D. A.

Evans Conformational Analysis: Part–4 Chem 206

■ Other Reading Material

[Link]
The Curtin-Hammett Principle
Chemistry 206
J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48.

Advanced Organic Chemistry J. I. Seeman, Chem Rev. 1983, 83, 83-134.

Leading References:
Eliel, pp. 647-655
Lecture Number 7
Carey & Sundberg,Part A, CH 4, pp 187-250

Conformational Analysis-4
■ Problems of the Day: (To be discussed)
■ Conformational Analysis of C6 → C8 Rings continued
Predict the stereochemical outcome of this reaction. The
■ Transition State Torsional Effects diastereoselection is 99:1
O
■ Curtin–Hammett Principle mCPBA
H
H
■ Reading Assignment for week
N N
Eliel & Wilen, Stereochemistry of Carbon Compounds" Ph Ph
Chapter 11 (on reserve in CCB library) O O

Martinelli, [Link]. Tett. Lett. 1989, 30, 3935

A. Carey & Sundberg: Part A; Chapter 4
"Study & Descrption of Reaction Mechanisms"
Rationalizethe stereochemical outcome of this reaction.
K. Houk, Science. 1986, 231, 1108-1117
Me
Theory & Modeling of Stereoselective Organic Reactions (Handout) CO2Me CO2Me
Me O LiNR2 Me O
J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48 Me-I
Me O Me Me O
The Curtin-Hammett Principle (Handout) Me
diastereoselection is 8:1.
Wednesday,
Matthew D. Shair October 2, 2002
Ladner, [Link]. Angew. Chemie, Int. Ed 1982, 21, 449-450
D. A. Evans Ground State Torsional Effects Chem 206

Torsional Effects Relevant Orbital Interactions:

Torsional Strain: the resistance to rotation about a bond H
H
H H H H
Torsional energy: the energy required to obtain rotation about a bond C C H
C C H
H H
Torsional Angle: also known as dihedral angle
B A
H H
Torsional steering: Stereoselectivity originating from transition state
torsional energy considerations H H
H H H
C C H C C H
H H
H H
σ C–H & π electrons are σ C–H's properly aligned for π∗ overlap
destabilizing hence better delocalization
∆G = +3 kcal mol-1
Dorigo, A. E.; Pratt, D. W.; Houk, K. N. JACS 1987, 109, 6591-6600.
eclipsed
Conformational Preferences: Acetaldehyde
staggered H H
Torsional Strain (Pitzer Strain): Ethane H H
A O H O H B

H
H H
CH2 staggered The eclipsed conformation (conformation A) is preferred.
C conformation Polarization of the carbonyl decreases the 4 electron destabilizing
H H Rotational barrier: 1.14 kcal/mol
H
H Houk, JACS 1983, 105, 5980-5988.
CH2 +2.0 kcal/mol
H
eclipsed C Conformational Preferences
conformation H 1-Butene (X = CH2); Propanal (X = O)
H
H H
Wiberg K. B.; Martin, E. J. Amer. Chem. Soc. 1985, 107, 5035-5041. Me Me
A X H X H B

See Lecture 5 for previous discussion H

H
Conformation A is preferred. There is little steric repulsion between the
methyl and the X-group in conformation A.
D. A. Evans Transition State Torsional Effects According to Houk Chem 206

Houk: "Torsional effects in transition states are more important than in ground states"
H* Transition states
H* H*
H H-radical and H-anion: antiperiplanar σ∗C–R orbital stabilized the TS
H H H
H illustrated for Nu addition
H2C C H H 2C C H H2C C H
H H H RL
H σ∗C-RL
lumo σ∗C-RL
C C
σC-Nu
0° 30° 60° 90° 120° σC-Nu
homo
no H* Nu
+1.6
Forming bond
Forming bond
+ +4.7 Same trends are observed for H+ addition
H
Houk, Science 1981, 231, 1108-1117
"The Theory and Modeling of Stereoselective Organic Reactions"
2 Kcalmol-1
0
H• +2.4 Nu
0 H H
H σ∗C-RL
+5.3 Transition state C C H
H- H σC-Nu
RL
0
Nu
0° 30° 60° 90° 120° H H
σ∗C-RL
Houk, JACS 1981, 103, 2438 Ground state C
Houk, JACS 1982, 104, 7162 R H
RL
σC-Nu
D. A. Evans Transition State Torsional Effects: Olefin Additions Chem 206

■ Olefin Addition Reactions: Case one ■ Olefin Addition Reactions: Case two

How do we account for the high exo selectivities in addition How do we account for the high selectilvities in the oxidation of
reactions to norbornene? the indicated olefin?

