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Welcome to Chem 206Fall Term, 2005, David A. Evans

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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.

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Dr. Regan Thomson

PhD: Australian Nat. Univ

Postdoctoral Fellow

Evans Research Group

Raised: New Zealand

Lab No. Converse 308B

Lab Phone: 617-495-3245rthomson@fas.harvard.edu

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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

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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

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Meredeth McGowen

Undergrad: Dartmouth

2nd-yr Graduate Student

Jacobsen Research Group

Lab No. Mallinckrodt 202

Lab Phone: 617-496-1836mcgowen@fas.harvard.edu

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Yimon Aye

Undergrad: Oxford Univ. UK

2nd-yr Graduate Student

Evans Research Group

Lab No. Converse 316

Lab Phone: 617-496-8569yimonaye@fas.harvard.edu

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Mon, Sept 24th: Study card day

Mon, Oct 10th: Columbus Day Class will be held

Fri, Oct 14th: Exam 1

Mon, Nov 21th: Exam 2Wed, 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

Significant Dates this Fall

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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/

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Course Grading

3 one-Hour Exams

10 Problem Sets

Final Examination

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.

300 pts

200 pts

300 pts

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Sections

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

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First Reading Assignment

! Reading Assignment for week:

Kirby, Stereoelectronic EffectsCarey & Sundberg: Part A; Chapter 1

Fleming, Chapter 1 & 2Fukui,Acc. Chem. Res.1971, 4, 57. (pdf)

Alabugin & Zeidan, JACS2002, 124, 3175 (pdf)

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Chem 206D. A. Evans

D. A. EvansMonday,September 19, 2005

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

! Reading Assignment for week:

Kirby, Stereoelectronic Effects

Carey & Sundberg: Part A; Chapter 1

Fleming, Chapter 1 & 2Fukui,Acc. Chem. Res.1971, 4, 57. (pdf)

Alabugin & Zeidan, JACS2002, 124, 3175 (pdf)

Chemistry 206

Advanced Organic Chemistry

Lecture Number 1

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

An Introduction to Frontier Molecular Orbital Theory-1

! Problems of the Day

The molecule illustrated below can react through either Path A or Path B toform salt 1 or salt 2. In both instances the carbonyl oxygen functions as thenucleophile in an intramolecular alkylation. What is the preferred reaction

path for the transformation in question?

+

+

Br

Br 1

2

Path A

Path B

BrNH

OBr

O

O

BrON

H

O

ONH

Br

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

http://evans.harvard.edu/problems/

O

PO

OMe

O

PO OMe

OP

O

O

A B C

(RO)3P +

(First hr exam, 1999)

The three phosphites illustrated below exhibit a 750fold span in reactivity witha test electrophile (eq 1) (Gorenstein, JACS1984, 106, 7831).

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

El(+) (RO)3PEl (1)+

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Chem 206D. A. Evans An Introduction to Frontier Molecular Orbital Theory-1

minor

major

Br: Nu:

Nonbonding interactions (Van der Waals repulsion) betweensubstituents within a molecule or between reacting molecules

! Steric EffectsUniversal Effects Governing Chemical Reactions

There are three:

C Br

Me

RR

C R

R

Me

Nu

RO

H

SN2

O

Me2CuLi

RO

H

OH

Me

RO

H

OMe

H

! Electronic Effects (Inductive Effects):

Inductive Effects: Through-bond polarizationField Effects: Through-space polarization

The effect of bond and through-space polarization byheteroatom substituents on reaction rates and selectivities

+ Br:

+SN1

rate decreases as R becomes more electronegative

CR

R

Me

Br C MeR

R

"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."

Geometrical constraints placed upon ground and transition statesby orbital overlap considerations.

!Stereoelectronic Effects

Fukui Postulate for reactions:

!General Reaction TypesRadical Reactions (~10%): A B+ A B

Polar Reactions (~90%): A(:) B(+)+ A B

Lewis BaseLewis Acid

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

"Organic chemists are generally unaware of the impact ofelectronic effects on the stereochemical outcome of reactions."

"The distinction between electronic and stereoelectronic effects isnot clear-cut."

!Examples to considerH2 2 Li(0)+

CH3I Mg(0)+ CH3MgBr

2 LiH

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Chem 206D. A. Evans The H2 Molecular Orbitals & Antibonds

The H2 Molecule (again!!)

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:

Energy

1s 1s

!" (antibonding)

! Rule one: A linear combination of n atomic states will create n MOs.

#E

#E

Let's now add the two electrons to the new MO, one from each H atom:

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

! (bonding)

! (bonding)

#E2

#E1

!" (antibonding)

1s1s

$2

$2

$1

$1

Energy

H H

HH

+C1!1" = C2!2

Linear Combination of Atomic Orbitals (LCAO): Orbital Coefficients

Each MO is constructed by taking a linear combination of theindividual atomic orbitals (AO):

Bonding MO

Antibonding MO C*2!2"# = C*1!1

The coefficients, C1 and C2, represent the contribution of each AO.

