suite en insérant des ions métalliques (par exemple Ag (I)) qui réticulent les SCNPs. En
particulier, dans le cas des précurseurs de NHC, l'ion métallique doit être lié au moins à deux
ligands pour favoriser le repliement intramoléculaire. Par conséquent, les PILs à base
d'imidazolium peuvent agir comme des ligands poly (NHC) offrant un grand nombre de
possibilités en fonction de l'ion métallique inséré.
Les précurseurs polymères linéaires de type imidazolium se sont avérés être des plates-formes
de départ polyvalentes pour déclencher le pliage intramoléculaire en SCNPs en suivant
différentes voies en fonction des propriétés attrayantes presque exclusives aux ILs
d'imidazolium.
7.2.3. SCNPs en tant que nanoréacteurs catalytiquement actifs
Dans le but ultime d'imiter les réactions naturelles de catalyse enzymatique, les SCNPs se
présentent comme l'alternative synthétique pour émuler ce phénomène. Peu des motivations les
plus importantes pour émuler des enzymes en tant que réacteurs catalytiques atteignent leur
haute spécificité, sélectivité, vitesse et / ou tolérance à différents environnements. Suivant
l'approche bioinspirée, l'organocatalyseur utilisé tout au long de cette thèse était le NHC, qui
trouve son analogue biologique dans la vitamine B1 sous sa forme thiazole.
250
En effet, tous les SCNPs à base de NHC utilisés dans cette étude ont été activés lors du
chauffage. Cette thermolatence a permis de manipuler et de stocker facilement ces
nanoréacteurs.
La présence des fractions catalytiques dans la poche SCNPs s'est avérée avoir un impact
dramatique sur les performances catalytiques en raison d'un effet favorable de l'effet de
confinement évitant l'inhibition du produit. De plus, l'incorporation de stabilisateurs PEG
latéraux a permis une recyclabilité aisée sans aucune perte d'activité.
La polyvalence des NHC pour médier différentes réactions organiques a été prouvée en
organocatalysant d'abord la condensation de benjoin intramoléculaire pour favoriser le
repliement des SCNP, puis en utilisant les nanoréacteurs obtenus pour organocatalyse les
réactions de transestérification.
Les métalloenzymes ont également été utilisées comme source de bioinspiration en développant
un SCNP organométallique réticulé par des ponts Ag-NHC. Bien que l'Ag-NHC puisse agir
comme un centre catalytique métallique, ou même comme un agent de transmétallation, dans
cette étude, les ponts organométalliques ont été thermolysés délivrant des poly (NHC) actifs.
7.3. Perspectives
En tant que thème le plus important de ce travail, les nanoparticules à chaîne unique à base de
poly (liquide ionique) ont été étudiées pour la formation de nanoréacteurs catalytiquement
actifs. En particulier, étant donné le grand intérêt pour les organocatalyseurs pris en charge
sophistiqués, la capacité d'accéder et de contrôler facilement l'assemblage des polymères dans
les SCNPs via un processus de réticulation intramoléculaire fournit une plate-forme pour
développer une gamme de nouveaux nanomatériaux.
D'autres recherches, en particulier pour les copolymères de PILs à base d'imidazolium,
étudieront l'incorporation de contre-anions fonctionnels qui ont de multiples rôles. Cette
approche devrait permettre la génération thermolatente de NHC actifs mais également
l'incorporation de cocatalyseurs, d'informations chirales, de stabilisants ou même d'agents de
contrôle de la polymérisation.
Il est également prévu que les futurs travaux dans le domaine des SCNPs cibleront l'activité
catalytique à l'échelle nanométrique, permettant le pliage intramoléculaire de nanostructures de
polymère linéaire pour créer des matériaux fonctionnels catalytiquement actifs encore plus
complexes. Une telle approche permettra non seulement d'utiliser des fragments d'imidazolium
251
ILs comme de véritables organocatalyseurs mais également comme ligands pour l'incorporation
d'un large éventail de centres métalliques. Les recherches potentielles dans ce domaine
pourraient chercher à exploiter la capacité des IL d'imidazolium à agir comme des ligands qui
peuvent se lier aux ions métalliques pour former différents complexes métal-NHC. Il est prévu
que des conditions douces ou des complexes de transmétallation intermédiaires (par exemple
Ag-NHC) pourraient être utilisés pour augmenter facilement la production de nanoréacteurs
organométalliques.
Enfin, le thème sous-jacent de ce travail est de fournir une transition d'un catalyseur à base de
NHC supporté moléculaire ou moins sophistiqué à un NHC plus optimisé et fonctionnel
contenant des nanoréacteurs basés sur SCNPs. A cet effet, ces nanoréacteurs pourraient médier
des réactions moléculaires mais aussi macromoléculaires comme leurs homologues
moléculaires par exemple. De cette manière, les SCNP pourraient agir comme des polymérases
synthétiques mais également comme des hydrolases pour les processus de dépolymérisation
dans des environnements confinés. Cependant, le défi ultime pour l'approche des performances
des enzymes naturelles, dans le cas des SCNP à base de NHC en tant que nanoréacteurs, est de
conserver l'activité catalytique dans des conditions biologiques (c'est-à-dire l'eau).
252