OH O
exo Highly exo selective for electrophilic, OsO4
nucleophilic and cycloaddition reactions OH mCPBA
H
H H
H
Rate enhancement due to strain
N N
H
N Ph
Ph
endo Ph O O
O 98 : 2 99 : 1
diastereoselectivity diastereoselectivity
The Controversy over origin of high exoselectivities
Nitrogen protecting group does not affect selectivities
Steric effects

Least nuclear motion

A
Orbital distortion

Schleyer: torsional steering

B B

Favored

Schleyer, P. R. J. Amer. Chem. Soc. 1967, 89, 701. Martinelli, [Link]. Tett. Lett. 1989, 30, 3935

Addition from exo face avoids eclipsing A & B hydrogens Addition from indicated olefin face avoids eclipsing A & B H's
(better hyperconjugative stabilization of transition state) (better hyperconjugative stabilization of transition state)

Martinelli has carried out further studies on related structures...........

D. A. Evans Transition State Torsional Effects: Olefin Additions Chem 206

Martinelli: Torsional steering important in selectivity

O
mCPBA
H
89°

99 : 1 diastereoselectivity
major

O
mCPBA

Me 62°
Me

50 : 50 diastereoselectivity
63°

O
mCPBA
H

major
99 : 1 diastereoselectivity

40°

74°

Authors propose that diastereoselection controlled by

TS torsional effects

Martinelli & Houk, J. Org. Chem. 1994, 59, 2204.

D. A. Evans Cyclohexanone Addition Reactions: Hydride Reduction Chem 206
HA
Stereoselective Reductions: Cyclic Systems Nu: Attack Trajectories for Cyclohexanone
H OH (Torsional Argument)
O HE
[H] OH H
Me3C Me3C Me3C

H H H
3
% Axial Diastereomer HE This approach favored
0 10 20 30 40 50 60 70 80 90 100 sterically
Nu:
HA

DIBAL-H 72:28 L-Selectride 8:92 The steric hindrance encountered by Nu-attack from the axial C=O face by the axial
K-Selectride 3:97
ring substituents (hydrogens in this case) at the 3-positions is more severe than the
NaBH4 79:21
steric hinderance encountered from Nu-attack from the equatorial C=O face.
Me
LiAlH(Ot-Bu)3 92:8 –
H B C CH 2Me
LiAlH4 93:7 M+ H
3
Axial Attack
Observation: Increasingly bulky hydride reagents prefer to attack from H: –
the equatorial C=O face.
O–C–C–He dihedral:
The most stereoselective Reductions
+63.0 °
H OH
O
[H] OH H
Me3C Me3C Me3C O–C–C–He dihedral:
+4.0 °
H H H H: –
Reagent Ratio Equatorial Attack O–C–C–He dihedral:
KBH(s-Bu)3 03 :97 –56.0 °
Li in NH3 99 :01 The Issues Associated with the Reduction Process
H NHR
NPh
Steric Effects: Attack across equatorial C=O face sterically more favorable.
[H] NHR H
Me3C Me3C Me3C
Torsional Effects: However, attack across the axial face of the C=O group avoids
H H H development of eclipsing interactions in the transition state.
(Note the dihedral angle sign changes between reactants &
(R) Reagent Ratio products shown above). These "torsional effects" favor axial attack.
Ganem, Tet. Let 1981, 22, 3447 R = Bn LiBH(s-Bu)3 03 :97 For "small" hydride reagents such as LiAlH4, torsional effects
Hutchins, JOC 1983, 48, 3412 R = Ph LiBH(s-Bu)3 01 :99 Prediction are felt to be dominant and this explains the predisposition for
private communication Al/Hg/MeOH ~90 :10 axial attack.

For "large" hydride reagents such as H–BR4, steric effects

Prediction now are dominant and this explains the predisposition for
equatorial attack.
K. A. Beaver, D. A. Evans Conformational Analysis and Reactivity: Curtin-Hammett Principle Chem 206
Leading References: J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48. Case 1: "Kinetic Quench"
J. I. Seeman, Chem Rev. 1983, 83, 83-134.
See also Eliel, pp. 647-655
k1, k2 >> kA, kB: If the rates of reaction are faster than the rate of
interconversion, A and B cannot equilibrate during the course of the
reaction, and the product distribution (PB/PA) will reflect the initial
composition.
How does the conformation of a molecule effect its [PB]
=
[B]o
[PA] [A]o
reactivity?

Consider the following example:

Me Me
N N
13 13
Me–I Me–I
∆GAB‡

Energy
∆G2‡
∆G1‡
∆G° PB

PA A B
Do the two different conformers react at the same rate, or different rates?
What factors determine the product distribution?
Rxn. Coord.

