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Molecular Medicine and
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Fluorine in
Pharmaceutical and
Medicinal Chemistry
From Biophysical Aspects

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Véronique Gouverneur
University of Oxford, UK
Klaus Müller
F Hoffmann-La Roche AG, Switzerland
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Molecular Medicine and Medicinal Chemistry — Vol. 6

FLUORINE IN PHARMACEUTICAL AND MEDICINAL CHEMISTRY
From Biophysical Aspects to Clinical Applications
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b1171_FM.qxd 3/21/2012 9:21 AM Page v
b1171 Fluorine in Pharmaceutical and Medicinal Chemistry
Foreword
François Diederich
For almost a century after the first preparation of elemental F2 by Moissan

in 1886, synthetic fluorine chemistry was pursued and developed by a
small community of experts capable of handling the aggressive gas using
special laboratory equipment. Important technological developments
resulted from this work, such as the bulk-scale preparation of fluorinated
hydrocarbons for refrigerators and other cooling devices, which, however,
later became banned due to their atmospheric greenhouse effects and the
depletion of the ozone layer. Nonetheless, lasting successful applications
resulted, for example, from the development of fluorinated polymers such
as Teflon®, of volatile gases for anesthesia, and of the separation of
uranium isotopes using UF6 centrifuges, for the production of nuclear fuel
for use in powerplants.
The development of fluorine-containing drugs started in 1957 and
was in the following years strongly aided by the increasing availability of
commercial fluorinating agents allowing the safe and selective introduc-
tion of organofluorine, i.e. C–F bonds, using common laboratory
equipment. This has resulted in the introduction of over 150 fluorinated
drugs to the market, and currently nearly 20% of all pharmaceuticals and
40% of all agrochemicals in development contain organofluorine.
The reasons for this explosive growth in interest in the introduction of
organofluorine are multiple. While beneficial effects on ADME (absorp-
tion, distribution, metabolism, and excretion) and safety were recognized
earlier on, the interest in organofluorine has lately focused on more
atom-based properties, such as distinct conformational and stereo-
electronic properties, modulation of the pKa-value of neighboring
v
b1171_FM.qxd 3/21/2012 9:21 AM Page vi
vi Foreword
Brønstedt acid/base centers, polarity, and the influence on lipophilicity as

expressed by the distribution coefficient logD and the partition coefficient
logP (both for the octanol/water system). Additionally, attention has shifted
on intermolecular interactions of organofluorine, such as H-bonding and
dipolar interactions, and it has been shown that selective organofluorine
interactions with protein residues can be used to substantially enhance
protein–ligand binding affinity and selectivity. New fluorinated building

blocks are emerging at an increasing speed and are introduced into inno-
vative drugs and agrochemicals. Substituting C–H by C–F bonds clearly

benefits from the fact that the size of organofluorine is only slightly larger
than the size and volume of the hydrogen substituent and that conse-
quently no particular steric hindrance is encountered in most H/F
replacements. All of this is extensively documented in the various chapters
of this timely monograph, which prepares the chemists in modern drug
discovery research and in crop protection sciences in great depth for using
organofluorine in an appropriate way to tune and improve the properties
of their actives and leads.
Another contemporary area in pharmaceutical and biomedical
research involving organofluorine is the development of new fluorinated
probes for use in solid-state 19F NMR investigations and in non-invasive
clinical and molecular imaging. Furthermore, the introduction of 18F-
radiolabels is increasingly competing with 11C-radiolabels for the
preparation of probes for positron emission tomography (PET) imaging.
These biomedical applications are also covered in great depth in this
monograph.
The twelve chapters in the monograph are written by leaders in the
field and are grouped into three sections. The first section describes the
synthesis of fluorinated biomolecules and how the introduction of
organofluorine alters and enhances physicochemical and molecular recog-
nition properties. The first chapter Synthesis and Properties of Fluorinated
Nucleobases in DNA and RNA by H. Gohlke, J. Bozilovic, and J. W. Engels
starts with an overview on organofluorine in molecular recognition,
which focuses on C–F...H–N interactions in the context of fluorinated
nucleobase analogs. The incorporation of the corresponding nucleotides
into oligonucleotides and their interactions with complementary native
b1171_FM.qxd 3/21/2012 9:21 AM Page vii
Foreword vii
nucleobases in RNA, ribozymes, and siRNA are subsequently reviewed.

Analysis of these interactions is based on a multi-dimensional approach
combining X-ray data, results from thermodynamic studies, and computer
simulations. Additionally, the synthesis of selected fluorinated nucleoside
analogs is covered. The nature and polarity of molecular environments is
critical for organofluorine interactions in proteins, as described in the sec-
ond chapter Molecular Interactions of Fluorinated Amino Acids within the

Hydrophobic Core of a Coiled Coil Peptide by T. Vagt, M. Salwiczek, and
B. Koksch. α-Helical coiled coils are investigated as model systems to deci-
pher the interactions of organofluorine within a native protein

environment. This is achieved by introducing amino acids with hydro-
phobic fluorinated side chains of different volume and polarity into the
folding peptides. The studies reveal that the effect of fluorinated amino
acids strongly depends on the immediate microenvironment: the helical
peptide model systems are selectively stabilized by interactions of
organofluorine, in particular of CF3 groups, with the lipophilic amino
acids Leu, Ile, and Val. The CF3 group is at the center of the chapter Probing
the Binding Affinity and Proteolytic Stability of Trifluoromethyl Peptide
Mimics as Protease Inhibitors by M. Zanda, A. Volonterio, M. Sani, and
S. Dall’Angelo. α,α-Difluoro- and α,α,α-trifluorocarbonyl residues are
fully hydrated in aqueous solution and these hydrates, as part of pep-
tidomimetic ligands, are good entities to bind to the catalytic Asp dyad in
aspartic proteases. In the meanwhile, α,α,α-trifluoroacetyl groups have
been recognized as general binding elements for biological targets with
polar active sites and their introduction into ligands for proteolytic
enzymes, such as endopeptidases and matrix metalloproteases, as well
as their specific intermolecular interactions with the proteins are
described. The last chapter in Section 1, entitled Trifluoromethyl-Substituted
α-Amino Acids as Solid-State 19F-NMR Labels for Structural Studies of
Membrane-Bound Peptides, written by V. S. Kubyshkin, I. V. Komarov, S.
Afonin, P. K. Mykhailiuk, S. L. Grage, and A. S. Ulrich presents the synthesis
of trifluoromethyl-substituted natural and unnatural α-amino acids as
19
F-NMR labels to study membrane-associated polypeptides in the solid
state. The chapter starts by outlining biostructural applications of solid-
state 19F NMR methods and subsequently focuses on the synthesis of
b1171_FM.qxd 3/21/2012 9:21 AM Page viii
viii Foreword
the probes and their incorporation into peptides. Challenges in the prepa-
ration of hitherto missing probes, such as F3C–substituted proline, are
identified.
Section 2 deals with the introduction of organofluorine into bio-
medical leads and drugs and their use against various biological targets.
The chapter by S. Swallow on Fluorine-Containing Pharmaceuticals starts
with a general survey of organofluorine in drug discovery and develop-

ment. It subsequently presents several interesting case studies that
highlight the effects of H/F substitutions on the development of com-

mercial drugs. Beneficial organofluorine contributions are established
and confirmed in revealing structure–activity relationships (SARs). The
range of these benefits is indeed quite impressive and extends from
improved potency to more favorable ADME, pharmacokinetic, and
safety properties. A more focused chapter by J. T. Welch describes
Applications of Pentafluorosulfanyl Substitution in Life Sciences Research.
While popular for quite some time in agrochemicals, this “super-
trifluoromethyl” group, with a size slightly smaller than a t-butyl group,
has in recent years also found increasing application in pharmaceuticals
development. As SF5–substituted building blocks become rapidly com-
mercially available, there is usually no need for direct fluorination. The
chapter Strategic Incorporation of Fluorine into Taxoid Anticancer Agents
by A. Pepe, L. Sun, and I. Ojima illustrates how the metabolic stability of
taxoid anticancer drugs is improved and their general cytotoxicity
reduced by introduction of organofluorine. It also describes the use of
solid-state 19F NMR spectroscopy to elucidate the bioactive conforma-
tions of taxoids. A comprehensive and useful coverage of Synthesis and
Antiviral, Antitumour Activities of Fluorinated Sugar Nucleosides is
provided by F. Zheng, X.-L. Qiu, and F.-L. Qing. They present the prepa-
ration of a large variety of nucleoside building blocks with fluorinated
ribose moieties and discuss the conformational effects resulting from
organofluorine introduction. M. Winkler and D. O’Hagan in their
chapter on Synthesis of Fluorinated Neurotransmitter Analogues report on
the development of non-peptidic fluorinated small molecules that find
application in biomedical 19F NMR and 18F PET studies. Fluorinated
adrenaline and dopamine analogs are covered as well as a diversity of
b1171_FM.qxd 3/21/2012 9:21 AM Page ix
Foreword ix
other compounds binding to central neuroreceptors such as the gluta-

mine, histamine, acetylcholine, and serotonin receptors.
The third and final section deals with the use of 19F probes in NMR
and of 18F-radiolabeled probes in PET imaging applications. An author-
itative survey of 18F-Radionuclide Chemistry is provided by R. Bejot and
V. Gouverneur. The introduction of the radiolabels into probes for PET
studies requires special protocols for synthesis and purification due to

the limited half-life of the radionucleus, and these protocols are covered
in an informative way. 18F-Labelled Tracers for PET Oncology and

Neurology Applications by S. K. Luthra and E. G. Robins describes the
protocols for the preparation of specific PET probes for in vivo imaging
to elucidate disease-based mechanisms in oncology and neurology. The
authors cover the synthesis of 18F-labeled nucleosides, RGD
(Arg–Gly–Asp) sequences, peptides that bind to specific biological tar-
gets (and the application of these probes to in vivo imaging of tumor
angiogenesis), apoptosis, and amyloid plaque formation. The final chap-
ter by V. D. Kodibagkar, R. R. Hallac, D. Zhao, J.-X. Yu, and R. P. Mason
on 19F NMR: Clinical and Molecular Imaging Applications discusses the
use of fluorinated probes in non-invasive clinical and molecular imaging
to investigate enzyme activities and cell tracking in various diseases. It
connects well to the earlier chapters reporting the synthesis of such
probes.
All chapters are carefully selected and contribute to a unique, well-
rounded monograph. Learning is fully ensured, as I can certify from the
preparation of this foreword. I am not aware of any other monograph
covering organofluorine applications in such depth and diversity. It will be
of great practical use to scientists in industry — both pharmaceutical and
agrochemical — and in academia. Both experts and novice practitioners
will benefit from the reading. The monograph should also find use as a
basis for advanced courses on organofluorine applications in biomedical
research in masters and doctoral degree programs. The chosen format of
individual chapters, namely comprehensive coverage of both modern syn-
thetic methodology and in vitro and in vivo biological applications of the
resulting building blocks and ligands, is highly attractive. It becomes quite
clear that there is lots of room for further developments of innovative
b1171_FM.qxd 3/21/2012 9:21 AM Page x
x Foreword
fluorinated building blocks and investigations of their physicochemical

and biological properties. There is no doubt that this monograph will
stimulate much future research on organofluorine in pharmaceutical and
biomedical chemistry.
François Diederich
Laboratorium für Organische Chemie

ETH Zurich, Hönggerberg, HCI
CH-8093 Zurich, Switzerland

Zurich, November 1, 2011
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b1171_FM.qxd 3/21/2012 9:21 AM Page xi
Preface
Véronique Gouverneur and Klaus Müller

