Welcome to Chem 206

Fall Term, 2005, David A. Evans

Chem 206 Teaching Fellows

Regan Thomson Pavel Nagornyy Keith Fandrick Yimon Aye Meredeth McGowan
These individuals are your mentors. They are here to help you through this course. Please take advantage of this opportunity.

Dr. Regan Thomson

PhD: Australian Nat. Univ Postdoctoral Fellow Evans Research Group Raised: New Zealand Lab No. Converse 308B rthomson@fas.harvard.edu Lab Phone: 617-495-3245

Pavel Nagornyy
Undergrad: Oregon State 5th-yr Graduate Student Evans Research Group Lab No. Converse 316 Lab Phone: 617-496-8569 nagornyy@fas.harvard.edu

Keith Fandrick
Undergrad: UC San Diego 5rd-yr Graduate Student Evans Research Group Lab No. Converse 306B Lab Phone: 617-495-3245 fandrick@fas.harvard.edu

Meredeth McGowen
Undergrad: Dartmouth 2nd-yr Graduate Student Jacobsen Research Group Lab No. Mallinckrodt 202 Lab Phone: 617-496-1836 mcgowen@fas.harvard.edu

Yimon Aye
Undergrad: Oxford Univ. UK 2nd-yr Graduate Student Evans Research Group Lab No. Converse 316 Lab Phone: 617-496-8569 yimonaye@fas.harvard.edu

Significant Dates this Fall

Mon, Sept 24th: Study card day Mon, Oct 10th: Columbus Day Class will be held Fri, Oct 14th: Exam 1 Mon, Nov 21th: Exam 2 Wed, Nov 24th: Class will not be held Thurs, Nov 24th: Thanksgiving recess begins Mon, Dec 19th: Exam 3 Wed, Dec 21st Winter recess begins Friday, January 23rd Scheduled Final Exam

Textbooks
Carey & Sundberg, Advanced Organic Chemistry, Parts A,B Kirby, A. J. Stereoelectronic Effects (See DAE) Fleming, I. Frontier Orbitals and Organic Chemical Reactions.

Web Problems (>500)

http://daecr1.chem.harvard.edu/problems/

Course Grading
3 one-Hour Exams 10 Problem Sets Final Examination 300 pts 200 pts 300 pts

We will grade your best effort. We will take your final exam score and manufacture an imaginary hr exam score (IHE). If this score is better than any two of your normalized hourly exam scores, the IHE score will replace those low scores. The IHE score will also be used in the event that an hourly exam was missed.

Sections

Sections will begin this week. Sign up prior to 5 PM this Wednesday

First Reading Assignment

! Reading Assignment for week:
Kirby, Stereoelectronic Effects Carey & Sundberg: Part A; Chapter 1 Fleming, Chapter 1 & 2 Fukui,Acc. Chem. Res. 1971, 4, 57. (pdf) Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf)

D. A. Evans

An Introduction to Frontier Molecular Orbital Theory-1

! Problems of the Day

Chem 206

http://www.courses.fas.harvard.edu/~chem206/ http://evans.harvard.edu/problems/

Chemistry 206 Advanced Organic Chemistry

Lecture Number 1

The molecule illustrated below can react through either Path A or Path B to form salt 1 or salt 2. In both instances the carbonyl oxygen functions as the nucleophile in an intramolecular alkylation. What is the preferred reaction path for the transformation in question? O O Br N H O Br
Path B Path A 1

Br

N O H Br O

Introduction to FMO Theory

! General Bonding Considerations ! The H2 Molecule Revisited (Again!) ! Donor & Acceptor Properties of Bonding & Antibonding States ! Hyperconjugation and "Negative" Hyperconjugation ! Anomeric and Related Effects

N O H Br

Br

This is a "thought" question posed to me by Prof. Duilo Arigoni at the ETH in Zuerich some years ago

(First hr exam, 1999)

The three phosphites illustrated below exhibit a 750fold span in reactivity with a test electrophile (eq 1) (Gorenstein, JACS 1984, 106, 7831).
(RO)3P OMe O P O A O

! Reading Assignment for week:

Kirby, Stereoelectronic Effects Carey & Sundberg: Part A; Chapter 1 Fleming, Chapter 1 & 2 Fukui,Acc. Chem. Res. 1971, 4, 57. (pdf) Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf)

El(+)
O P O B

+ (RO)3PEl

(1)

O P OMe O C

Rank the phosphites from the least to the most nucleophilic and provide a concise explanation for your predicted reactivity order.