! Rule Three: (C1)2 + (C2)

2 = 1

= 1antibonding(C*1)2+bonding(C1)

2! Rule Four:

Energy

$# (antibonding)

$ (bonding)

Consider the pibond of a C=O function: In the ground state pi-COis polarized toward Oxygen. Note (Rule 4) that the antibonding MOis polarized in the opposite direction.

C

C

O

C O

The squares of the C-values are a measure of the electron populationin neighborhood of atoms in question

In LCAO method, both wave functions must each contributeone net orbital

! Rule Two:

O

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Chem 206D. A. Evans Bonding Generalizations

When one compares bond strengths between CC and CX, where Xis some other element such as O, N, F, Si, or S, keep in mind thatcovalent and ionic contributions vary independently. Hence, the

mapping of trends is not a trivial exercise.

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

!" CSi!" CC

! CSi

! CC

Bond length = 1.87 Bond length = 1.534 H3CSiH3 BDE ~ 70 kcal/molH3CCH3 BDE = 88 kcal/mol

Useful generalizations on covalent bonding

For example, consider elements in Group IV, Carbon and Silicon. We

know that C-C bonds are considerably stronger by Ca. 20 kcal mol-1than C-Si bonds.

! Overlap between orbitals of comparable energy is more effectivethan overlap between orbitals of differing energy.

C-SP3

Si-SP3

C-SP3C-SP3

better thanC C C C C Si SiC

!Weak bonds will have corresponding low-lying antibonds.!SiSi = 23 kcal/mol!CSi = 36 kcal/mol!CC = 65 kcal/mol

This trend is even more dramatic with pi-bonds:

Formation of a weak bond will lead to a corresponding low-lying antibondingorbital. Such structures are reactive as both nucleophiles & electrophiles

Betterthan

For ! Bonds:

For " Bonds:

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

than

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

A B A B

BABA

Betterthan

Betterthan

Case-2: Two anti sigma bonds

! CYHOMO

!* CXLUMO

!* CXLUMO

lone pairHOMO

!* CXLUMO

!* CXLUMO

lone pairHOMO

Case-1: Anti Nonbonding electron pair & CX bond

! Anti orientation of filled and unfilled orbitals leads to better overlap.This is a corrollary to the preceding generalization.

There are two common situations.

! CYHOMO

A C A C

C CC C

A C

X

A

Y

C

XY

Y

X X

XX

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Chem 206D. A. Evans Donor-Acceptor Properties of Bonding and Antibonding States

C-SP3

!!"CO is a better acceptor orbital than !"CC

!! CC is a better donor orbital than ! CO

! The greater electronegativity of oxygen lowers both the bonding& antibonding C-O states. Hence:

Consider the energy level diagrams for both bonding & antibondingorbitals for CC and CO bonds.

Donor Acceptor Properties of C-C & C-O Bonds

O-SP3

!* C-O

! C-O

C-SP3

! C-C

!* C-C

!!"

CSP3-CSP2 is a better acceptor orbital than!"

CSP3-CSP3

C-SP3

!* CC

! CC

C-SP

3

! CC

!* CC

C-SP2

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

! The greater electronegativity of CSP2 lowers both the bonding &antibonding CC states. Hence:

!! CSP3-CSP3 is a better donor orbital than ! CSP3-CSP2

better donor

better acceptor

decreasing donor capacity

Nonbonding States

poorest donor

The following are trends for the energy levels of nonbonding states

of several common molecules. Trend was established byphotoelectron spectroscopy.

best acceptor

poorest donor

Increasing!"-acceptor capacity

!-anti-bonding States: (CX)

!-bonding States: (CX)

decreasing!-donor capacity

Following trends are made on the basis of comparing the bonding andantibonding states for the molecule CH3X where X = C, N, O, F, & H.

Hierarchy of Donor & Acceptor States

CH3CH3CH3H

CH3NH2

CH3OH

CH3F

CH3H

CH3CH3

CH3NH2

CH3OH

CH3F

For the latest views, please readAlabugin & Zeidan, JACS2002, 124, 3175 (pdf)

very close!!

HCl:

H2O:

H3N:H2S:

H3P:

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Chem 206D. A. Evans Hybridization vs Electronegativity

3 P Orbital

This becomes apparent when the radial probability functions for Sand P-states are examined: The radial probability functions for the

hydrogen atom S & P states are shown below.

3 S Orbital

Electrons in 2S states "see" a greater effective nuclear chargethan electrons in 2P states.