Titre: Synthèse de nouvelles nanoparticules composées de chaines uniques basé sur de carbènes N-
hétérocycliques comme de nanoréacteurs catalytiquement actifs.
Résume: Des poly(liquides ioniques) (PILs) arrangés sous la forme de copolymères aléatoires ont été développés
avec des architectures telle que ce des nanoparticules à chaine unique ou bien sous la forme de (macro)gels. Ces
différentes systèmes ont été employés comme précurseurs de carbènes N-heterocycliques (NHC)s à des fins de
catalyses organiques. L’introduction d’anions relativement basiques dans des unités PIL dérives d’imidazolium
permet la génération in situ des NHCs actifs pour la catalyse. D’abord, le développement de (macro)gel base sur
des unités PIL réactives représente l’étude préliminaire pour la compréhension et analyse de performance
catalytique a l’échelé macroscopique. Cette étude a permit cibler des réaction model ainsi comme des conditions
et des standards pour établir un système de référence tout au long de cette thèse. Ensuite, ce gel a servi comme
base pour développer des nanogels connues comme nanoparticules composées d‘une chaine unique polymère
repliée sur elle-même (SCNP en anglais). Ces SCNPs ont été spécialement conçues base sur la mouillabilité des
PILs et ont été obtenues par polymérisation contrôlée (méthode RAFT). Dans le premier cas, la nature ionique des
precatalyseur NHC a été exploite en promouvant l’interaction entre les dérives d’imidazolium avec des anions
basiques supportes dans les polymère en formant un SCNP ioniquement réticulée. Deuxièmement, les propriétés
termolatentes des précurseurs de NHC a été mis en valeur en compatibilisant des substrats et precatalyseurs sur la
même chaine des polymère en promouvant le repliement des chaines en condensant les substrats sous l’application
de chaleur. Finalement, la capabilité intrinsèque des poly(NHC)s pour actuer comme poly-ligands a été démontre
de manière novatrice en formant des SCNPs par une réaction de complexation organométallique a l’aide d’un sel
d’argent. Dans tout les différentes support polymériques, des aspectes relie aux performances catalytiques ont été
mis en avance comme le recyclage du catalyseur, des effet de confinement, la facilite pour augmenter l’echele de
synthese des nanoreacteurs, la versatilite des NHC catalyseurs et l’adaptation de different systems pour manipuler
ces especes polycarbeniques de une manière simple et efficace.
Mots cles: Poly(liquides ioniques), imidazolium, N-heterocyclique carbenes, NHC, carbenes masquees, catalyse
supportée, organocatalyse, confinement, catalyse biomimétique, nanoréacteurs, mimétique enzymatique,
nanoparticules, SCNPs, SNCPs.
Title : Synthesis of new N-Heterocyclic Carbene (NHC)-based Single Chain Nanoparticles (SNCPs) as
catalytically active nanoreactors
Abstract: Random copolymers based on poly(ionic liquids) have been developed under different architectures
such as single chain nanoparticles (SCNPs) or as (macro)gels. Those different systems have been employed as N-
heterocyclic carbenes (NHCs) precurors to be used as organocatalysts. The incorporation of relatively basic
counteranions in PIL units derived from imidazolium moieties allows the in situ generation of active NHC species
for catalysis. Firstly, a reactive PIL based (macro)gel represents the preliminary study to better understand and
analyse the catalytic performance in the macroscale. This study has permitted the identification of suitable model
reactions as well as conditions and standards, becoming a reference system all along this thesis. Moreover, this
(macro)gel has served as a base for the further development of more sophisticated nanogels known as single chain
nanoparticles (aka SCNPs). These SCNPs have specially been designed based on their PIL tunability and
synthesised by reversible additions fragmentation chain transfer (RAFT) polymerisation. In first place, the ionic
nature of the NHC precatalyst was exploited by triggering the interaction between imidazolium derivatives and
basic anions supported in the polymer leading to a ionically cross-linked SCNP. Secondly, the thermolatent
properties of NHC precursors was harnessed by proving the compatibility of both substrates and precatalyst
supported on the same polymer chain and triggering the folding by condensing the substrates by the simple
application of heat. Finally, the intrinsic capacity of poly(NHC)s to act as poly-ligands was innovatively
demonstrated by forming SCNPs after organometallic complexation using a silver salt. Overall, the different
polymeric supports have served to highlight different aspects related to the catalytic performance of supported
catalysts such as recycling, confinement effect, nanoreactor scaling up processes, NHC catalysts versatility as well
as the adaptability of these systems for enabling and easy and efficient handling and storage.
Keywords: poly(ionic liquids), imidazolium, N-heterocyclic carbene, NHC, masked carbenes, supported catalysis,
organocatalysis, confinement, biomimetic catalysis, nanoreactors, enzyme mimicry, nanoparticles, SCNPs,
SNCPs.
Laboratoire de Chimie des Polymeres OrganiqueUMR5629 | 16 avenue Pey-Berland | F-33607 Pessac
253