D. A. Evans

Monday, September 19, 2005

D. A. Evans

An Introduction to Frontier Molecular Orbital Theory-1

! Stereoelectronic Effects

Chem 206

Universal Effects Governing Chemical Reactions There are three:

! Steric Effects
Nonbonding interactions (Van der Waals repulsion) between substituents within a molecule or between reacting molecules
Me SN2 Me Nu C R RO H H Me Me2CuLi RO Me H H O R

Geometrical constraints placed upon ground and transition states by orbital overlap considerations. Fukui Postulate for reactions:
"During the course of chemical reactions, the interaction of the highest filled (HOMO) and lowest unfilled (antibonding) molecular orbital (LUMO) in reacting species is very important to the stabilization of the transition structure."

Nu:

C R

Br

Br:

RO H

major

! General Reaction Types Radical Reactions (~10%):

A + B A(:) + B(+)
Lewis Acid

A A

B B

minor

Polar Reactions (~90%):

! Electronic Effects (Inductive Effects):

The effect of bond and through-space polarization by heteroatom substituents on reaction rates and selectivities Inductive Effects: Through-bond polarization Field Effects: Through-space polarization

Lewis Base

FMO concepts extend the donor-acceptor paradigm to non-obvious families of reactions

! Examples to consider H2 + 2 Li(0) Mg(0) 2 LiH CH3MgBr

Me R C R Br

SN1

+
R R C Me + Br:

CH3I +

"Organic chemists are generally unaware of the impact of electronic effects on the stereochemical outcome of reactions." "The distinction between electronic and stereoelectronic effects is not clear-cut."

rate decreases as R becomes more electronegative

D. A. Evans

Steric Versus Electronic Effects; A time to be careful!!

Chem 206

! Steric Versus electronic Effects: Some Case Studies

When steric and electronic (stereoelectronic) effects lead to differing stereochemical consequences
Woerpel etal. JACS 1999, 121, 12208.

O R3SiO EtO TiCl4 Nu OSiR3 O

AlCl3

OSiR3 diastereoselection >94:6 OSiR3 H O diastereoselection 93:7 H OSiR3

OAc

SnBr4 Me SiMe3

O Me

R3Si

Me

stereoselection 99:1 stereoselection >95:5

OAc

SnBr4 BnO

OSiR3 Danishefsky et al JOC 1991, 56, 387

BnO

BnO

O EtO2C O EtO2C (R)2CuLi Bu OTBS O OTBS diastereoselection 8:1

O Ph N O
only diastereomer

N N

AcO AcO

H H N N N O O only diastereomer Ph

Bu3Al
R3 O Al O

EtO2C

OAc OAc

O H Ph N O H

Bu OTBS

OAc OAc H H N O O Ph 60-94%

EtO

Yakura's rationalization:

R R

Al

O TBS R

Yakura et al Tetrahedron 2000, 56, 7715

Mehta et al, Acc Chem. Res. 2000, 33, 278-286

D. A. Evans
The H2 Molecule (again!!)

The H2 Molecular Orbitals & Antibonds

Chem 206

Linear Combination of Atomic Orbitals (LCAO): Orbital Coefficients

Let's combine two hydrogen atoms to form the hydrogen molecule. Mathematically, linear combinations of the 2 atomic 1s states create two new orbitals, one is bonding, and one antibonding:
! Rule one: A linear combination of n atomic states will create n MOs. !" (antibonding) #E

! Rule Two: Each MO is constructed by taking a linear combination of the individual atomic orbitals (AO): Bonding MO Antibonding MO " = C1!1 + C2!2 "# = C*1!1 C*2!2

The coefficients, C1 and C2, represent the contribution of each AO. ! Rule Three: (C1)2 + (C2)2 = 1

Energy

H $1

1s #E

1s

H $2

The squares of the C-values are a measure of the electron population in neighborhood of atoms in question ! Rule Four: bonding(C1)2 + antibonding(C*1)2= 1

! (bonding)

In LCAO method, both wave functions must each contribute one net orbital Consider the pibond of a C=O function: In the ground state pi-CO is polarized toward Oxygen. Note (Rule 4) that the antibonding MO is polarized in the opposite direction.

Let's now add the two electrons to the new MO, one from each H atom:
!" (antibonding) #E1 H $1 #E2 ! (bonding) 1s 1s H $2

$# (antibonding)

Energy

Energy

Note that #E1 is greater than #E2. Why?

$ (bonding)

D. A. Evans

Bonding Generalizations

Chem 206

! Bond strengths (Bond dissociation energies) are composed of a covalent contribution (! Ecov) and an ionic contribution (! Eionic). Bond Energy (BDE) = ! Ecovalent + ! Eionic (Fleming, page 27)

! Orbital orientation strongly affects the strength of the resulting bond.

For " Bonds: A B Better than A B

When one compares bond strengths between CC and CX, where X is some other element such as O, N, F, Si, or S, keep in mind that covalent and ionic contributions vary independently. Hence, the mapping of trends is not a trivial exercise.