The situation: In this case, the product distribution depends solely on the initial ratio
of the two conformers.
Consider two interconverting conformers, A and B, each of which can steric
undergo a reaction resulting in two different products, PA and PB. hindrance Me Me
N
Me
less stable H more stable
kA Me H
k1 k2
PA A B PB (1) N O O
kB
-78°C
major minor
∆G = -3.0 kcal/mol
Me–Br (ab initio calculations) Me–Br
We'll consider two limiting cases:

(1) The rate of reaction is faster than the rate of conformational interconversion Me Me

(2) The rate of reaction is slower than the rate of conformational interconversion Me N Me N major product
Me H
minor product
If the rates of conformationall interconversion and reaction are comparable, the O H O Me
reactants are not in equilibrium during the course of the reaction and complex
mathmatical solutions are necessary. See Seeman, Chem. Rev. 1983, 83 - 144 for While enolate conformers can be equilibrated at higher temperatures, the products of
analytical solutions. alkylation at -78° C always reflect the initial ratio of enloate isomers.

Padwa, JACS 1997 4565

K. A. Beaver, D. A. Evans Curtin - Hammett: Limiting Cases Chem 206
Case 2: Curtin-Hammett Conditons
k1, k2 << kA, kB: If the rates of reaction are much slower than the rate of To relate this quantity to ∆G values, recall that ∆Go = -RT ln Keq or Keq =
interconversion, (∆GAB‡ is small relative to ∆G1‡ and ∆G2‡), then the ratio of e-∆G°/RT, k1 = e-∆G1‡/RT, and k2 = e-∆G2‡/RT. Substituting this into the above
A to B is constant throughout the course of the reaction. equation:
[PB] k2 e-∆G2/RT
= Keq = (e-∆G°/RT) = e-∆G2/RTe-∆G°/RTe∆G1/RT (4)
k1 kA k2 (1) [PA] k1 -∆G /RT
PA A B PB e 1

slow kB slow
Combining terms:
fast

∆∆G‡ [PB] [PB]

= e-(∆G2 + ∆G°-∆G1)/RT or =
[PA] [PA] e-∆∆G/RT

∆G1‡ ∆G2‡
∆GAB‡ Where ∆∆G‡ = ∆G 2‡+∆G°-∆G1‡
Energy

∆G° PB Curtin - Hammett Principle: The product composition is not solely

A dependent on relative proportions of the conformational isomers in the
PA B
substrate; it is controlled by the difference in standard Gibbs energies
of the respective transition states.
major minor
Rxn. Coord.

The Derivation: Within these limits, we can envision three scenarios:

d[P ] d[PB]
Using the rate equations dt A = k1[A] and dt = k2[B] we can write:
• If both conformers react at the same rate, the product distribution will be
the same as the ratio of conformers at equilibrium.
d[PB] k2[B] k2[B]
= or d[PB] = d[PA] (2)
d[PA] k1[A] k1[A] • If the major conformer is also the faster reacting conformer, the
product from the major conformer should prevail, and will not reflect the
[B] equilibrium distribution.
Since A and B are in equilibrium, we can substitute Keq =
[A]
• If the minor conformer is the faster reacting conformer, the product
ratio will depend on all three variables in eq (2), and the observed product
k2 [PB] k2
d[PB] = Keq d[PA] Integrating, we get = K (3) distribution will not reflect the equilibrium distribution.
k1 [PA] k1 eq

This derivation implies that you could potentially isolate a product

When A and B are in rapid equilibrium, we must consider the rates of which is derived from a conformer that you can't even observe in the
reaction of the conformers as well as the equilibrium constant when ground state!
analyzing the product ratio.
K. A. Beaver, D. A. Evans Some Curtin-Hammett Examples Chem 206

Tropane alkylation is a well-known example.

Enantioselective Lithiation:
Me N
Me
N N i-Pr2N O
H i-Pr2N O N
less stable more stable Li
s-BuLi (-)-Sparteine
Me
Me

13
faster Me–I 13
Me–I slower Because sparteine is
chiral, these two
(-)-Sparteine complexes are
13
Me + Me Me + 13
Me diastereomeric and
N N have different
major product minor product properties.
i-Pr2N O
Li•sparteine i-Pr2N O
Li•sparteine

Me
Me

The less stable conformer reacts much faster than the more stable
conformer, resulting in an unexpected major product!
faster Cl
slower
JOC 1974 319

Oxidation of piperidines: i-Pr2N O

i-Pr2N O
Me
Me
N N Me
Me3C Me3C Me
less stable more stable
H Keq = 10.5 H
82 - 87% ee

slower k1 H2O2 k2 faster

Enantioselectivities are the same, regardless of whether or not the starting material is
Me O– chiral, even at low temperatures. Further, reaction in the absence of (-)-sparteine
results in racemic product.
N+ N
Me3C O– Me3C + Me
Note that the two alkyllithium complexes MUST be in equilibrium, as the
H H
minor product enantioselectivity is the same over the course of the reaction. If they were not
Ratio: 5 : 95 major product equilibrating, the enantioselectivity should be higher at lower conversions.