Fluorine has a distinctive place in the periodic table and has absorbed the
attention of numerous scientists over many decades. Fluorine chemistry
today is a well-established branch of modern sciences, which has tremen-
dously benefited various research areas from material to medical sciences.
The synthesis of fluorinated compounds has been extensively explored.
Today, this field of research still stretches to the limit the creativity of
chemists eager to develop new concepts for both selective fluorination and
clever design and manipulation of fluorinated building blocks. The
increased availability of fluorinated compounds has led to insightful stud-
ies aimed at deciphering the effects of fluorine substitution on
physicochemical properties. Aspects of fluorine chemistry have been
competently discussed in numerous books and reviews. This monograph
is intended for a broad readership of professionals and researchers partic-
ularly interested in life sciences and medicine. An effort has been made to
integrate chemistry, biology, drug discovery and medicine in a way that
gives the reader an appreciation of how fluorine has enriched the life sci-
ences in many respects. Molecules substituted with fluorine have
improved our understanding of the molecular mechanisms of disease
states and are continuously contributing to the advancement of drug dis-
covery and diagnostic imaging. These aspects are covered in this book,
which is organised around three sections. The first part provides answers
on the fundamental question of how the introduction of fluorine modulates
the physicochemical and molecular recognition properties of biologically
xi
b1171_FM.qxd 3/21/2012 9:21 AM Page xii
xii Preface
relevant molecules. This is followed by an in-depth coverage of the impact

that fluorine has made on drug discovery and development. The last sec-
tion gives the reader informative accounts on the use of 19F-spinlabelled
and 18F-radiolabelled probes for imaging by nuclear magnetic resonance
and positron emission tomography, respectively.
In this multi-authored monograph, industrial and academic experts
in the field bring the reader up to date with twelve chapters discussing all
aspects of their respective research areas from essential background infor-
mation to the most recent developments. In the process of editing this

book, we have come to appreciate the enormous amount of talent of
‘fluorine scientists’ that has enabled spectacular advances in molecular
medicine. We wish to express our most sincere gratitude and thanks to the
authors of this monograph (Holger Gohlke, Jelena Bozilovic, Joachim W.
Engels, Toni Vagt, Mario Salwiczek, Beate Koksch, Matteo Zanda,
Alessandro Volonterio, Monica Sani, Sergio Dall’Angelo, Vladimir S.
Kubyshkin, Igor V. Komarov, Sergii Afonin, Pavel K. Mykhailiuk, Stephan
L. Grage, Anne S. Ulrich, Steve Swallow, John T. Welch, Antonella Pepe,
Liang Sun, Iwao Ojima, Feng Zheng, Xiao-Long Qiu, Feng-Ling Qing,
Margit Winkler, David O’Hagan, Romain Bejot, Véronique Gouverneur,
Sajinder K. Luthra, Edward G. Robins, Vikram D. Kodibagkar, Rami R.
Hallac, Dawen Zhao, Jian-Xin Yu and Ralph P. Mason), to François
Diederich who has kindly agreed to comment on this monograph and to
the countless chemists, biologists, physicists, physicians and clinicians
around the world who have contributed to advancing life sciences and
medicine over the years using fluorine as an enabling element. Heartfelt
thanks to the members of the Gouverneur research group for helping with
the proofreading (Matthew Tredwell, Matthew Hopkinson, Jamie
Wolstenhulme, Charlotte Hollingworth, George Blessley, Ida Sofia
Stenhagen and Guy Giuffredi).
We very much hope that this monograph will inspire many dedicated
scientists and stimulate further developments relying on fluorine, with
even more key discoveries in and for the future.

Oxford, 9 November 2011
b1171_FM.qxd 3/21/2012 9:21 AM Page xiii
Contents
Foreword v
François Diederich
Preface xi
Section 1 1
1 Synthesis and Properties of Fluorinated Nucleobases
in DNA and RNA 3
Holger Gohlke, Jelena Bozilovic and Joachim W. Engels
1.1 Introduction 3
1.2 Fluorine in Molecular Recognition 4
1.3 Synthesis of Fluoro-Substituted Benzenes, Benzimidazoles
and Indoles, and their Incorporation into Model RNA 6
1.3.1 Chemical syntheses of fluoro-substituted
benzenes, benzimidazoles and indoles 6
1.3.2 Synthesis of 12-mer RNA duplexes that
incorporate fluoronucleosides 12
1.3.3 RNA melting studies and thermodynamic data 13
1.4 Origin of the Molecular Recognition Properties of
Fluorinated Nucleobases 16
1.4.1 Stacking and desolvation: Insights from
thermodynamic analyses 16
1.4.2 C–H…F–C interactions: Crystallographic
analysis of fluoro-substituted NNIs 17
xiii
b1171_FM.qxd 3/21/2012 9:21 AM Page xiv
xiv Contents
1.4.3 Molecular dynamics simulations and free

energy calculations 20
1.5 Incorporation of Fluoro-Substituted NNI into
the Hammerhead Ribozyme and siRNA Constructs
and their Acceptance by Polymerases 22
1.5.1 Hammerhead ribozyme 22
1.5.2 Fluorobenzene and benzimidazoles in RNA

interference and siRNA 24
1.5.3 Polymerase acceptance of fluorobenzimidazoles 26

1.6 Conclusion 26
Acknowledgements 27
References 27
2 Molecular Interactions of Fluorinated Amino Acids within

the Hydrophobic Core of a Coiled Coil Peptide 33
Toni Vagt, Mario Salwiczek and Beate Koksch
2.1 Introduction 33
2.2 The α-Helical Coiled Coil as a Model System to
Investigate Fluorinated Amino Acids within a Native
Protein Environment 35
2.3 Single Fluoroamino Acid Substitutions within a
Heterodimeric Coiled Coil 39
2.3.1 The α-helical coiled coil as a model for a natural
protein environment 39
2.4 Biophysical Characterisation of the Interactions 41
2.4.1 Hydrophobicity of the fluorinated amino acids 41
2.4.2 The impact of fluorine substitutions on coiled
coil structure 44
2.4.3 The impact of fluorine substitutions on the
thermodynamic stability of the dimer 47
2.5 Screening for Native Interaction Partners 52
2.6 Conclusions and Outlook 57
Acknowledgements 58
References 58
b1171_FM.qxd 3/21/2012 9:21 AM Page xv
Contents xv
3 Probing the Binding Affinity and Proteolytic Stability of

Trifluoromethyl Peptide Mimics as Protease Inhibitors 63
Matteo Zanda, Alessandro Volonterio, Monica Sani
and Sergio Dall’Angelo
3.1 Introduction 63
3.2 Peptidyl Trifluoro-Ketones 64
3.3 Peptidomimetics Containing the Trifluoroethylamine

Function as Peptide Bond Replacement 66
3.4 Trifluoromethyl-Peptidomimetics as Protease Inhibitors 73

3.4.1 MMP inhibitors 73
3.4.2 β-Fluoroalkyl β-sulfonyl hydroxamates 75
3.4.3 Dual ACE/NEP inhibitors 77
3.4.4 Crystallographic analysis of the role of the
CF3-group in the binding process to enzyme
active sites 80
References 86
4 Trifluoromethyl-Substituted α-Amino Acids as Solid-State

19
F NMR Labels for Structural Studies of Membrane-Bound
Peptides 91
Vladimir S. Kubyshkin, Igor V. Komarov, Sergii Afonin,
Pavel K. Mykhailiuk, Stephan L. Grage and Anne S. Ulrich
4.1 Introduction 91
4.2 Solid-State NMR for Structure Analysis of
Membrane-Associated Polypeptides 93
4.3 Choice of the CF3 Group as a Label for 19F NMR of
Peptides in Membranes 96
4.4 Suitable CF3-Labelled Amino Acids for 19F NMR
Analysis 98
4.5 α-CF3-Substituted Amino Acids: TfmAla 99
4.5.1 Synthesis 99
4.5.2 Separation of the TfmAla enantiomers 106
4.5.3 Incorporation of TfmAla into peptides 107
19
4.5.4 F NMR structure analysis of peptides
with TfmAla 109
b1171_FM.qxd 3/21/2012 9:21 AM Page xvi
xvi Contents
4.6 Amino Acids with a Rigid Spacer Between Cα

and the CF3 Group: 4-TfmPhg and TfmBpg 111
4.6.1 Synthesis of 4-TfmPhg 111
4.6.2 Separation of the 4-TfmPhg enantiomers 117
4.6.3 Incorporation of 4-TfmPhg into peptides 118
4.6.4 Synthesis of TfmBpg 120
4.6.5 Synthesis of peptides containing TfmBpg 121

19
4.6.6 F NMR structure analysis of peptides
with 4-TfmPhg and TfmBpg 122

4.7 Conclusions and Perspectives 124
Acknowledgements 128
References 128
Section 2 139
5 Fluorine-Containing Pharmaceuticals 141
Steve Swallow
5.1 Introduction 141
5.1.1 Survey of fluorine-containing pharmaceuticals 142
5.2 Case Studies 144
5.2.1 Ezetimibe (Zetia) 144
5.2.2 Celecoxib (Celebrex) 147
5.2.3 Sitagliptin (Januvia) 147
5.2.4 Fluconazole (Diflucan) and Voriconazole
(Vfend) 154
5.2.5 Fluoroquinolones 158
5.2.6 Fluticasone propionate (Flovent, Flixotide) 160
5.2.7 Aprepitant (Emend) 165
5.3 Summary and Future Outlook 169
References 170
6 Applications of Pentafluorosulfanyl Substitution

in Life Sciences Research 175
John T. Welch
6.2 General Preparative Information 177
b1171_FM.qxd 3/21/2012 9:21 AM Page xvii
Contents xvii
6.2.1 Synthesis of 1-fluoro-4-nitro-2-

(pentafluorosulfanyl)benzene and derivatives 178
6.2.2 Synthesis of 4,5-dihydroisoxazoles with allylic
pentafluorosulfanyl substituents 178
6.2.3 Pentafluorosulfanyl (SF5) pyrrole carboxylic
acid esters 179
6.3 Agrochemical Applications 180

6.3.1 3-(2-Chloro-4-(pentafluorosulfanyl)phenoxy)
benzoic acid 180

6.3.2 Pentafluorosulfanylphenyl and
benzoylisoxazoles 181
6.3.3 Trifluralin analogue 182
6.3.4 Insecticidal derivatives of substituted
phosphorylated phenylalkyl iminooxazolines
and iminothiazolines 183
6.3.5 Fungicidal (E)-methyl 2-(2-(3-
(pentafluorosulfanyl)phenoxymethyl)
phenyl)-3-methoxyacrylate, 44 183
6.3.6 N-(3-Phenylpropyl) and (3-phenylethyl)
benzamides 184
6.4 Medicinal Chemistry 184
6.4.1 1-(Pentafluorosulfanylphenyl)-3-(1,2,4-triazol-
3-ylthioalkyl)-3-azabicyclo[3.1.0]hexanes,
dopamine D3 receptor modulators 185
6.4.2 Pentafluorosulfur piperazinylpiperidines 186
6.4.3 Pentafluorosulfanyl arene containing pyrazoles 187
6.4.4 N-(phenoxycyanomethylethyl)
(pentafluorosulfanyl) benzamide 187
6.4.5 Preparation of pentafluorosulfanyl-substituted
compounds for use as vanilloid receptor VR1
ligands 188
6.4.6 4-Fluoro-N-(4-pentafluorosulfanylphenyl)
-4-(3-fluoropyridin-2-yl)
cyclohexanecarboxamide 84 189
6.4.7 Pentafluorosulfanylarene aminoimidazoles 190
6.4.8 3-Phenylhydantoins 191
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6.4.9 Pentafluorosulfanyl benzoylguanidines 192