Above observation correctly implies that the stability of nonbonding electronpairs is directly proportional to the % of S-character in the doubly occupied orbital

Least stable Most stable

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

RadialProbability

100 %

2 P Orbital

2 S Orbital2 S Orbital

1 S Orbital

100 %

RadialProbability

S-states have greater radial penetration due to the nodal properties of the wave

function. Electrons in S-states "see" a higher nuclear charge.

CSP3 CSP2 CSP

2

2.5

3

3.5

4

4.5

5

PaulingElectronegativity

20 25 30 35 40 45 50 55

% S-Character

CSP3

CSP2

CSP

NSP3

NSP2

NSP

25

30

35

40

45

50

55

60

PkaofCarbonAcid

20 25 30 35 40 45 50 55

% S-Character

CH4

(56)

C6H

6(44)

PhCC-H (29)

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

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

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Chem 206D. A. Evans Hyperconjugation: Carbocation Stabilization

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.

! The interaction of a vicinal bonding orbital with a p-orbital is referredto as hyperconjugation.

C C

R

H

HH

HC

H

HCH

H

R

This is a traditional vehicle for using valence bond to denote chargedelocalization.

+

Syn-planar orientation between interacting orbitals

Stereoelectronic Requirement for Hyperconjugation:

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

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

! CR

!" CR

! CR

!" CR

The Molecular Orbital Description

CH

HC

H

H

+ +

[F5SbFSbF5]

The Adamantane Reference(MM-2)

T. Laube, Angew. Chem. Int. Ed.1986, 25, 349

First X-ray Structure of an Aliphatic Carbocation

110

100.6

1.530

1.608

1.528

1.431

Bonds participating in the hyperconjugative interaction, e.g. CR,will be lengthened while the C(+)C bond will be shortened.

Physical Evidence for Hyperconjugation

Me

Me

Me

H

Me

Me

Me

C+

+

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"Negative" HyperconjugationD. A. Evans Chem 206

! Delocalization of nonbonding electron pairs into vicinal antibondingorbitals is also possible

C X

R

H

HHH X H

H

CH

H

R ""

This decloalization is referred to as "Negative" hyperconjugation

""

As the antibonding CR orbital

decreases in energy, the magnitude

of this interaction will increase! CR

!!

!" CR

The Molecular Orbital Description

X

Since nonbonding electrons prefer hybrid orbitals rather that Porbitals, this orbital can adopt either a syn or anti relationship

to the vicinal CR bond.

Nonbonding e pair

Note that ! CR is slightly destabilized

antibonding !" CR

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

+

Anti Orientation

filledhybrid orbital

filledhybrid orbital

antibonding !" CRSyn Orientation

+C X

H

H

C X

H

HCH

CH

H

R

X

H

R

XC X

H

H

C X

H

H

R:

R:

""

""""

""

R

R

NMR Spectroscopy! Greater e-density at R

! Less e-density at X NMR Spectroscopy

! Longer CR bond X-ray crystallography

Infrared Spectroscopy! Weaker CR bond

! Stronger CX bond Infrared Spectroscopy

X-ray crystallography! Shorter CX bond

Spectroscopic ProbeChange in Structure

The Expected Structural Perturbations

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Chem 206D. A. Evans Lone Pair Delocalization: N2F2

This molecule can exist as either cis ortrans isomers

The interaction of filled orbitals with adjacent antibonding orbitals canhave an ordering effect on the structure which will stabilize a particular

geometry. Here are several examples:

Case 1: N2F2

There are two logical reasons why the trans isomer should be morestable than the cis isomer.

! The nonbonding lone pair orbitals in the cis isomer will be destabilizingdue to electron-electron repulsion.

! The individual CF dipoles are mutually repulsive (pointing in samedirection) in the cis isomer.

N N

F F

N

F

N

F

The cis Isomer

! Note that two such interactions occur in the molecule even thoughonly one has been illustrated.

! Note that by taking a linear combination of the nonbonding andantibonding orbitals you generate a more stable bonding situation.

!" NF

filledN-SP2

antibonding!" NF

filledN-SP2

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 CFantibonding orbitals.

(LUMO)

N

F

N

F

(HOMO)

The trans IsomerNow carry out the same analysis with the same 2

orbitals present in the trans isomer.

filledN-SP2antibonding!" NF

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

filledN-SP2

(HOMO)

!" NF

(LUMO)N N

F

F

Conclusions

! Lone pair delocalization appears to override electron-electron anddipole-dipole repulsion in the stabilization of the cis isomer.

! This HOMO-LUMO delocalization is stronger in the cis isomer dueto better orbital overlap.

Important Take-home Lesson

Orbital orientation is important for optimal orbital overlap.

forms stronger pi-bond than

forms strongersigma-bond than

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

A B A B

A B BA