When the equilibrium constant is known, the Curtin-Hammett derivation This is a case of Dynamic Kinetic Resolution: Two enantiomeric alkyl
lithium complexes are equilibrating during the course of a reaction with an
can be used to calculate the relative rates of reaction of the two
electrophile.
conformers. Substituting the above data into [PB]/[PA] = k2K/k1, the ratio
k2/k1 ~ 2.
Beak, Acc. Chem. Res, 1996, 552
Note that in this case, the more stable conformer is also the faster reacting conformer!
Tet. 1972 573
Tet. 1977 915
K. A. Beaver, D. A. Evans Mechanism of Asymmetric Hydrogenation Chem 206

S MeO 2C NHAc
The asymmetric hydrogenation of prochiral olefins catalyzed by P
Rh
Rhodium is an important catalytic process.
S,S P S Ph

coordination coordination
MeO2C NHAc [L2Rh]+ MeO2C NHAc
CO2Me
MeO 2C
NH HN
Ph Ph P P
> 95% ee Rh minor major Rh
Ph Ph
P P
O O
Enantioselectivities are generally very high when the ligand is a chelating Me
Me
diphosphine. (ee's are given for S,S-CHIRAPHOS)

When a chiral ligand is used, there are two diastereomeric complexes which hydrogen hydrogen
addition faster slower addition
may be formed:
MeO2C CO2Me CO 2Me
MeO 2C
NH HN P NH HN P
P P
Rh H P
* Ph Ph Rh
* Rh Ph Ph Rh
P P
O O P
O H
Me Me O
minor complex 1 major complex H Me Me H
2
(NMR, X-Ray)

H2 fast slow migration +S +S migration

H2

P CH 2Ph P
PhH2C
MeO2C NHAc H CO2Me MeO2C
MeO2C NHAc H
R Rh R S Rh
S P S S P
Ph
Ph O NH HN O
observed product
Me Me
Observations:

• Complex 2 is the only diasteromer observed for the catalyst-substrate complex

(1HNMR, X-Ray crystallography) in the absence of hydrogen reductive -L2RhS2 reductive
-L2RhS2 elimination
elimination
• The enantioselectivity is strongly dependant on the pressure of H2, and
degrades rapidly at higher hydrogen pressures
• The observed enantiomer is exclusively derived from the minor complex 2 MeO2C NHAc MeO2C NHAc
R S
These observations may be explained using the Curtin - Hammett Principle
Ph Ph
> 95% ee Halpern, Science, 217, 1982, 401
K. A. Beaver, D. A. Evans Reactions Involving Interconverting Isomers Chem 206

The Curtin-Hammett treatment can be extended to ANY case where different

products are formed from two rapidly intereconverting starting materials,
whether they are conformers, tautomers or isomers.

kA "It was pointed out by Professor L. P. Hammett in 1950 (private

k1 k2
PA A B PB communication) that ..."
kB
major minor
David Y. Curtin, 1954

Stannylene ketals provide an efficient way to acylate the more hindered site of 1,2-diols.
" Because Curtin is very generous in attributing credit, this is
Ph O
O O sometimes referrred to as the Curtin-Hammett principle rather
Cl
SnBu2 Cl than the Curtin principle."
O
O2 N
O2N
Louis Plack Hammett, 1970

Ph OCOAr Ph Ph OSnBu2Cl
O
Ar
OSnBu2Cl
OSnBu2Cl O OCOAr Curtin - Hammett Principle: The product composition is
more stable less stable not solely dependent on relative proportions of the
Ratio 2:1 conformational isomers in the substrate; it is controlled by
Ar= p-NO2C6H4 the difference in standard Gibbs energies of the
TMS-Cl faster slower TMS-Cl respective transition states.

Ph OCOAr Ph OTMS

Product Ratio 22:1

OTMS OCOAr
THE TAKE-HOME LESSON:

The two stannyl esters are in equilibrium at room temperature, and the Never assume that the most stable conformation of a
more stable isomer is initially formed more slowly. The stannyl esters are compound is the most reactive. It may be, but then again,
allowed to equilibrate before quenching with TMS-Cl, which reacts more it may not.
rapidly with the less hindered primary alkoxystannane.

JOC 1996, 5257