6.4.10 Pentafluorosulfanylphenoxy-substituted
benzoylguanidines 193
6.4.11 Functionalization of
pentafluorosulfanylphenoxy-substituted
benzoylguanidines 193
6.4.12 Pentafluorosulfanyl-containing diarylamine

trypanothione reductase inhibitors 193
6.4.13 A pentafluorosulfanyl-containing quinoline,

a mefloquine analogue 196
6.4.14 Fluoxetine analogues 197
6.4.15 Fenfluramine and norfenfluramine 199
6.4.16 5-Hydroxytryptamine 200
6.5 Conclusions and Outlook 202
References 202
7 Strategic Incorporation of Fluorine into Taxoid

Anticancer Agents 209
Antonella Pepe, Liang Sun and Iwao Ojima
7.2 Paclitaxel, Docetaxel and New-Generation Taxoids 210
7.3 Synthesis and Biological Evaluation of
Fluorine-Containing New-Generation Taxoids 213
7.4 Synthesis and Biological Evaluation of
Fluorine-Containing C-Seco-Taxoids 221
7.5 Use of Solid-State 19F NMR and Computational
Analysis for the Determination of Bioactive
Conformation of Paclitaxel and Fluorinated Taxoids 226
7.6 Use of Fluorine in Tumour-Targeting Anticancer
Agents 232
References 235
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Contents xix
8 Synthesis and Antiviral, Antitumour Activities

of Fluorinated Sugar Nucleosides 241
Feng Zheng, Xiao-Long Qiu and Feng-Ling Qing
8.2 Nucleosides Fluorinated at C2′ 242
8.2.1 2′-α-Fluoro nucleosides 243
8.2.2 2′-β-Fluoro nucleosides 246

8.2.3 2′, 2′-Difluoronucleosides 250
8.2.4 2′-Fluoro-2′,3′-didehydro-2′,3′-dideoxy
nucleosides 252
8.3.1 3′-α-Fluoro nucleosides 254
8.3.2 3′-β-Fluoro nucleosides 256
8.3.3 3′,3′-Difluoro nucleosides 258
8.3.4 3′-Fluoro-2′, 3′-didehydro-2′, 3′-dideoxy
nucleosides 260
8.6 5′-Fluorinated and Phosphonodifluoromethylenated
Nucleosides 269
8.7 Nucleosides Bearing Exocyclic Fluorocarbon
Substituents at C2′, C3′ and C4′ 272
8.7.1 Nucleosides containing a trifluoromethyl
group 272
8.7.2 Nucleosides containing a difluoromethylene,
fluoromethylene or difluoromethyl group 274
8.8 Other Fluorinated Nucleosides 276
8.8.1 Fluorinated cyclopropyl nucleosides 276
8.8.2 Fluorinated cyclobutyl and oxetanosyl
nucleosides 278
8.8.3 Fluorinated pyranosyl nucleosides 278
8.9 Conformational Studies of Fluorinated Nucleosides 280
8.10 Conclusion 284
References 284
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xx Contents
9 Synthesis of Fluorinated Neurotransmitter Analogues 299

Margit Winkler and David O’Hagan
9.2 Adenosine Receptors 300
9.3 Adrenoreceptors 305
9.3.1 Epinephrine (adrenaline) 305
9.3.2 Norepinephrine (noradrenaline) 306

9.3.3 Octopamine 307
9.3.4 Tyramine 308

9.4 Cannabinoid Receptors 308
9.5 Dopamine Receptors 310
9.5.1 Dopamine 310
9.5.2 L-DOPA 311
9.6 GABA Receptors 312
9.7 Glutamate Receptors 314
9.8 Histamine Receptors 317
9.9 Muscarinic Receptors 318
9.10 Nicotinic Acetylcholine Receptors 319
9.11 Serotonin Receptors 321
9.12 Melatonin Receptors 323
9.13 Vanilloid Receptors 323
9.14 Capsaicin 323
9.15 Anandamide 324
9.16 Conclusion 324
References 325
Section 3 333
18
10 F-Radionuclide Chemistry 335
Romain Bejot and Véronique Gouverneur
10.1.1 Radioisotope 18F 335
10.1.2 Nuclear reactions 335
10.1.3 Production of 18F 337
10.1.4 Positron emission tomography (PET) 338
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Contents xxi
10.1.5 Specific activity 339

10.1.6 Kinetics and radiochemical yield 341
10.2 Carrier-Added 18F-Labelled Probes 342
10.2.1 Carrier-added [18F]fluoride 342
10.2.2 Surface interactions with 18F-labelled probes 344
10.2.3 Catalytic fluorination 345
10.3 Nucleophilic 18F-Radiolabelling 345

10.3.1 Reactive [18F]fluoride 346
10.3.2 Nucleophilic carbon–fluorine bond formation 348

10.3.3 Silicon–fluorine bond formation 357
10.3.4 Boron–fluorine bond formation 358
10.3.5 Aluminium–fluorine bond formation 359
10.3.6 Phosphorus–fluorine bond formation 359
10.4 Electrophilic 18F-Radiolabelling 360
10.4.1 Electrophilic fluorination agents 360
10.4.2 Electrophilic carbon–fluorine bond formation 364
10.5 Prosthetic Groups 367
10.6 Purification 369
References 370
18
11 F-Labelled Tracers for PET Oncology
and Neurology Applications 383
Sajinder K. Luthra and Edward G. Robins
11.1 Introduction to Molecular Imaging 383
11.2 Positron Emission Tomography (PET) 384
11.3 Biological Imaging Targets 385
11.4 Tracer Development 385
11.5 Oncology Applications 388
11.6 2-[18F]Fluoro-2-Deoxy-D-Glucose ([18F]FDG) 389
11.7 3′-Deoxy-3′-[18F]Fluoro-L-Thymidine ([18F]FLT) 391
11.8 Imaging Tumour Angiogenesis 396
11.9 Choline Metabolism 404
11.10 Apoptosis 408
11.10.1 PS targeting radiotracers 408
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xxii Contents
11.11 Caspase Targeting Radiotracers 411

11.12 CNS Neurosciences Applications 413
11.13 Beta-Amyloid Plaques and Neurofibrillary Tangles 414
11.13.1 FDDNP 415
11.13.2 BTA derivatives 417
11.13.3 Stilbenes 421
11.14 Peripheral Benzodiazepine Binding Sites

or TSPO-18kDa 423
11.14.1 Aryloxyanilide-based ligands 424

11.14.2 [18F]FEDAA1106 425
11.14.3 [18F]FEAC and [18F]FEDAC 426
11.14.4 PBR06 426
11.14.5 [18F]FEPPA 428
11.14.6 Pyrazolopyrimidine ligands 429
11.15 Serotonin 5-HT1A Antagonists and Agonists 431
11.16 Imaging the Cannabinoid 1 Receptor (CB1) 435
11.17 Ion Channels 440
11.18 Summary 440
References 441
19
12 F NMR: Clinical and Molecular Imaging Applications 461
Vikram D. Kodibagkar, Rami R. Hallac, Dawen Zhao,
Jian-Xin Yu and Ralph P. Mason
12.2 Clinical Applications and Drug Metabolism 468
12.3 Reporter Molecule Strategies 473
12.3.1 Physical interactions 474
12.3.2 Chemical association 480
12.3.3 Chemical interactions 484
12.4 Passive Reporter Molecules 490
12.5 Recent Innovations, Novelties and Future Improvements 492
12.5.1 Chemistry and molecular engineering 492
12.5.2 Biology 495
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Contents xxiii
12.5.3 Physics 496

12.5.4 Innovative new applications 496
12.6 Context of 19F NMR in Biomedicine Today 497
Acknowledgments 500
References 500
Index 525
b1171_Chapter-01.qxd 3/21/2012 9:43 AM Page 3
1
Synthesis and Properties
of Fluorinated Nucleobases
in DNA and RNA
by MCGILL UNIVERSITY on 03/01/13. For personal use only.
Holger Gohlke,* Jelena Bozilovic † and Joachim W. Engels †
1.1 Introduction
The stability of nucleic acid structures is predominantly governed by hydro-
gen bonding, base stacking, and solvation. To probe these interactions, a
common approach is to replace the native bases adenine (A), uracil
(U)/thymidine (T), guanosine (G) and cytosine (C) with analogues in which
functional groups are added, deleted, blocked or rearranged. The size and
shape of the analogues should be preserved as closely as possible to native
bases. Such ‘non-polar nucleoside isosteres’ (NNIs) then allow detection of
the predominant forces within nucleic acid structures without introducing
steric effects. For DNA, this concept was introduced by Kool and coworkers
in 1994 (Schweitzer and Kool, 1994). Initially, these molecules were intended
to be used as probes of the importance of hydrogen bonding and base stack-
ing in the formation of stable DNA duplex structures (Schweitzer and Kool,
1994; Kool and Sintim, 2006). In the context of DNA replication, it was later
* Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität,

Universitätsstr. 1, 40225 Düsseldorf, Germany.
†
Institute of Organic Chemistry and Chemical Biology Goethe-University, Max-von-Laue-
Str. 7, 60438 Frankfurt, Germany. E-mail: joachim.engles@chemie.uni-frankfurt.de
3
b1171_Chapter-01.qxd 3/21/2012 9:43 AM Page 4
4 H. Gohlke, J. Bozilovic and J. W. Engels
concluded by these authors that steric effects rather than hydrogen bonding
was the chief explanation for replication fidelity (Kool, 1998; Kool and
Sintim, 2006). In 1999, the concept of NNI was introduced into the RNA
world by Engels and coworkers, initially using fluorinated benzenes and
benzimidazoles as pyrimidine and purine base analogues, respectively
(Parsch and Engels, 1999, 2000). Syntheses and crystallographic studies of
these and other NNIs as well as thermodynamic analyses and computer sim-
ulations of model RNAs incorporating them are reviewed here. These
combined studies have proved invaluable for probing the physical forces that
govern the stability of RNA and shedding light on the role of fluorine in
by MCGILL UNIVERSITY on 03/01/13. For personal use only.
molecular recognition. As a biological application, the incorporation of flu-

orinated NNI into ribozymes and siRNA is finally described.
1.2 Fluorine in Molecular Recognition

