http://www.courses.fas.harvard.edu/~chem206/
J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48
The Curtin-Hammett Principle (Handout) O
OMe
Me Me
CO2Me
N
Ph O
H
LiNR2
Me-I
N
Ph
O
O
H
O
OMe
Me Me
CO2MeMe
Chem 206D. A. Evans
Matthew D. Shair Wednesday, October 2, 2002
a73 Reading Assignment for week
A. Carey & Sundberg: Part A; Chapter 4"Study & Descrption of Reaction Mechanisms"
Conformational Analysis: Part–4
Chemistry 206
Advanced Organic Chemistry
Lecture Number 7
Conformational Analysis-4 a73 Problems of the Day: (To be discussed)
K. Houk, Science. 1986, 231, 1108-1117Theory & Modeling of Stereoselective Organic Reactions (Handout)
a73 Conformational Analysis of C6 → C8 Rings continued
a73 Transition State Torsional Effects
a73 Curtin–Hammett Principle
Leading References:
The Curtin-Hammett Principle
J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48.
J. I. Seeman, Chem Rev. 1983, 83, 83-134.
Eliel, pp. 647-655
Carey & Sundberg,Part A, CH 4, pp 187-250
a73 Other Reading Material
mCPBA
Martinelli, et.al. Tett. Lett. 1989, 30, 3935
Predict the stereochemical outcome of this reaction. The diastereoselection is 99:1
Rationalizethe stereochemical outcome of this reaction.
Ladner, et.al. Angew. Chemie, Int. Ed 1982, 21, 449-450
Eliel & Wilen, Stereochemistry of Carbon Compounds" Chapter 11 (on reserve in CCB library)
diastereoselection is 8:1.
Torsional Angle: also known as dihedral angle
H
H
H
H
H HO
Me HX
H
C HC
H
H
H
C HC
H
H H
H
H
C HC
H
H
C HC
H
H
H
H
HO
H
H
H
H
H
HX
H
H
Me
H
H
AB
B
C
HH
H
CH2
CH2
H
A B
A
H
CH
HH
D. A. Evans Chem 206Ground State Torsional Effects
Torsional Strain: the resistance to rotation about a bond
Torsional energy: the energy required to obtain rotation about a bond
Torsional steering: Stereoselectivity originating from transition state torsional energy considerations
?G = +3 kcal mol-1
Torsional Strain (Pitzer Strain): Ethane
staggered
eclipsed
Relevant Orbital Interactions:
Dorigo, A. E.; Pratt, D. W.; Houk, K. N. JACS 1987, 109, 6591-6600.
Wiberg K. B.; Martin, E. J. Amer. Chem. Soc. 1985, 107, 5035-5041.
σ C–H's properly aligned for pi? overlap
hence better delocalizationσ C–H & pi electrons are destabilizing
Conformational Preferences: Acetaldehyde
The eclipsed conformation (conformation A) is preferred.Polarization of the carbonyl decreases the 4 electron destabilizing
Rotational barrier: 1.14 kcal/mol
Houk, JACS 1983, 105, 5980-5988.
Conformational Preferences1-Butene (X = CH
2); Propanal (X = O)
Conformation A is preferred. There is little steric repulsion between the methyl and the X-group in conformation A.
Torsional Effects
eclipsed conformation
staggered conformation
+2.0 kcal/mol
See Lecture 5 for previous discussion
D. A. Evans Chem 206Transition State Torsional Effects According to Houk
CH2C
H*
CH2C
H*
CH2C
H*
60° 90°
0°
120°
30° 60° 90° 120°
2 Kcalmol-1
+4.7
0
0
H
0
HH
+1.6
HHH
0°
H
30°
HH
+5.3
+2.4
no H*
Transition states
Houk, JACS 1981, 103, 2438
Houk: "Torsional effects in transition states are more important than in ground states"
C
Nu
C
RL
H-radical and H-anion: antiperiplanar σ?C–R orbital stabilized the TS
illustrated for Nu addition
Houk, Science 1981, 231, 1108-1117"The Theory and Modeling of Stereoselective Organic Reactions"
Same trends are observed for H+ addition
σC-Nu
σ?C-RL
σC-Nu
homo
σ?C-RL
lumo
Forming bond Forming bond
Houk, JACS 1982, 104, 7162
H H H
C HCHH
RL
H H
Nu
σC-Nu
σ?C-RLTransition state
C
HR
RL
H HNu
σC-Nu
σ?C-RLGround state
H-
H?