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THÈSE PRÉSENTÉE

POUR OBTENIR LE GRADE DE

École Doctorale des Sciences Chimiques

Par Sofiem GARMENDIA

Synthesis of new N-Heterocyclic Carbene (NHC)-based Single

Synthèse de nouvelles nanoparticules composées de chaines uniques basé sur de carbènes

Soutenue le 22/ 01/ 20

M. POMPOSO, Jose A., Professeur, University of the Basque Country Rapporteur

Chapter I: Introduction to Single Chain Nanoparticles (SCNPs) as nanoreactors

1.1 Single Chain Nanoparticles (SCNPs) ……………...........................................…..………31

1.1.1 Introduction ……………………………………………..…...................…….31-32

1.1.2 Synthetic methods towards single-chain nanoparticles.….....….........................…32

1.1.2.1 SCNPs via irreversible and reversible bonds.……….....................…..32-33

1.1.2.1.1 Covalent bonds………………..…................….........……33-39

1.1.2.1.2 Organometallic bonds…………….................…..…..……39-44

1.1.2.1.3 Supramolecular chemistry……………..................…...….44-50

1.1.2.1.4 Dynamic covalent chemistry…………...................…...….50-54

1.1.3 Characterisation of Single Chain Polymer Nanoparticles: analytical

1.1.3.1 Size exclusion chromatography (SEC)………….................…..…..….55-57

1.1.3.2 Spectroscopic characterisation of SCNPs…………..................……….....57

1.1.3.2.1 NMR spectroscopy ………………………………….……...57-59

1.1.3.2.2 IR, UV-VIS, CD and fluorescence spectroscopy……………59-62

1.1.3.3.1 Morphological characterisation via TEM…...…....................62-63

1.1.3.3.2 Morphological characterisation via AFM….......................…63-64

1.1.3.3.3 Morphological characterisation via scattering (DLS, SAXS,

1.1.4.1.1 Drug delivery and imaging………..…………………..…….69-72

1.1.4.2 Nanoreactors for catalysis.………………………..........................………73

1.1.4.2.1 Organocatalysis …………………………….....................…73-77

1.1.4.1.2 Organometallic catalysis………….……....................…...…77-85

1.1.4.1.3 Enzymatic catalysis …………………....................……...…85-86

1.1.4.3 Other uses……………………………..……………….................…...86-89

1.3 Conclusions and aims of the PhD thesis......................................................……...…....89-91

Supports for Organocatalysis by N-Heterocyclic Carbenes

2.3. Synthesis, characterisation…………………………………………………………105-110

2.4. Manipulation of gel-supported pre-catalyst…………………………..……………110-113

2.5. Organocatalysis from gel-supported NHCs…………………………..……………113-116

Chapter III: Reversible Ionically-crosslinked Single Chain Nanoparticles as Bioinspired and

Recyclable Nanoreactors for N-Heterocyclic Carbene Organocatalysis

3.3. Synthesis of catalytically active SCNPs……………………………………………143-148

3.4. Benzoin condensation catalyzed by SCNP 5………………………………………148-152

3.7 Experimental section………………………………………………………………158-169

Chapter IV: Self-catalysed folding of single chain nanoparticles (SCNPs) by NHC-mediated

intramolecular benzoin condensation

4.3. Synthesis of catalytically active SCNPs....................................................................176-182

4.4. Transesterification reaction catalysed by SCNP 5.....................................................182-186

4.7. Experimental section................................................................................................190-209

Chapter V: Catalytically Active N-Heterocyclic Carbene Release from Single-Chain Nanoparticles

following a Thermolysis-driven Unfolding Strategy

5.3. Synthesis of catalytically-active SCNPs…………………………………...………216-220

5.4. NHC-mediated benzoin condensation reaction………………………….…………220-223

5.7. Experimental Section…………………………………………...………………….228-239

Chapter VI: Summary, principal conclusions and outlook

6.2. Principal conclusions………………………………………...…………………………243

6.2.1. Importing PILs to SCNPs technology…………………...…………………243-244

6.2.2. Different SCNPs folding techniques………………….……………………244-245

6.2.3 SCNPs as catalytically active nanoreactors………………..………………245-246

7.2. Conclusions principales……………………………………...…………………………248

7.2.1. Importacion de PILs dans la technologie SCNPs…………………………..248-249

7.2.2. Différentes techniques de pliage SCNPs……………….…………………..249-250