Substituting hydrogen by fluorine in organic compounds influences a
variety of the molecule’s properties. In medicinal chemistry, fluorine
substitution has long been known as a means of enhancing metabolic sta-
bility, modifying chemical reactivity and conformational equilibria, and
improving transportation and absorption characteristics of pharmaceuti-
cals (Müller et al., 2007; Bégué and Bonnet-Delpon, 2008; Hagmann,
2008). In contrast, the role of ‘organic fluorine’ in influencing molecular
recognition properties, i.e. specific bonding between two or more mole-
cules through non-covalent interactions, is much less understood. Here we
focus on influences that are particularly important in the context of
fluorinated NNIs.
The properties of the C–F bond provide a starting point for appreci-
ating some of these influences. Replacing F for H is considered the most
conservative substitution for hydrogen on steric grounds, although a fluo-
rine atom is closer in size (and bond length) to oxygen than hydrogen
(O’Hagan, 2008). Hydrogen and fluorine are also quite different regarding
their electronic influences. The high electronegativity of fluorine imparts
a less covalent and more electrostatic character to a highly polarized C–F
bond, allowing interactions between the C–F bond dipole and other
dipoles in close proximity (O’Hagan, 2008). In turn, fluorine’s three lone
pairs are held tightly, as manifested by the atom’s high ionization potential
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that he refused to sell his customers any leather, until every drop of
moisture had been dried out of it, because the water would make it
weigh more, you know, and, of course, he would get money that did
not really belong to him. I think, had John lived in New York, some
of the business men here would have thought him crazy, or he would
have thought them crazy; but, you see, John couldn’t cheat; not even
though he should never be found out in it. Most young men, when
they are of John’s age, think more about their own affairs than
anything else—their own business, their own pleasures, etc.; whether
they will ever be rich men, how rich they will be, and all that. It was
not so with John. He wanted money, ’tis true, but all this time he had
not forgotten the little slave boy, and others like him, and it was for
such as he that he wanted money, that he might help them away
from their masters, and help them to be free by and by. He married,
and had many children of his own, and when these children grew up,
they all felt just as their father did about the slaves. After a time,
John helped eleven slaves to get away to Canada, where they were
quite safe. How glad they must have been! and how they must have
loved John! Somebody asked John how he felt when he got them
there? he said that he was so happy about it, that he was quite ready
to die then. But there was other work for John and his boys to do.
There was a place called Kansas, where John’s boys went to live; but
as soon as the people there found out that John’s boys and himself
loved the slaves, they began to steal their cattle, and burn their
fences, and try, in every possible way, to trouble and bother them. So
John’s boys wrote home to the old man about it, and told him that he
must send them some guns and muskets, to defend their property
and their lives with. Well, the old man didn’t have to stop to think
long about that. He told his other boys, who were living at home with
him, about it, and they agreed to start right off for Kansas, with as
many guns and muskets as they could get. John had no idea of his
boys out there being murdered and robbed, without fighting for
them, especially when they were treated so merely for pitying the
poor slaves. When they reached there, John and his four boys, they
each had a short, heavy broadsword strapped to their sides. Each one
had a quantity of firearms and revolvers, and there were poles
standing endwise round the wagon box, with fixed bayonets,
pointing upward. Oh! I can tell you, he was in real earnest about it!
Well, they suffered great hardships there, while fighting for their
rights: one of John’s boys was taken by the enemy, and driven with
chains on him, so far in a hot sun to prison, that he became a maniac;
another of his sons was so injured, that he became a cripple for life;
another son was murdered while quietly walking along the road, and
as he lay a corpse on the ground, one of his brutal enemies
discharged a loaded pistol in his mouth. All this John had to bear,
but he only said, “It is very hard; but my sons have died in a good
cause—died for the poor slaves.” Most people thought, “John has had
enough of it now; he will fight no more about slavery; he has taken
the rest of his boys back to his old home in the mountains, and he
will not be in a hurry to have them killed.”
They were mistaken. John was only waiting to whet his sword. He
knew how to wait. One day, the whole country about Harper’s Ferry
was in a state of distraction. The women and children were
frightened to death, for John Brown was down there; and it was said
he was going to help all the slaves he could to get away from their
masters; and that his boys were there to help him, and a great many
other men; and that they had guns, and swords, and pistols in plenty,
and meant to fight fiercely, if anybody tried to hinder them. John
chose Harper’s Ferry, because there were mountains all about it, and
he had known every turn in them, and all their valleys, too, for
seventeen years, and in case they were beaten, he thought it would be
a good place for himself and the slaves to hide in, as well as a good
place to fight from. The first night of John’s attack on the town, he
and his men put out all the lights in the street, and took possession of
the armory, where the firearms, you know, are kept. Then they took
three watchmen, and locked them up in the guardhouse. There must
have been friendly black people in the town who helped them do all
this. Some of them cut down the telegraph wires, and others tore up
the railroad track after the train had passed. When it came daylight,
John and his men took prisoner every person who came out into the
streets, and when people said, “Why do you do this? What do you
mean?” John and his men said, “We mean to free the slaves!” One of
the workmen employed at the armory, when he came to work that
morning, and saw an armed guard at the gate, asked of John’s guard,
“By what authority have you taken possession of this building?” “By
the authority of God Almighty!” said he.
Well, one after another, the workmen who came to their work in
the armory that day, were taken prisoners. There was a terrible
panic, I can tell you. John and his five sons were inside the armory
grounds, while others were stationed outside the walls, to hold the
town—some at the bridges, some at one place, some another. When
the workmen whom John took prisoners told him how troubled their
wives and children would be about them, John kindly allowed them
to go home, under a guard of his soldiers, to tell them not to be
frightened. John wanted, in doing this, to make the people
understand that the prisoners in his hands should not be hurt; a
brave man, you know, is always a tender-hearted man. Poor John! he
lingered too long about these things. The people whom he allowed to
go in the cars, before he tore up the railroad track, wrote on little
slips of paper terrible accounts of him, and scattered them through
the country as the cars went flying through; so the first thing he
knew, one hundred soldiers came to Harper’s Ferry from
Charlestown. Now, indeed, they had bloody work. John’s men began
to get killed, but not one of them but sold his life as dearly as he
could, fighting fiercely till he could fight no longer. Some lay dying in
the street, some of the corpses floated down the river, some were
taken, bleeding and gasping, to prison. Even after John’s men were
dead, his enemies continued to kick and beat their insensible bodies,
and many ran sticks into their wounds. And now John knew that all
that was left him, was to sell his life as dearly as he could. With one
son dead by his side, and another shot through, he felt the pulse of
his dying boy with one hand, and held his rifle with the other, and
told his few men about him to be firm and calm. He said that his
boys came with him to fight of their own accord, and that they had
died in a good cause. Well, the soldiers soon battered down the
building, and got in where John and his men were. An officer, as
soon as he saw John, although he and his men had then done firing,
struck him in the face, and knocked him down. The same officer
repeated the blow several times, and then, when John was lying on
the ground, helpless, another soldier ran his bayonet twice into the
old man’s body, whose face and hair were clotted with blood. Then
they searched his pockets, and took what they wanted, and then
carried him, bleeding, to the guard house, and laid him on the bare
floor, without anything under him. Then the governor hurried down
to see him, with several of his friends, and though the poor old man
was writhing in agony with his wounds, and the blood and the smoke
were not yet washed from his face, for thirty hours they let him lie
upon the floor, with his head propped up on a chair, while they
questioned him, and while the mob insulted him. After that, John
was carried off to Charlestown jail, under a guard of soldiers. The
body of John’s son was carried off for the doctors to cut up. Seven
days after this John was dragged from his bed, and being unable to
stand, was supported on each side by an officer into court, and there
laid on a bed, to be tried by the laws of Virginia, for what he had
done. Well, John had a “Virginia trial.”
A trial, you know, is a fair hearing on both sides. John was faint
and bleeding, and unable to stand; they refused to let him have a
lawyer to speak for him, and declared him guilty without hearing at
all his side; although the law declares a man innocent till he is
proved by law to be guilty. Then they told the jailer to shoot him if
anybody tried to help him escape; and this was John’s trial. Now,
John did not wish to die with the character of a robber or a
murderer, and before they took him out of court, he lifted his head
up from his mattress and told them that he had not had a fair trial;
that he was too sick to talk; that his money, fifty or sixty dollars in
gold, had been taken from him, and that he could not now pay
anybody to do any errands for him; that they ought to give him time
to send for his friends. But it was of no use, because they had
determined not to give him time; so he was brought into court again
on his bed soon after, and sentenced to be hung, i. e., if he did not die
first, on Friday, the second day of December; and when the judge
said that John would be hung where everybody would have a chance
to see it, one man jumped up before John and clapped his hands,
because he was so glad that he should see the brave old man die.
Forty-two days in all, John lay in a Charlestown prison. All that
time, sick as he was, no clean clothes were given him, although sixty
dollars of his money were taken from his pocket when he was
arrested. All those forty-two days and nights, he had lain there in the
stiff, dirty, blood-stained garments in which he fell.
Well, John had two Virginia militia companies come out of
curiosity to see him in prison. He treated them civilly, but told the
jailer, after they left, that he did not like being made a monkey show
of. Everybody who loved slavery, was allowed to gape and stare at
John as much as they pleased; but John’s friends, although they were
ladies and gentlemen who had traveled a long distance, found it hard
work to get leave to take a peep at him.
John’s wife wanted to come and see him before he died, and bid
him good by. John told her she would be insulted and badly treated,
and she had better stay at home with the children; and besides, I
suppose, John was afraid it would make it harder for him to die, and
leave her and the girls all alone in the world. But the poor woman
could not bear not to look in the face of her children’s father once
more, and at last John told her she might come. When she got there,
the jailer led her into the cell, but she could not speak to John, nor
John to her. She only laid her head upon his breast, and clasped his
neck with her arms.
Then, seeing a heavy chain on John’s ankles, and fearing it might
pain him, she kneeled on the floor and pulled two pair of woolen
socks on his feet. Then John told her what to say to his children at
home, and how he wanted them to live, when he was dead; and that
she must pay some money to some persons for him, whom he
named; and then he read her his “will,” which he had made. And
then John and his wife ate their “last supper” together. Perhaps these
words will remind you, as they did me, of another “Last Supper.” And
then the jailer, Captain Anis, told the poor wife that she must go. And
then John said to his wife, “God bless you! Mary; good by;” and then
she went out, and never saw John more, till she looked upon his dead
face.
There were three ropes sent to hang John Brown with; South
Carolina sent one, Missouri one, and Kentucky one. They chose the
Kentucky rope, because it was the stronger, and then it was shown,
in public, to the people. Well, the second day of December, when the
old man was to be strangled, came at last. It was a lovely day, so mild
and warm that the windows of all the houses were open. The scaffold
was to be in a field, half a mile from the jail. At seven in the morning
the carpenters came to fix it. At eight o’clock the soldiers began to
come; horsemen, dressed in scarlet jackets, were placed about the
field, and a double line of sentries farther on; then the State of
Virginia, fearing, after all this, that it would not be safe enough from
a feeble, sick old man, brought a huge brass cannon, so placed and
pointed, that if a rescue were attempted, John might be blown into
little atoms in a moment. There were about five hundred soldiers in
the field; and lines of them were stretched over fifteen miles. There
were not many people of the place there to see John hung, for they
dared not leave their slaves alone at home, for fear of mischief in
their absence; for all the poor slaves knew very well that John was to
be hung that day, because he was their friend.
At eleven o’clock, they brought John out of jail, and put him in the
wagon, to drive him to execution.
As John stepped from out the door of his prison, a black woman,
with a little child in her arms, stood near. He stopped for a moment,
stooped over, and kissed the little black child. Soon after, as he
passed along, another black woman said, “God bless you! old man. I
wish I could help you, but I cannot.” This made the tears come in
John’s eyes for the first time.
By John’s side was seated the undertaker, and on the wagon was a
black coffin, enclosed in a box, because his body was to go to his poor
wife after these Virginians had done with him. Then several
companies of soldiers, mounted on horseback, rode beside the
wagon, which was drawn by two white horses. As they went along,
John looked at the lovely Blue Mountains and the bright sky, and the
warm sunshine spread over all, and said, calmly, “This is a beautiful
country; I have not seen it before.” The jailer, who sat beside him,
could hardly say “yes,” he was so astonished to see John so quiet and
smiling, as if he were only taking a ride on that lovely day. Then the
undertaker said to John, “You are more cheerful than I am, Captain
Brown.”
“Yes,” said the old man, “I ought to be.”
And now the wagon had come to the field, where stood the gallows,
and all those hundreds of soldiers, and the great brass cannon. The
bright sun shone on the bayonets and muskets of the soldiers and
their gay uniforms, and the lovely Blue Mountains looked very calm
and peaceful; and the soldiers kept very close to old John, for
Virginia felt uneasy till the breath was out of him. Then John got out
of the wagon and stood on the scaffold, and took his hat off for the
last time, and laid it down by his side. Then he thanked the jailer,
who had been kind to him; then they tied his elbows and ankles; then
they drew a white cap over his eyes, and then they put the Kentucky
rope around his neck. Then the sheriff told John to step forward; and
John said, “I can’t see; you must lead me.” Then the sheriff asked
John to drop his handkerchief, for a signal for him to hang him; and
John said, “Now I am ready; only don’t keep me long waiting.”
When John asked his enemies for time for his trial, they wouldn’t
let him have any; now, when he did not want any more time, they
kept him waiting. So they made the old man stand there, blindfolded,
full ten minutes, while they marched the soldiers up and down, and
in and out, just as if they were drilling on parade. Some of the
soldiers felt ashamed of this cruelty to the old man, and muttered
between their teeth, for it was as much as their necks were worth to
say it loud, “Shame! shame!” Then, at last, after the military
maneuvers were over, the rope was cut, and John struggled and
strangled and died. Then, you know, after that, Virginia had to be
very sure the old man was really dead; so first the Charlestown
doctors went up and poked him over, and pulled him about; then the
military doctors had their turn; lifting up his arms, and putting their
ears a great deal closer to his breast than they would have cared to do
once, to see if he breathed; then they swung the body this way and
that, in the air, for thirty-eight minutes. Then they lifted the body
upon the scaffold, and it fell into a harmless heap. Then, although all
the doctors who had pulled him around declared that he was dead,
still Virginia was so afraid of John, that she insisted on cutting the
dead body’s head off, or making it swallow some poison, for fear, by
some hocus pocus, it might wake up again. But it didn’t wake—at
least, not in the way they expected. But there is fierce fighting down
in Virginia to-day; for, though John Brown’s body lies mouldering in
the grave,
His soul is marching on!
THE PLOUGHBOY POET.
M other Nature does not always, like other mothers, lay her pet
children on downy pillows, and under silken canopies. She
seems to delight in showing that money shall buy everything but
brains. At any rate, she not only opened our poet’s big, lustrous eyes,
in a clay cottage, put roughly together by his father’s own hands, but,
shortly after his birth, she blew it down over his head, and the
mother and child were picked out from among the ruins, and carried
to a neighbor’s for safe keeping—rather a rough welcome to a world
which, in its own slow fashion, after the mold was on his breast,
heaped over it honors, which seemed then such a mockery.
But the poor little baby and his mother, happy in their mutual
love, knew little enough of all this. A good, loving mother she was,
Agnes by name; keeping her house in order with a matron’s pride;
chanting old songs and ballads to her baby-boy, as she glided
cheerfully about; not discouraged when things went wrong on the
farm, and the crops failed, and the table was scantily supplied with
food—singing, hoping, trusting, loving still; a very woman, over
whose head cottages might tumble, so that her heart was but
satisfied.
Robert’s father was a good man, who performed each day’s duty as
carefully as though each day brought other reward than that of
having done his duty. It is a brave, strong heart, my dear children,
which can do this. All can labor when success follows; it is disaster,
defeat, difficulties, which prove what a man’s soul is made of. It is
just here that the ranks grow thin in life’s battle—just here that the
faint-hearted perish by the wayside, or desert, like cowards, to the
enemy. William Burns stood manfully to his duty, plodding on, year
after year;—when one plan failed, trying another; never saying, when
his day’s work was done, “Ah! but this is too discouraging! I’ll to the
alehouse, to drown my griefs in strong drink!” Neither did he go
home moody and disconsolate, to drive his children into corners, and
bring tears to the eyes of his toiling wife. But morning and evening