H+
Steric effects
Least nuclear motion
Orbital distortion
Nitrogen protecting group does not affect selectivities
H
H
N
Ph O
OH
OH
H
OsO4
N
Ph O
H
A
B
A
N
Ph O
O
H
B
D. A. Evans Chem 206Transition State Torsional Effects: Olefin Additions
a73 Olefin Addition Reactions: Case one
How do we account for the high exo selectivities in addition reactions to norbornene?
exo
endo
Highly exo selective for electrophilic, nucleophilic and cycloaddition reactions
The Controversy over origin of high exoselectivities
Schleyer: torsional steering
Rate enhancement due to strain
Schleyer, P. R. J. Amer. Chem. Soc. 1967, 89, 701.
Addition from exo face avoids eclipsing A & B hydrogens
(better hyperconjugative stabilization of transition state)
98 : 2 diastereoselectivity 99 : 1 diastereoselectivity
Martinelli, et.al. Tett. Lett. 1989, 30, 3935
mCPBA
a73 Olefin Addition Reactions: Case two
Favored
Addition from indicated olefin face avoids eclipsing A & B H's
(better hyperconjugative stabilization of transition state)
How do we account for the high selectilvities in the oxidation of the indicated olefin?
Martinelli has carried out further studies on related structures...........
63°
62°
74°
40°
major
Me
O
H
Me
O
O
H
D. A. Evans Chem 206Transition State Torsional Effects: Olefin Additions
Martinelli: Torsional steering important in selectivity
99 : 1 diastereoselectivity
50 : 50 diastereoselectivity
99 : 1 diastereoselectivity
Martinelli & Houk, J. Org. Chem. 1994, 59, 2204.
mCPBA
mCPBA
mCPBA
89°
major
Authors propose that diastereoselection controlled by TS torsional effects
Nu:
Nu:
H
Me3C
O
[H]
H
Me3C
H
OH
M+
H B CH
Me
CH2Me
H
Me3C
OH
H
HA
H
Me3C
O H
Me3C
H
OH
H
Me3C
OH
H
H
NHR
Me3C
H
NHR
H
Me3C
HNPh
Me3C
H
LiBH(s-Bu)3
(R)
[H]
KBH(s-Bu)3
LiBH(s-Bu)3
[H]
HA
private communication
Hutchins, JOC 1983, 48, 3412 R = Ph 01 :99
03 :97R = Bn
Al/Hg/MeOH
Ganem, Tet. Let 1981, 22, 3447
Cyclohexanone Addition Reactions: Hydride ReductionD. A. Evans Chem 206
–
3
DIBAL-H 72:28 L-Selectride 8:92
K-Selectride 3:97NaBH4 79:21
LiAlH(Ot-Bu)3 92:8
LiAlH4 93:7
1009080706050403020100
% Axial Diastereomer
Increasingly bulky hydride reagents prefer to attack from the equatorial C=O face. Observation:
Stereoselective Reductions: Cyclic Systems
The most stereoselective Reductions
Reagent Ratio
03 :97
99 :01Li in NH3
~90 :10
RatioReagent
The steric hindrance encountered by Nu-attack from the axial C=O face by the axial ring substituents (hydrogens in this case) at the 3-positions is more severe than the
steric hinderance encountered from Nu-attack from the equatorial C=O face.
Attack Trajectories for Cyclohexanone(Torsional Argument)
HE
This approach favored stericallyHE
O–C–C–He dihedral: +63.0 °
Axial Attack
Equatorial Attack
O–C–C–He dihedral: +4.0 °
O–C–C–He dihedral: –56.0 °
H: –
H: –
Attack across equatorial C=O face sterically more favorable.
However, attack across the axial face of the C=O group avoids development of eclipsing interactions in the transition state.
(Note the dihedral angle sign changes between reactants & products shown above). These "torsional effects" favor axial attack.
Steric Effects:
Torsional Effects:
For "small" hydride reagents such as LiAlH4, torsional effects are felt to be dominant and this explains the predisposition for
axial attack.
Prediction
Prediction For "large" hydride reagents such as H–BR4, steric effects now are dominant and this explains the predisposition for
equatorial attack.
The Issues Associated with the Reduction Process
3
J. I. Seeman, Chem Rev. 1983, 83, 83-134.
J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48.
NMeN Me
PA
[PA]
[PB] [B]o
[A]o
A B PB (1)k
B
kA k2k1
PA
ON
Me
Me H
A
Me–Br
N
O
Me
Me
Me
H
B
Me
O
NMe
H
N
O
Me
Me
H
Me
PB
Me–Br
Conformational Analysis and Reactivity: Curtin-Hammett PrincipleK. A. Beaver, D. A. Evans Chem 206
Leading References:
How does the conformation of a molecule effect its reactivity?