For ! Bonds:

Useful generalizations on covalent bonding

! Overlap between orbitals of comparable energy is more effective than overlap between orbitals of differing energy. For example, consider elements in Group IV, Carbon and Silicon. We know that C-C bonds are considerably stronger by Ca. 20 kcal mol-1 than C-Si bonds.
C C !" CC !" CSi C C

Better than

This is a simple notion with very important consequences. It surfaces in the delocalized bonding which occurs in the competing anti (favored) syn (disfavored) E2 elimination reactions. Review this situation.

! Anti orientation of filled and unfilled orbitals leads to better overlap. This is a corrollary to the preceding generalization. There are two common situations. Case-1: Anti Nonbonding electron pair & CX bond
X A C
lone pair HOMO

better than

Si

Si

Si-SP3 C-SP3 ! CC C-SP3 C-SP3 ! CSi

X A C

!* CX LUMO

X Better than
lone pair HOMO

!* CX LUMO

H3CCH3 BDE = 88 kcal/mol Bond length = 1.534

H3CSiH3 BDE ~ 70 kcal/mol Bond length = 1.87

Case-2: Two anti sigma bonds

X C
! CY HOMO

This trend is even more dramatic with pi-bonds: ! CC = 65 kcal/mol ! CSi = 36 kcal/mol ! SiSi = 23 kcal/mol ! Weak bonds will have corresponding low-lying antibonds.
Formation of a weak bond will lead to a corresponding low-lying antibonding orbital. Such structures are reactive as both nucleophiles & electrophiles
A Y

Y
!* CX LUMO

X C

Better than

X C

! CY HOMO

!* CX LUMO

D. A. Evans

Donor-Acceptor Properties of Bonding and Antibonding States

Chem 206

Donor Acceptor Properties of C-C & C-O Bonds Consider the energy level diagrams for both bonding & antibonding orbitals for CC and CO bonds.
!* C-C !* C-O

Hierarchy of Donor & Acceptor States Following trends are made on the basis of comparing the bonding and antibonding states for the molecule CH3X where X = C, N, O, F, & H.
!-bonding States: (CX)
CH3CH3 CH3H CH3NH2 CH3OH

C-SP3

C-SP3 O-SP3

very close!!

decreasing !-donor capacity

! C-C ! C-O

CH3F

poorest donor

! The greater electronegativity of oxygen lowers both the bonding & antibonding C-O states. Hence:
! ! CC is a better donor orbital than ! CO ! !"CO is a better acceptor orbital than !"CC

!-anti-bonding States: (CX)

CH3H

For the latest views, please read Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf)
CH3CH3 CH3NH2 CH3OH CH3F

Donor Acceptor Properties of CSP3-CSP3 & CSP3-CSP2 Bonds

!* CC !* CC better acceptor

Increasing !"-acceptor capacity

best acceptor

C-SP3

C-SP3 C-SP2

The following are trends for the energy levels of nonbonding states of several common molecules. Trend was established by photoelectron spectroscopy.
Nonbonding States

! CC

better donor

! CC

H3P: H2S: H3N: H2O: HCl:

! The greater electronegativity of CSP2 lowers both the bonding & antibonding CC states. Hence: ! ! CSP3-CSP3 is a better donor orbital than ! CSP3-CSP2 ! !"CSP3-CSP2 is a better acceptor orbital than !"CSP3-CSP3

decreasing donor capacity

poorest donor

D. A. Evans

Hybridization vs Electronegativity

Chem 206

Electrons in 2S states "see" a greater effective nuclear charge than electrons in 2P states. This becomes apparent when the radial probability functions for S and P-states are examined: The radial probability functions for the hydrogen atom S & P states are shown below.
100 % 100 %

There is a linear relationship between %S character & Pauling electronegativity

5

NSP
4.5

Pauling Electronegativity

Radial Probability

Radial Probability

1 S Orbital

NSP2
3.5

NSP3
C
SP

2 S Orbital

2 S Orbital 2 P Orbital

2.5

CSP2 CSP3

3 S Orbital 3 P Orbital

20

25

30

35

40

45

50

55

% S-Character

There is a direct relationship between %S character & hydrocarbon acidity

60

55

CH4 (56)

S-states have greater radial penetration due to the nodal properties of the wave function. Electrons in S-states "see" a higher nuclear charge.
Pka of Carbon Acid

50

Above observation correctly implies that the stability of nonbonding electron pairs is directly proportional to the % of S-character in the doubly occupied orbital
Least stable Most stable

45

C6H6 (44)
40

35

CSP3

CSP2

CSP
30

PhCC-H (29)

The above trend indicates that the greater the % of S-character at a given atom, the greater the electronegativity of that atom.