the prayer went up, with unfailing trust in Heaven. Oh! but that was
glorious! I love William Burns! Did he say at night, when so weary,
“Now, at least, I’ll rest?” Not he: there were little bright eyes about
him, out of which the eager soul was looking. So he gathered them
about his armchair on those long winter evenings, and read to them,
and taught them, and answered their simple yet deep questions. One
of Robert’s sweetest poems, the Cotter’s Saturday Night, was written
about this. Robert’s father told his children, too, of the history of
their country; of skirmishes, sieges, and battles; old songs and
ballads, too, he repeated to them, charming their young ears. Was
not this a lovely home picture? Oh! how much were these peasant
children to be envied above the children of richer parents, kept in the
nursery, in the long intervals when their parents, forgetful of these
sweet duties, were seeking their own pleasure and amusement. More
blessed, surely, is the humblest roof, round whose evening hearth
gather nightly, all its inmates, young and old.
Nor—poor as they were—did they lack books. Dainties they could
forego, but not books; confusedly thrown about—soiled and
thumbed; but—unlike our gilded, center-table ornaments—well
selected, and well read. And so the years passed on, as does the life of
so many human beings, quiet, but eventful.
Who sneers at “old women”? I should like to trace, for a jeering
world, the influence of that important person in the Burns family.
Old Jenny Wilson! Little she herself knew her power, when, with
Robert Burns upon her knee, she poured into his listening ear her
never-ending store of tales about fairies, and “brownies,” and
witches, and giants, and dragons. So strong was the impression these
supernatural stories made upon the mind of the boy, that he declared
that, in later life, he could never go through a suspicious-looking
place, without expecting to see some unearthly shape appear. Who
shall determine how much this withered old woman had to do with
making the boy a poet? And yet, poor humble soul—that is an idea
which seldom enters the mind of his admirers. The bent figure, with
wrinkle-seamed face, gliding noiselessly about your house, doing
odds and ends of household labor, now singing a child to sleep, now
cooking at the kitchen fire, now repairing a garment, or watching by
a sickbed—always on hand, yet never in anybody’s way; silent,
grateful, unobtrusive, yet beloved of Heaven—have you not known
them?
Robert’s mother, the good Agnes, had a voice sweet as her name.
The ballads she sang him were all of a serious cast. She had learned
them, when a girl, from her mother. Oh, these songs! Many a simple
hymn, thus listened to by childhood’s ear, has been that soul’s last
utterance this side the grave. All other childish impressions may have
faded away, but “mother’s hymn” is never forgotten. That strain,
heard by none else, will sometimes come, an unbidden, unwelcome
guest; and neither in noise nor wine can that bearded man drown it—
this mother’s hymn! Sing on, sing on, ye patient, toiling mothers!
over the cradle—by the fireside. Angels smile as they listen. The lark
whom the cloud covers, is not lost.
The father of Robert Burns did not consider, because he was a
poor man, that it was an excuse for depriving his boys of any
advantages of education within his reach, as many a farmer, similarly
situated, and intent only on gain, has thought it right to do. His good
sense, in this respect, was well rewarded; for Robert’s first teacher
said of him, that “he took such pleasure in learning, and I in
teaching, that it was difficult to say which of the two was most
zealous in the business.” It is such scholars as these who brighten the
otherwise dreary lot of the teacher. Pupils who study, not because
they must, and as little as possible at that, but because they have an
appetite for it, and crave knowledge. Of course, a good teacher
endeavors to be equally faithful to all the pupils who are intrusted to
him—the stupid and wayward, as well as the studious. But there
must be to him a peculiar pleasure in helping, guiding, and watching
over a pupil so eager to acquire. The mother bird, who coaxes her
fledglings to the edge of the nest, and, by circling flights overhead,
invites them to follow, understands, of course, how the little,
cowering thing, who sits crouched on a neighboring twig, may be too
indolent, or too timid to go farther; but she looks with proud delight
upon the bold little soarer, who, observing well her lesson, reaches
the top of the tallest tree, and sits, swaying and singing, upon its
topmost branch.
Robert, however, had not always the good luck to have, as in this
case, an intelligent, appreciative teacher. I suppose it is not treason
to admit, even in a child’s book, which, by some, is considered a
place for tremendous fibbing, that a teacher may occasionally err, as
well as his pupil. That teachers have been known to mistake their
vocation, when they have judged themselves qualified, after trying
and failing in every other employment, to fill such a difficult and
honorable position.
It seems there was a certain Hugh Rodgers, to whose school
Robert was sent. It was the very bad custom of those times, when
pupils of his age first entered a school, to take the master to a tavern,
and treat him to some liquor. This Robert did, in company with
another boy, named Willie, who entered at the same time. Do you
suppose that schoolmaster ever thought remorsefully about this in
after years, when he heard what a wreck strong drink had made of
poor Robert? Well, the boy Willie and Robert became great friends
from that day; often staying at each other’s houses, and always
spending the intervals between morning and afternoon school, in
each other’s company. When the other boys were playing ball, they
would talk together on subjects to improve their minds. Now, as they
walked while they talked, their omitting to play ball was not of so
much consequence as it would otherwise have been—at least,
according to my motto, which is, chests first, brains afterward. But
to go on. These disputatious youngsters sharpened their wits on all
sorts of knotty subjects, and also invited several of their companions
to join their debating society—whether to improve them, or to have
an audience to approve their skill, I can’t say; perhaps a little of both.
By and by the master heard of it. He didn’t like it. He had an idea
boys should have no ideas that the master didn’t put into their heads
for them. So one day, when the school was all assembled, he walked
up to the desks of Robert and Willie, and began, very unwisely, to
taunt them about it before all the scholars—something in this style:
“So, boys, I understand that you consider yourselves qualified to
decide upon matters of importance, which wiser heads usually let
alone. I trust, from debating, you won’t come to blows, young
gentlemen,” &c., &c. Now, the boys who had not joined their
debating society, set up a laugh, like little rascals, at the rebuked
Robert and Willie. This, of course, as the teacher should have known,
stung them to the quick; and Robert, with a flushed face, resolved to
“speak up” to the master. I find no fault with his reply, which was
this; that both he and Willie rather thought that he (the master)
would be pleased, instead of displeased, at this effort to improve
their minds. At this, Hugh Rodgers laughed contemptuously, and
said he should be glad to know what these mighty nonsensical
discussions might be about. Willie replied that they had a new
subject every day; that he could not recollect all; but that the
question of that day had been, whether is a great general, or
respectable merchant, the more valuable member of society. At this,
Hugh Rodgers laughed more uproariously and provokingly than
before, saying, that it was a very silly question, since there could be
no doubt for a moment about it. “Very well,” said Robert Burns, now
thoroughly roused, “if you think so, I will take any side you please, if
you will allow me to discuss it with you.”
The unfortunate schoolmaster consented. He commenced the
argument with a pompous flourish in favor of the general. Burns
took the other side, and soon had the upper hand of the
schoolmaster, who made a very lame reply. Soon the schoolmaster’s
hand was observed to shake, his voice to tremble, and, in a state of
pitiable vexation, he dismissed the school.
Poor man! he understood mathematics better than human nature;
and himself least of all. This was an unfortunate victory, for two
reasons. It was an unnecessary degradation of a man who had his
estimable qualities, and it increased the self-sufficiency of young
Burns, who was born with his arms sufficiently a-kimbo. Alexander-
fashion, he soon sighed for another conquest. His bedfellow, John
Nevins, was a great wrestler. Nothing would do, but he must floor
John Nevins. Strutting up to John, he challenged him to the combat.
John soon took that nonsense out of him, by laying him low.
Vanquished, he sprang to his feet, and challenged him to a
discussion. There he had him!—John having more muscle than
brain. Burns’s pride was comforted, and he retreated, a satisfied
youth. This is all I know about Robert’s childhood.
Silver hairs were now gathering thickly on his good father’s
temples, as he toiled on, to little use, while children grew up fast
about his knees, to be fed, schooled, and clothed by his labor. Robert
and his brother looked sadly on, as his health declined. Robert had
little inclination for his father’s work, and yet, somebody must take
his place; for consumption was even then making rapid and fearful
havoc with his constitution. The good old man ceased from his labors
at last, and went where the weary rest. For a while, Robert strove to
fill his place—strove well, strove earnestly. But the farmer who stops
to write poems over his plough, seldom reaps a harvest to satisfy
hungry mouths. And so, poverty came, instead of potatoes, and
Robert Burns, although the troubled eyes of his wife looked into his,
and his little children were growing up fast about him, and needed a
good father, to teach them how to live in this world, and to earn
bread for them till they became big enough to earn it for themselves,
it came about that, instead of doing this, he drank whisky to help him
forget that he ought to keep on ploughing, if poetry did not bring him
bread, and so made poverty a great deal worse. His wife was very,
very sorrowful about it, and his little children became tired of waiting
for him to love them, and care for them. Perhaps you say, Oh, how
could he do so? My dear children, how can anybody ever do wrong?
How can you ever vex your dear mother, who is so good to you, and
go pouting to bed, and never tell her that you are “sorry”? and still,
while you are sleeping, that dear, good, forgiving mother stoops over
your little bed, and kisses your forehead, and looks to see if you are
warm and comfortable, before she can sleep, the same as if you had
been a good child, instead of a bad one. I hope you will think of this
before that good mother dies, and tell her that you are very sorry for
grieving her; and I hope, too, that Robert Burns, before it was too
late, said that he was sorry for grieving those who loved him, and for
wasting his life; but I do not know about that.
OLD HICKORY.
M any a time, I dare say, you have sat on your bench at school,
with your cotton handkerchief spread over your knee, looking
at the stern face of this famous man upon it; every bristling hair
upon his head seeming to say for itself, In the name of the
commonwealth, stand and deliver! You have thought, perhaps, that a
man with such a sharp eye and granite face as that, must be a very
terrible person, whose heart was quite left out when he was made,
and whom little children had better run away from. It is just because
this was not true, that I first believed in General Jackson. A brave
man is never a mean one; and it is mean to despise or bully children
and women. I place children first, because every woman who has
ever had one, does so. But to my story. We, who have lived so
peacefully and quietly in the land for which our brave ancestors
fought, do not think as often as we ought of the sufferings and trials
through which they purchased it for us. Until lately, our houses were
not burned down over our heads, or ransacked and robbed, nor our
mothers and sisters insulted before our eyes, nor our fathers and
brothers dragged off as prisoners of war, and kicked and cuffed for
sport by the enemy. All this, Andrew Jackson’s boyish eyes saw. Do
you wonder at the fire in them? One of his earliest recollections was
of the meeting house in his native place turned into a hospital for his
wounded, maimed, dying, brave countrymen; and his own widowed
mother, leading him there by the hand to nurse them, and dress their
wounds, and comfort them, as only a woman with a strong heart and
angel touch can. Could the boy stand by and see all this, and not long
for the time when he should grow big, and stout, and tall, and help
fight for his country? Could he help being impatient, he, the son of
this unprotected mother, when one after another of these poor
fellows was brought in, with their fresh, ghastly wounds, and laid
down to die? And when, later, his cousin’s house was taken by the
British, and the furniture was broken in pieces, and his cousin’s wife
was insulted by the officers, and he and his brother were taken
prisoners, and ordered by the officer, with an oath, to clean his
muddy boots; and, because they both refused, were cut and slashed
across the face and head by this bullying, cowardly fellow, Andrew
then being only twelve years old; and then were marched miles and
miles away down South, and not allowed a morsel of food by the way,
and forbidden even to scoop up water from the streams they were
fording, to quench their feverish thirst? Ah! do you wonder now at
that stern face? Suppose your dear mother, whom your dear father,
whom you can just remember, loved so tenderly, was driven across
the country with you and your little brother, from place to place, for
safety, in those troublous times, and subjected to all kinds of
hardships, bearing up under it bravely, as good women will. Suppose
that when you and your brother—still boys—were dragged off as
prisoners of war, this dear, brave mother traveled off alone, and
never rested till she managed, by an exchange of prisoners with the
British general, to get her dear boys back again; but wan and wasted
with small pox, and the wounds that they had received from that big,
cowardly British officer, all undressed and uncared for; these boys,
her Andrew, her Robert? Well, as your mother would have nursed
you and your brother through her tears, so Andrew Jackson’s mother
nursed her fatherless boys. But was Andrew a boy to forget either his
mother’s love, or the British? No, indeed! And when, after he became
well, and the whole band went to live in the house of a friend, and
Andrew picked beans, and pulled fodder, and drove cattle, and went
to mill, do you wonder that when he was sent to the blacksmith’s, to
get the farm tools mended, he brought home spears of iron, and all
sorts of odd-looking, rough weapons, that, while waiting for the
blacksmith, he had himself manufactured “to kill the British with”?
Do you wonder that he fastened the blade of a scythe to a pole, and
exclaimed, fiercely, as he cut down the weeds with it, “Oh! if I were
only a man, wouldn’t I sweep off the British with my grass blade?”
And he did it, too, afterward. Let those who call him “fierce, savage,
vindictive,” remember how these sorrows of his childhood were
burned in upon his soul; remember what burning tears must have
fallen upon the little bundle containing all his dead mother’s clothes,
she who had struggled and suffered through the war of the
Revolution, and left him an orphan at fifteen years, with only the
memory of her love and his country’s wrongs. As he stood weeping
over that little bundle, friendless, homeless, and heart-broken,
thinking of all she had been to him, and looking wistfully forward
into the dim unknown, he did not see the future President of the
United States, and hear his voice falter as he said, “I learned that,
years ago, from my dear, good mother!” Well might he remember her
then. You ask me if Andrew found no opportunity to get an education
in these troublous times? You may be sure his mother knew the value
of that! and sent her boys, when quite young, to the best schools she
could find in their native place. Schools, in those days, were not the
furnace-heated, mahogany-desked affairs we see now. Pupils did not
carry an extra pair of shoes to put on when they entered, for fear of
soiling the floor. Velvet jackets were not worn by the boys, nor gold
bracelets by the girls. Andrew Jackson’s schoolroom was an old log
house made of pines, the crevices being filled in with clay, which the
boys used to pick out when it came spring, to let in the fresh air. In
this school no French, nor drawing, nor “moral science,” was taught.
Reading, writing, and arithmetic was all. For a gymnasium, there
were the grand old trees, which the freckled, sunburnt, redheaded
Andrew was free to swing upon when school was done; and he went
up and down them like a squirrel. I think he was better at that than
at his books, if the truth must out; however, “learning” did not go
before chests in those days, luckily for us, who enjoy the blessings for
which our fathers’ strong arms fought. So Andrew studied some, and
leaped, and wrestled, and jumped more;—was kind to defenceless
small boys, but had his fist in the face of every fellow who made fun
of him, or taunted him, or in any way pushed him to the wall.
Andrew had one very bad habit when a boy, which, I am sorry to
say, followed him all his life. He swore fearfully! An oath, from
anybody’s mouth, is hateful; but from a child’s mouth! I know
nothing more saddening and pitiful. Often, I know, children will use
such words, quite unconscious of their meaning, as they pick them
up from those who have no such excuse for their utterance, till the
habit becomes so fixed, that only in later life, when they pain some
person who is “old-fashioned” enough to reverence the name they
use so lightly, do they become conscious of the extent of this
disgusting habit. The idea of its being “manly” to swear is ridiculous
enough; since the lowest, most brutal ruffian in creation, can, and
does, outdo you in this accomplishment. I think Andrew would have
enjoyed his boyish sports quite as well without these bad words; and
he was a splendid fellow for all athletic exercises. Had he been alive
when that game of cricket was won by the English cricketers, I don’t
know what would have happened; well, it wouldn’t have happened;
or had it, the victors would never have gone home alive to tell of it!
Andrew was a good son to his mother; he was honest, and truthful,
and kind to her always. He never forgot her as long as he lived. He
used often, when President of the United States, to stop in the midst
of his conversation, and say, reverently and proudly, “That I learned
from my good mother!”
One cannot help feeling sad that she should have lived long
enough only to bear the burden and heat of the day, and not share
with her boy its calm repose and reward. And yet, who can believe
that a mother and son so loving are divided, though one crosses
alone the dark river before the other? We have seen, of a fine
summer morning, after the sun shone out, fine gossamer threads,
before invisible, floating, yet fixed, in the air above us. So, when the
light of eternity shines on our life-path, shall these chords of a
mother’s love be seen to have entwined themselves around and about
us—leading us in a way we knew not.
Jackson’s life was a strange one. It is for me only now to speak of
his childhood and youth. His relation to our country’s history will not
suffer you to rest satisfied with this. His after-life is better told than I
could tell it you, by a man who is now looking over my shoulder, and
who says, I have just told you a fib. If you read “Parton’s Life of
Andrew Jackson,” however, you will see that I have told the truth.
THE DEAF AND DUMB FRENCH BOY.
I was sitting, this morning, at my window, looking at a fine sunrise,