Consider the following example:
Do the two different conformers react at the same rate, or different rates? What factors determine the product distribution?
minormajor
Consider two interconverting conformers, A and B, each of which can
undergo a reaction resulting in two different products, PA and PB.
The situation:
See also Eliel, pp. 647-655
13 Me–I13 Me–I
?G°
?GAB?
?G1?
?G2?
Rxn. Coord.
En
erg
y
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 (P
B/PA) will reflect the initial composition.
=
In this case, the product distribution depends solely on the initial ratio of the two conformers.
major product
minor product
less stable more stable
Padwa, JACS 1997 4565
?G = -3.0 kcal/mol(ab initio calculations)
Case 1: "Kinetic Quench"
We'll consider two limiting cases:
(1) The rate of reaction is faster than the rate of conformational interconversion
(2) The rate of reaction is slower than the rate of conformational interconversion
-78°C
While enolate conformers can be equilibrated at higher temperatures, the products of alkylation at -78° C always reflect the initial ratio of enloate isomers.
If the rates of conformationall interconversion and reaction are comparable, the 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 analytical solutions.
steric hindrance
PB
(2)
(3)
Using the rate equations
(4)=[PB][P
A]BA
k2[B]
[B]
[A]
[PB]
[PA]
[PB]
[PA]
PA k
B
kA k2k1
d[PA]
d[PB] =
k1[A] d[PA]d[PB] k1[A]=
k2[B]or
Since A and B are in equilibrium, we can substitute Keq =
k1=
k2 K
eq e
-?G2/RT
e-?G1/RT
(e-?G°/RT) e-?G2/RTe-?G°/RTe?G1/RT=
e-(?G2 + ?G°-?G1)/RT= or e-??G/RT=
A
B
PB
[PB]
[PA]
PA
K. A. Beaver, D. A. Evans Chem 206Curtin - Hammett: Limiting Cases
k1, k2 << kA, kB: If the rates of reaction are much slower than the rate of
interconversion, (?GAB? is small relative to ?G1? and ?G2?), then the ratio of
A to B is constant throughout the course of the reaction.
?G°
??G?
?G1? ?G2?
Rxn. Coord.
En
erg
y
minormajor
d[PA]
dt = k1[A] and
d[PB]
dt = k2[B] we can write:
d[PA]d[PB] k
1
= k2 Keq k
1
= k2 KeqIntegrating, we get
To relate this quantity to ?G values, recall that ?Go = -RT ln Keq or Keq =
e-?G°/RT, k1 = e-?G1?/RT, and k2 = e-?G2?/RT. Substituting this into the above
equation:
Where ??G? = ?G2?+?G°-?G1?
The Derivation:
Curtin - Hammett Principle: The product composition is not solely
dependent on relative proportions of the conformational isomers in the
substrate; it is controlled by the difference in standard Gibbs energies
of the respective transition states.
When A and B are in rapid equilibrium, we must consider the rates of reaction of the conformers as well as the equilibrium constant when
analyzing the product ratio.
(1)
Case 2: Curtin-Hammett Conditons
Within these limits, we can envision three scenarios:
? If the major conformer is also the faster reacting conformer, the product from the major conformer should prevail, and will not reflect the
equilibrium distribution.
? If both conformers react at the same rate, the product distribution will be the same as the ratio of conformers at equilibrium.
? 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
distribution will not reflect the equilibrium distribution.
This derivation implies that you could potentially isolate a product which is derived from a conformer that you can't even observe in the
ground state!
Combining terms:
?GAB?
slow slow
fast
N Me
H
Me3C
O –
Me3C
H
MeNN
Me
H
Me3C
NMeN Me
NMe
13Me
N Me
13Me
+
++
i-Pr2N O
Me
H
i-Pr2N O
Me
Li?sparteine
s-BuLi
Me3C
H
Me
N O –
i-Pr2N O
Me
Cl
H2O2
i-Pr2N O
Me
Li
i-Pr2N O
Me
i-Pr2N O
Me
Li?sparteine
N
N
Some Curtin-Hammett ExamplesK. A. Beaver, D. A. Evans Chem 206
k1 k2
Keq = 10.5
Ratio: 5 : 95
+
more stableless stable
fasterslower
minor product major product
Oxidation of piperidines:
major product minor product
13 Me–I13 Me–I slowerfaster
less stable more stable
Tropane alkylation is a well-known example.
When the equilibrium constant is known, the Curtin-Hammett derivation
can be used to calculate the relative rates of reaction of the two
conformers. Substituting the above data into [PB]/[PA] = k2K/k1, the ratio
k2/k1 ~ 2.