25 20 25 30 35 40 45 50 55

% S-Character

D. A. Evans

Hyperconjugation: Carbocation Stabilization

Chem 206

! The interaction of a vicinal bonding orbital with a p-orbital is referred to as hyperconjugation. This is a traditional vehicle for using valence bond to denote charge delocalization.
R H H C

Physical Evidence for Hyperconjugation

Bonds participating in the hyperconjugative interaction, e.g. CR, will be lengthened while the C(+)C bond will be shortened. First X-ray Structure of an Aliphatic Carbocation

+
C

R H H H H C C H H

The graphic illustrates the fact that the C-R bonding electrons can "delocalize" to stabilize the electron deficient carbocationic center. Note that the general rules of drawing resonance structures still hold: the positions of all atoms must not be changed.

1.431

[F5SbFSbF5]

+
C

Stereoelectronic Requirement for Hyperconjugation: Syn-planar orientation between interacting orbitals

100.6

1.608

Me

Me Me

The Molecular Orbital Description

!" CR !" CR
T. Laube, Angew. Chem. Int. Ed. 1986, 25, 349

+
C

H H

+
C

H H

The Adamantane Reference (MM-2)

H

1.528

110

! CR

! CR

Me Me

Me

1.530

! Take a linear combination of ! CR and CSP2 p-orbital:

"The new occupied bonding orbital is lower in energy. When you stabilize the electrons is a system you stabilize the system itself."

D. A. Evans

"Negative" Hyperconjugation
Syn Orientation
R
""

Chem 206
antibonding !" CR R: H H C X+ H H antibonding !" CR R: R X+ H H C filled X hybrid orbital
""

! Delocalization of nonbonding electron pairs into vicinal antibonding orbitals is also possible R H H C
""

R C X

""

R H H H H

""

C H

filled hybrid orbital

H H

This decloalization is referred to as "Negative" hyperconjugation

Anti Orientation
R H C X
""

H H

Since nonbonding electrons prefer hybrid orbitals rather that P orbitals, this orbital can adopt either a syn or anti relationship to the vicinal CR bond.

The Molecular Orbital Description

!" CR

! Overlap between two orbitals is better in the anti orientation as stated in "Bonding Generalizations" handout.

The Expected Structural Perturbations

Change in Structure
X
!!

Spectroscopic Probe
X-ray crystallography X-ray crystallography Infrared Spectroscopy Infrared Spectroscopy NMR Spectroscopy NMR Spectroscopy

Nonbonding

pair

! Shorter CX bond ! Longer CR bond ! Stronger CX bond ! Weaker CR bond ! Greater e-density at R

! CR

As the antibonding CR orbital decreases in energy, the magnitude of this interaction will increase Note that ! CR is slightly destabilized

! Less e-density at X

D. A. Evans

Lone Pair Delocalization: N2F2

The trans Isomer

Chem 206
Now carry out the same analysis with the same 2 orbitals present in the trans isomer.

The interaction of filled orbitals with adjacent antibonding orbitals can have an ordering effect on the structure which will stabilize a particular geometry. Here are several examples: Case 1: N2F2 F N N This molecule can exist as either cis or trans isomers F F N N F There are two logical reasons why the trans isomer should be more stable than the cis isomer. ! The nonbonding lone pair orbitals in the cis isomer will be destabilizing due to electron-electron repulsion. ! The individual CF dipoles are mutually repulsive (pointing in same direction) in the cis isomer.
In fact the cis isomer is favored by 3 kcal/ mol at 25 C. Let's look at the interaction with the lone pairs with the adjacent CF antibonding orbitals. The cis Isomer F
filled N-SP2 F antibonding !" NF !" NF (LUMO) filled N-SP2 (HOMO)

filled N-SP2

N F

F antibonding !" NF filled N-SP2 (HOMO)

!" NF (LUMO)

! In this geometry the "small lobe" of the filled N-SP2 is required to overlap with the large lobe of the antibonding CF orbital. Hence, when the new MO's are generated the new bonding orbital is not as stabilizing as for the cis isomer.

Conclusions
! Lone pair delocalization appears to override electron-electron and dipole-dipole repulsion in the stabilization of the cis isomer. ! This HOMO-LUMO delocalization is stronger in the cis isomer due to better orbital overlap. Important Take-home Lesson Orbital orientation is important for optimal orbital overlap.

forms stronger pi-bond than

! Note that by taking a linear combination of the nonbonding and antibonding orbitals you generate a more stable bonding situation. ! Note that two such interactions occur in the molecule even though only one has been illustrated.

forms stronger sigma-bond than

This is a simple notion with very important consequences. It surfaces in the delocalized bonding which occurs in the competing anti (favored) syn (disfavored) E2 elimination reactions. Review this situation.