when suddenly I thought, how terrible, were I to become blind!
And then I asked myself, were I to choose between blindness and
deafness, how should I decide? Never to see the dear faces, never to
see the blue sky, or green earth, or delicate flowers;—never to listen
to the melody of birds, or the sweet voices of the trees and streams,
or hum of busy insect-life; or, more dreadful still, never to hear the
sweet voices of those I love;—oh, how could I choose? When we
murmur and complain, surely we forget the blessings of hearing and
sight; they are so common, that we forget to be grateful; so common,
that we need to have written pitying words to the deaf of our own
kin, or led the sightless, fully to understand their sufferings. And yet
all the world is not now dark to the blind, or voiceless to the deaf,
thanks to the good people who teach both these unfortunates. How
different was their position once, a long while ago! Let me tell you
about it.
In France lived a little boy, born of parents who had six deaf and
dumb children, three boys and three girls. It must have been very
dull to them all; but one of them, little Pierre, seemed to feel it most.
Children of his own age would not play with him, they seemed to
despise him; so he trotted round like a little dog, trying to amuse
himself with sticks, and stones, and anything that came in his way;
his body grew tall, like other children’s, but his mind remained a
little baby. He didn’t know whether he had been made, or had made
himself. His father taught him to make prayers by signs, morning
and evening. Poor little fellow! he would get on his knees, and look
upward, and make his lips move, as if he had been speaking; but he
did not know there was any God: he was worshiping the beautiful
sky. He took a great fancy to a particular star, because it was so
bright and beautiful; and at one time, when his mother lay very sick,
he used to go out every evening, and kneeling down, make signs to it,
to make her well; but finding that she did not get any better, he grew
very angry, and threw stones at the star, supposing that it might,
after all, be the cause of his deafness, his mother’s sickness, and all
their other troubles. Seeing others move their lips when speaking, he
moved his, hoping the talk would come out; and sometimes he made
noises like an animal. When people told him the trouble was in his
ears, then he took some brandy, poured it into his ears, and then
stopped them up with cotton, as he had seen people do who had cold
in their heads. Pierre desired much to learn to read and write. He
often saw young boys and girls who were going to school, and he
desired to follow them; not that he knew what reading and writing
really were, but from a feeling that there were some privileges and
enjoyments from which he ought not to be shut out. The poor child
begged his father, as well as he knew how, with tears in his eyes, to
let him go to school. His father refused, making signs to him that he
was deaf and dumb, and therefore could never learn anything. Then
little Pierre cried very loud, and taking some books, tried to read
them; but he neither knew the letters nor the words. Then he became
angry, and putting his fingers into his ears, demanded impatiently to
have them cured. Then his father told him again, that there was no
help for it; and Pierre was quite heart-broken. He left his father’s
house, and without telling him, started off alone to school, and going
into the schoolhouse, asked the master, by signs, to teach him to read
and write. The schoolmaster (I think he could not have had any little
children of his own) refused him roughly and drove him away from
the school. Then Pierre cried very much; but you will be glad when I
tell you that, although only twelve years old, he was such a little hero
that he wouldn’t give up. He took a pen, and tried, all alone, to form
the writing signs; and that, indeed, was the best and only thing he
could do, and he stuck to it, though everybody discouraged him.
His father used sometimes to set him to watch the flocks;
oftentimes people, in passing, who found out his condition, gave the
boy money. One day—and it was a great day for poor Pierre—when
he was thus watching the flocks, a gentleman who was passing took a
fancy to him, and inviting him to his house, gave him something to
eat and drink. Then the gentleman went off to Bordeaux, where he
lived. Not long after, Pierre’s father, for some reason or other, moved
to Bordeaux; and then this kind gentleman spoke of Pierre to a
learned man of his acquaintance, who was interested in deaf and
dumb persons, and he consented to take Pierre and try to teach him.
Are you not glad? and you will be gladder still, when I tell you how
fast he learned, and how, by his own strong will, assisted by his kind
tutor, he unriveted, one by one, the chains with which his wits were
bound, and casting them aside, stood forth under the bright star, at
which he used to throw stones, and understood now what it was, and
who made it. You may be sure that nobody had to tease little Pierre
to learn his lessons, as some little children have to be teased to study
theirs. No indeed! he felt like jumping and leaping for joy that he was
able to learn; and it seemed to him that there was nothing left in the
world worth fretting about, now that he could learn, like other
children.
That is all I know about little Pierre, but I hope he grew up a good
as well as a smart man; don’t you?
THE THREE GIFTED SISTERS.
“Like as a father pitieth his children.”
A ccording to this text, Charlotte Brontë, though no orphan, had