Note that in this case, the more stable conformer is also the faster reacting conformer!
The less stable conformer reacts much faster than the more stable conformer, resulting in an unexpected major product!
JOC 1974 319
Tet. 1972 573Tet. 1977 915
(-)-Sparteine
slowerfaster
82 - 87% ee
This is a case of Dynamic Kinetic Resolution: Two enantiomeric alkyl lithium complexes are equilibrating during the course of a reaction with an
electrophile.
Beak, Acc. Chem. Res, 1996, 552
Enantioselective Lithiation:
(-)-Sparteine
Enantioselectivities are the same, regardless of whether or not the starting material is chiral, even at low temperatures. Further, reaction in the absence of (-)-sparteine
results in racemic product.
Note that the two alkyllithium complexes MUST be in equilibrium, as the enantioselectivity is the same over the course of the reaction. If they were not
equilibrating, the enantioselectivity should be higher at lower conversions.
Because sparteine is chiral, these two
complexes are diastereomeric and
have different properties.
Rh
O
P
H
P
H
Ph
HN
Me
CO2Me
Rh
O
H
P
P
H
Ph
NH
Me
MeO2C
Rh
O
P
P
Ph
NH
Me
MeO2C
Rh
S
H
P
P
O
Me
NH
CO2Me
CH2Ph
Rh
O
P
P
Ph
HN
Me
CO2Me
S
R S
Rh
O
P
P
Ph
NH
Me
MeO2C
S
Rh
O
P
P
Ph
HN
Me
CO2Me
Ph
NHAcMeO2C
R
Ph
NHAcMeO2C
Ph
NHAcMeO2C
R Rh
S
H
P
P
O
Me
HN
MeO2C
PhH2C
Ph
NHAcMeO2C
> 95% ee
2
Ph
NHAcMeO2C
H2 H2
Ph
NHAcMeO2C
S,S
Rh
S
SP
P Ph
NHAcMeO2C
Mechanism of Asymmetric HydrogenationK. A. Beaver, D. A. Evans Chem 206
The asymmetric hydrogenation of prochiral olefins catalyzed by Rhodium is an important catalytic process.
[L2Rh]+
> 95% ee
Enantioselectivities are generally very high when the ligand is a chelating diphosphine. (ee's are given for S,S-CHIRAPHOS)
coordinationcoordination
hydrogen addition hydrogen addition
migration
reductive eliminationreductive
elimination
migration
-L2RhS2-L2RhS2
Observations:
? Complex 2 is the only diasteromer observed for the catalyst-substrate complex (1HNMR, X-Ray crystallography) in the absence of hydrogen
? 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
These observations may be explained using the Curtin - Hammett Principle
Halpern, Science, 217, 1982, 401
When a chiral ligand is used, there are two diastereomeric complexes which may be formed:
observed product
major complex1
* *
faster slower
(NMR, X-Ray)
+ S + S
minor complex
majorminor
fast slow
PBBAPA k
B
kA k2k1
Cl
O
O2NO
SnBu2
OPh
Cl
O
O2N
O
OPh
OSnBu2Cl
Ar
OCOAr
OSnBu2ClPh
TMS-Cl
OCOAr
OTMSPh
OSnBu2Cl
OCOArPh
TMS-Cl
OTMS
OCOArPh
Reactions Involving Interconverting IsomersK. A. Beaver, D. A. Evans Chem 206
Ar= p-NO2C6H4
Ratio 2:1
Product Ratio 22:1
more stable less stable
Stannylene ketals provide an efficient way to acylate the more hindered site of 1,2-diols.
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.
minormajor
The two stannyl esters are in equilibrium at room temperature, and the
more stable isomer is initially formed more slowly. The stannyl esters are
allowed to equilibrate before quenching with TMS-Cl, which reacts more
rapidly with the less hindered primary alkoxystannane.
THE TAKE-HOME LESSON:
Never assume that the most stable conformation of a compound is the most reactive. It may be, but then again,
it may not.
Curtin - Hammett Principle: The product composition is not solely dependent on relative proportions of the
conformational isomers in the substrate; it is controlled by the difference in standard Gibbs energies of the
respective transition states.
"It was pointed out by Professor L. P. Hammett in 1950 (private communication) that ..."
David Y. Curtin, 1954
" Because Curtin is very generous in attributing credit, this is sometimes referrred to as the Curtin-Hammett principle rather
than the Curtin principle."
Louis Plack Hammett, 1970
JOC 1996, 5257
faster slower