no father. She was born in the little village of Haworth, England.
Her father was a clergyman, and a very curious man, if the stories
told of him are true. I dare say he may have been a good man in his
way, but I don’t fancy his way. I don’t like his burning up some pretty
little red shoes, belonging to his little children, because he did not
like the color. I don’t like his firing off pistols, when he got angry, and
terrifying his little meek wife. I shouldn’t want to hear such a terrible
minister preach, had I gone to his church. Well, never mind that. His
feeble little wife was taken very sick, and the doctor said she must
die; die, and leave those little children to the care of this father I have
spoken of, who seemed to be about as fit for the charge, as an
elephant would be to take care of little humming birds. One touch of
his great paw would crush the life out of them.
LITTLE CHARLOTTE.—Page
82.
You may be sure the poor dying mother felt badly enough about all
this, as she lay in her bed, growing thinner, and paler, and weaker
each day. She could see the churchyard where she was to be buried
from her chamber window; in fact, one had to pass through it, with
its moss-grown tombstones, to get to the house, which was a very
gloomy one at best, as parsonage houses are too apt to be. I suppose
she tried very hard to feel willing to leave them; but she found she
could not do it, if she saw their dear little faces every day. So they did
not go to her sick-room any more; she could hear the pattering of
their tiny feet in the entry, and their hushed whispers as they passed
her door, and so, pressing her hands tightly over her mother heart, to
still its pain, and leaning on the Crucified, she passed away.
It is very dreadful for a child to lose its mother—much worse, I
think, than to lose a father; because a father, be he ever so good and
kind, must be away from his little ones, and cannot, by any
possibility, understand their little wants and ways as a mother can;
and a child’s heart is such a tender thing to touch; one may mean
well, and give it such exquisite pain, and the poor thing cringes, and
shrinks, and has no words by which it can tell its distress. But
suppose the father understands nothing about a child’s heart.
Suppose he thinks to treat it like a grown person’s, who has been
knocked about the world till he don’t care for anything, who never
cries, never laughs, never is glad, never is sorry, never wants to lay
his head on a dear, kind shoulder, and cry—what then? Suppose that
father, instead of taking breakfast, dinner, and supper with his lonely
little children, takes his meals up in his own room, and leaves them
sobbing over theirs, while they try to swallow the food that tasted so
sweet when their dear mother sat at the head of the table—what
then? Suppose it was a bleak, dreary country where they lived, where
no flowers grew, where were no gardens; and that, when these little
children became tired of huddling together, like a frightened flock of
lambs, in their gloomy nursery, where never a cheerful fire was
lighted, or cheerful lamps twinkled when night came on—suppose
they tied on their little bonnets, and, led by the eldest, who was only
seven, went through the damp churchyard, past their mother’s grave,
and out on the bleak, cold hills to walk, without their father to lead
them by the hand, or take them up in his arms when tired, or speak a
kind word, or warm their little chilled hearts or hands in any way?
Suppose day after day went by in this fashion, what sort of children
do you suppose they would become? Healthy, hearty, rosy, jumping
little things, such as God and man love to see, loving play and frolic,
with broad chests and shoulders, and bright eyes and hearts? Not at
all. They never once thought of playing; they hadn’t a toy in the
house; their heads grew big, and their bodies grew little; and they
were as wide awake at night, as if somebody had hired them not to go
to sleep. But their father slept soundly, all the same as if their little
hearts were not like an empty cage, out of which music and beauty
has taken wing forever. Well, God loved them; that’s a comfort, and
that thought kept little Charlotte’s heart from sinking, when she tried
to be mother to her younger brothers and sisters; all the while she
needed a mother herself, more than any dictionary could ever tell.
After a while, an aunt came to their house, to take charge of them.
I was glad of that. I hoped she would make them play dolls, and run,
and jump about; I hoped she would make the fires and lamps burn
cheerily, and go round the house shedding brightness from her finger
tips, as only a woman knows how. I hoped she would go out to walk
with the little orphans, and when they came home to supper, sit
down with them at the table, and say funny things to make them
laugh; and good things to make them happy and glad. I hoped she
would tie on their little night dresses with her own hands, and kiss
them down on their pillows, and say, God bless you, my little
darlings! It was such a pity she didn’t. I am sure a woman ought to
understand little children better than she seemed to. But she just
shut herself up in her room, the same way their father did, and took
all her meals alone. I have no patience with her. I wish I had lived
near them; they should have eaten and drank with me, poor little
souls! Well, they had a kitchen, and a good old servant, named
Tabby, in it, and, from what I can find out, she was more of a mother
to them, in her rough fashion, than anybody else. I told you these
children had no toys; and, what was worse, they did not want any;
they used to read newspapers and talk politics, just as your father
and his gentleman friends might, in your parlor. As to “Mother
Goose,” I am sure they never heard of her, though they read many
books that are considered much wiser, and which were just as much
out of place in a nursery, as a joint of roast beef would be to set
before your little month-old baby, for its dinner. But how should they
know that? Nobody about them seemed to think that childhood
comes but once; or, in fact, was intended to come at all for them.
“Milk for babes” was not the fashion at Haworth parsonage. Well,
time passed on, till their father concluded to send Charlotte away to
school, with her sisters. So they were put into a little covered cart
with their things, and jolted along. I hope their father kissed them
when they went away, but I am not at all sure of it. I am afraid he was
too dignified. It is hard enough for a child to go away to school with a
warm kiss on the lips, and a trunk full of comfortable clothes, in
every stitch of which is woven a mother’s blessing. It is hard enough
for a healthy, romping child, who is able to ask for what it wants
everywhere, and on all occasions, to leave home, and go a long
distance to a strange school, even though it may have letters often,
and plum cakes often, and all sorts of little love-tokens, which home
delights to send to the absent one. But to these little timid ones, who
had never played with children, and were as much afraid of them as
of strange, grown people; who had come up, shy and awkward and
old-fashioned, and were painfully conscious of it, as soon as it was
brought to their notice by contrast with those children, who had
come from their warm firesides like some graceful house-plants, full
of blossoms and verdure—ah! it was very sad for the poor little
Brontë girls. What could they do when they got there, but stand at
the window, and cry, as they looked out upon the snowy landscape?
And when the girls urged them to play ball, and other such healthful
games, they had no heart for it—no physical strength for it, either;
they would have been tumbled over forty times in a minute, by their
playmates, like so many ninepins, with a great, thumping ball. Well,
they had a bad time of it, any way, at this school—bad food, bad air,
and exposure. I suppose, too, their clothes were not warm enough,
for the hand was cold that would have made the warm garment for
those bloodless, shrunken limbs. It is “mother’s” fingers that fit the
cloak close to the little neck, so that through no treacherous crevice
the cruel “croup” may creep; it is “mother’s” fingers that quilt the
little winter skirt with the soft, warm wool, and furnish the thick
stocking, and comfortable hood. It is “mother’s” eye which sees just
the thing that is needed to meet all weathers. We can imagine how
they went shivering along, half clad, to the church on Sunday, where
never a fire was lighted; how blue were their fingers; how cold their
little feet! No wonder they grew sick. Little Maria Brontë, who was
delicate under the remains of the whooping cough, suffered most
severely from cold, and want of nourishing food. A blister was
applied to her side for her relief, and the poor, weak child, happening
to linger in bed one morning later than the usual hour for rising, was
harshly dragged in this state into the middle of the room, and then
punished, because she had not strength enough to dress herself in
time to appear with the other scholars. This must have been very
hard to bear. Perhaps you ask, Why didn’t Charlotte Brontë write
home about it? She had two reasons: one was, that both she and her
sisters were most anxious to learn everything that they could learn at
this school; and in the next place, they had been so accustomed to
keep all their childish troubles to themselves, although their hearts
were nearly breaking, that I don’t suppose they once imagined, if
they thought of it, that it would do any good to complain. So they
shivered in the cold, and tried to swallow the bad food that was given
them, when they grew so hungry they could not do without it, until
poor little Maria grew so very bad, that her father had to be sent for.
God pitied the poor child, and took her to heaven, to be with her
mother. She died a few days after reaching home. Charlotte and
Emily, the two remaining sisters, did not long stay in the school after
their sister’s death. I think their father at last woke up to the thought,
that they might die too, and nobody might be left at the old, gloomy
parsonage, to send up his meals, or wait upon him, or read to him, or
mend his clothes. So he brought them home too. I believe all children
are fond of being in the kitchen. They are active, and like to see what
is going on; they like to watch the cooking, and ask questions about it
—often, much better than the cook likes to answer. The little Brontë
girls’ cook was named Tabby, and a funny old woman she was. She
was very kind to them, but she would have her own way, and made
them do as she said; still, I have no doubt, from what I know of her,
that she put by many a nice little bit for their hungry mouths, and
told them a great many fairy stories, as they cuddled round the old
kitchen fire, when her work was done; but I think they had to be very
careful not to meddle with anything without leave, or get in her way,
when she was hurried or busy; and that was all right enough, for the
poor old thing must have elbow-room, you know; besides, it is a good
thing for a child to be taught that it may not order about a good,
faithful servant, old enough to be its mother, merely because she is a
servant.
About this time the little girls began to amuse themselves writing
little plays, poetry, and “compositions” for their own amusement.
They had a little “make believe” newspaper, too, for which they and
their brother Patrick used to write, and old Tabby had to speak pretty
sharp, sometimes, to make them go to bed, when they were busy with
these things. I suppose they did not care to go to bed early, for they
did not sleep as healthy, happy children do, the moment their heads
touch the pillow, until a mother’s soft kiss wakes them to a new day
of joy; but no doubt they turned and tossed, and wished it were
daylight, and all their sorrows grew larger and more intolerable to
bear in the silent, dreary night. They who have been in great trouble
know this; when the faintest leaf-whisper, from one tree to another,
seems like spirit voices, torturing one with a language which you try,
but cannot understand; when the dear ones who are dead seem so
very near, and yet so very far away; when their faces seem to look out
from the darkness, like a star suddenly appearing from a black cloud,
and then again wrapped in its dusky folds. No wonder the nervous,
lonely little Brontës begged Tabby not to send them to bed.
Charlotte did not stay long at home; her father resolved to send
her away to school again, and her little sister and brother were forced
to do without her.
When persons interest us very much, it is natural to wish to know
how they look.
Well, then, Charlotte Brontë, at the time she went to this school,
was a very homely little girl. One of her schoolmates draws for us this
picture of her, at that time: “I first saw her coming out of a covered
cart, in very old-fashioned clothes, looking very cold, and very
miserable. When she afterward appeared in the schoolroom, her
dress was changed, but just as old-fashioned. She looked like a little
old woman, so short-sighted that she always appeared to be seeking
something, and moving her head from side to side to catch sight of it.
She was very shy and nervous, and spoke with a strong Irish accent.
When a book was given her, she dropped her head over it, till her
nose nearly touched it, and when she was told to hold her head up,
up went the book after it, so that it was not possible to help
laughing.” Another schoolmate says, that the first time she saw
Charlotte, she was standing by the schoolroom window, looking out
on the snowy landscape and crying, while all the rest of the girls were
at play. Poor child! no doubt she felt desolate enough. Fortunately
for Charlotte, her teacher, Miss Woolen, was a lady of intelligent
mind and kind heart. She understood the odd-looking, timid, wise
little being before her. She knew that there was a gem, all but the
setting. So she did not overlook the knowledge stowed away in that
little busy brain, because grammar and geography had found no
place there. Then came the question, how to manage this little
sensitive pupil, without keeping back the other girls in the class, who
already understood these branches, though, perhaps, they were far
behind her in others. At first she thought she must put her in the
second class, till, as school girls say, she had “caught up” with the
other girls. But the moment she mentioned it, Charlotte’s
mortification and distress were such, that, like a wise teacher, she
saw that if she only saved her this pain, by allowing her to go into the
first class, she immediately would make up by private study wherein
she was deficient; and so it proved.
One feels as glad at this kindness, as though she were one’s own
little sister. We find her, at this time, not playing with the other
romping girls, but standing in the playground with a book, or looking
dreamily at the scenery. When urged to join them in their sports, she
said No—always pleasantly. Playing ball, and such healthful games,
she probably disliked, as much, perhaps, for lack of bodily strength,
as from any other cause; though that would have come by degrees,
had she only allowed herself to try; it was a great pity she did not.
However, she was always so good-natured and amiable, that she was
a favorite with the girls, although she wouldn’t play with them.
Sometimes, with the natural freedom of their age, they would tell her
that she was “awkward,” or ugly; but this never displeased her,
though, I have no doubt, she felt sorry that they thought so. In the
portraits of that fine face of hers, which I have seen, the term “ugly”
seems to be sadly misapplied. Those might think so, who fancy a
pink and white doll-face; but neither could such see the moral
beauty of her daily life, over that thorny road, every meek, patient
step of which was as the Saviour’s at Gethsemane.
Charlotte remained a year at this school, studying very hard. This
was well, had she also remembered that her fragile body needed
equal care with her mind; for of what use is knowledge if there is no
bodily strength by which we can make it useful to those about us?
Charlotte had no watchful mother, to impress this upon her as a
religious duty; to remind her that she was as responsible for the care
of her body, as for the improvement of her mind. And so her mind
kept on expanding, and threatening to shatter its feeble prison house
in pieces. It was a great pity; but it seems even in England, where so
much more attention is paid than here to “raising” perfect, robust
specimens of men and women, such things do happen. At Miss
Woolen’s school, Charlotte formed an agreeable intimacy with two
schoolmates—young ladies of her own age. This was a great benefit
to her, because she had been made so prematurely old in her
feelings, by loneliness and sorrow. One cannot help catching
animation and hope from a bright, joyous, fresh-hearted, breezy
companion, though one is ever so apt to look on the gloomy side of
things. And so it is quite cheering to know that, upon leaving Miss
Woolen’s school, and going back to her father’s dull house, these
young girls exchanged letters and visits with one another. And now,
perhaps, you suppose, that when Charlotte reached home, she sat
down and folded her hands in utter hopelessness, saying, “How
awful dull it is here! there is no use in trying to live in such a desolate
old cage of a place; it is really too bad for a young creature like me to
be shut up here. It is too bad for any girl so fond of reading, writing,
and drawing, to be a mere drudge in this lonesome place!” Perhaps
you think that, as she was a “genius,” she said or thought all this. Not
at all; and I’ll tell you why; because her genius was genuine, not
sham. It is only make believe geniuses who think the every-day
duties of life beneath their intellects. I want you to remember that
Charlotte Brontë did not shrink from one of them. She swept, and
she dusted, and she made beds, and she made bread (good, light,
wholesome bread, too), and pared potatoes, and watched the pot
boil, and kept everything in as nice order as if she had no taste for
anything but housekeeping. Perhaps you think then that she folded
her hands, and said, “I should think I had done enough now!” There
you are wrong again. She looked from her window into the little
churchyard, where her mother was lying, and said, “Now I must be a
mother to my brothers and sisters!” and she repaired their clothes,
and she taught them; for she had thoroughly learned her own
lessons and all those things she had studied at school. There’s a girl
for you! and all this, when she was so very fond of reading and
writing, which stood to her lonely heart in place of loving friends, for
whom she longed.
At length, on account of want of money, it became necessary for
some one of the family to go out into the world to earn it. Who
should it be? One would have naturally supposed the brother, as
being a sturdy, healthy fellow, better able to fight his way than his
delicate sisters, who shrank timidly from the sight of strange faces
and strange voices. It seemed not the thing for them to go out into
the wilderness, to make the path easy for his feet? If so, which of the
sisters should do this? Emily? Anne? or Charlotte? Emily grew
homesick to that degree when away, that her life was in danger, and
was obliged to be recalled for that reason. So, whoever was sent, she
must not go; for were there not two sisters already in the
churchyard? Anne was too young. Charlotte, then, was, as usual, to
buckle on the armor of duty over her brave heart, and stagger forth
with what strength she might, to face the world. She was to be a
governess! Imagine, if you can, the most torturing situation in which
to place such a nature as hers; and the daily trial of it, could not come
up to that included to her in the little word “governess.” Fortunately,
her first experiment was with Miss Woolen, her old teacher—her
scholars being younger sisters of her own playmates. Whatever she
did, she did with her might; therefore, so zealous was she to make
herself useful in her new situation, and so conscientious in the
discharge of duties which a less noble girl would have dodged, or
evaded sufficiently, at least, to make the position bearable, that we
soon hear of the breaking down of her feeble body, so that she almost
became crazy.
She had frightful thoughts and gloomy ideas about religious
things; anxiety about her sister Emily, who, resolving not to burden
her father with her support, had concluded to go forth likewise. Then
she was troubled, too, about the home affairs, which, as the elder
sister, she could not, even at a distance, shake off; and thus, leaving
childhood, which had been but childhood in name to her, we find
Charlotte a woman, brave yet fearful; timid but courageous; the
lion’s heart in the humming bird’s body. I meant only to have told
you about her childhood; and yet you may ask me, was Charlotte
never again comfortable, light-hearted, and happy? Did nobody but
her sisters ever love her very dearly? Did nobody else find out what a
good, intelligent, gifted girl she was? Oh yes, at last! At last came
fame and honor to the little, quiet Charlotte. Great men and great
women wanted to know her, because she wrote so beautifully, or, as
they said, was “a genius;” and she had plenty of complimentary
letters and invitations to visit, and all the publishers wanted to
publish her books; and she earned money enough to put a great
many pretty things in the little dull parlor at home, so that she hardly
knew it to be the same room; but, dear me! by that time all her
sisters lay in the little churchyard with her mother; and poor
Charlotte looked about at all these pretty things, and great tears
came into her eyes, as she thought, Oh, why didn’t all my money and
my friends come while they were alive, and could have been made
comfortable and happy by them, so that we could all have lived at
home together, and not been separated, to go away and teach school?
Why? Poor Charlotte could not find out that why, as she sat in that
little parlor, looking, with tearful eyes, at all the pretty things her
money had bought. Perhaps you ask what her father said now to his
good, gifted daughter. Oh, he sat up alone in his room, and was very
proud of her; but that didn’t warm her heart any, you know. By and
by a gentleman came along and asked her to be his wife. And after a
while she said, Yes, I will. I suppose she thought, I want to be loved,
more than anything in this world. It is very well, perhaps, to be “a
genius,” and to be admired; but my heart aches all the same. Yes, I
will be loved; and then I shall be happy; for, after all, the brightest

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Fluorine in Pharmaceutical and Medicinal Chemistry: From Biophysical

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From Biophysical Aspects

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British Library Cataloguing-in-Publication Data

Molecular Medicine and Medicinal Chemistry — Vol. 6

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Jihan - Fluorine in Pharmaceutical.pmd 2 3/20/2012, 11:02 AM

For almost a century after the first preparation of elemental F2 by Moissan

Brønstedt acid/base centers, polarity, and the influence on lipophilicity as

protein–ligand binding affinity and selectivity. New fluorinated building

vative drugs and agrochemicals. Substituting C–H by C–F bonds clearly

nucleobases in RNA, ribozymes, and siRNA are subsequently reviewed.

ond chapter Molecular Interactions of Fluorinated Amino Acids within the

pher the interactions of organofluorine within a native protein

with a general survey of organofluorine in drug discovery and develop-

highlight the effects of H/F substitutions on the development of com-

other compounds binding to central neuroreceptors such as the gluta-

studies requires special protocols for synthesis and purification due to

in an informative way. 18F-Labelled Tracers for PET Oncology and

fluorinated building blocks and investigations of their physicochemical

Laboratorium für Organische Chemie

CH-8093 Zurich, Switzerland

Véronique Gouverneur and Klaus Müller

relevant molecules. This is followed by an in-depth coverage of the impact

mation to the most recent developments. In the process of editing this

Véronique Gouverneur and Klaus Müller

1.4.3 Molecular dynamics simulations and free

1.5.2 Fluorobenzene and benzimidazoles in RNA

1.5.3 Polymerase acceptance of fluorobenzimidazoles 26

2 Molecular Interactions of Fluorinated Amino Acids within

3 Probing the Binding Affinity and Proteolytic Stability of

3.3 Peptidomimetics Containing the Trifluoroethylamine

3.4 Trifluoromethyl-Peptidomimetics as Protease Inhibitors 73

4 Trifluoromethyl-Substituted α-Amino Acids as Solid-State

4.6 Amino Acids with a Rigid Spacer Between Cα

4.6.5 Synthesis of peptides containing TfmBpg 121

with 4-TfmPhg and TfmBpg 122

6 Applications of Pentafluorosulfanyl Substitution

6.2.1 Synthesis of 1-fluoro-4-nitro-2-

6.3 Agrochemical Applications 180

benzoic acid 180

6.4.9 Pentafluorosulfanyl benzoylguanidines 192

6.4.12 Pentafluorosulfanyl-containing diarylamine