D. A.

Evans Acyclic Conformational Analysis-1 Chem 206

http://www.courses.fas.harvard.edu/colgsas/1063 Problem 61. The following stereoselective hydroboration has been reported by Kishi in
his synthesis of monensin (JACS 1979, 101, 259). Provide the stereostructure of the
major product and rationalize the stereochemical outcome as indicated in the directions.

Chemistry 206
BH3, THF
The product ?
Advanced Organic Chemistry O OCH2Ph
H2O2, -OH Stereoselection: 8/1
Me Me

Lecture Number 4
Problem 68. The following stereoselective enolate alkylation has been reported by Kim
(Tetrahedron Lett. 1986, 27, 943). Provide the stereostructure of the major product and
Conformational Analysis-1 rationalize the stereochemical outcome as indicated in the directions.

Me
LiNR2 The product ?
TsO
! Ethane, Propane, Butane & Pentane Conformations CO2Me Stereoselection: >40:1

C4H9
! Simple Alkene Conformations

Problem 722. Carbonium ion A has been calculated to be 38

! Reading Assignment for week kcal/mol more stable than carbonium ion B (Jorgensen JACS 1985,
R3Si CH2 CH2
107, 1496). The profound stabilization of carbonium ions by silicon in A
A. Carey & Sundberg: Part A; Chapters 2 & 3 this fashion is referred to as the "beta-silicon effect". For example,
vs
the SN1 solvolysis reaction of 1 is 10+12 times as fast as the
R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070 corresponding reaction of 2. The solvolysis of 2 leads to the olefin.
Conformation Design of Open-Chain Compounds (handout) For a good review see: Lambert Acc. Chem. Res. 1999, 32, 183-190 R3 C CH2 CH2

The Ethane Barrier Problem B

F. Weinhold, Nature 2001, 411, 539-541
SiMe3 Me
"A New Twist on Molecular Shape" (handout) Solvolysis (CF3CH2OH)
Me3C H Me3C H
F. M. Bickemhaupt & E. J. Baerends, Angew. Chem. Int. Ed. 2003, 42, 4183- H H
k1
4188,"The Case for Steric Repulsion Causing the Staggered Conformation H OCOCF3 = 2.4 x 10+12 H OCOCF3
1 k2 2
in Ethane" (handout)
F. Weinhold,, Angew. Chem. Int. Ed. 2003, 42, 4188-4194,"Rebuttal of the
Bikelhaupt–Baerends Case for Steric Repulsion Causing the staggered Part A: Identify the HOMO– 1-LUMO 2-LUMO
Connformation of Ethane" (handout) LUMO interactions in the SN1
reactions of 1 and 2. 1-HOMO 2-HOMO
Monday,
D. A. Evans September 25, 2006
D. A. Evans Acyclic Conformational Analysis-1 Chem 206

Ethane Rotational Barrier: The FMO View

F. Weinhold, Angew. nature 2001, 411, 539-541"A New Twist on Molecular Shape"

One explanation for the rotational barrier in ethane is that better overlap is
possible in the staggered conformation than in the eclipsed conformation as
shown below.

In the staggered conformation there are 3 anti-periplanar C–H Bonds

H !" C–H
H !* C–H
LUMO
C C C C
! C–H
HOMO
H H ! C–H

In the eclipsed conformation there are 3 syn-periplanar C–H Bonds

H H !" C–H
H H
C C ! C–H !* C–H
HOMO LUMO
C C
! C–H

Following this argument one might conclude that:

For purposes of analysis, each eclipsed conformer may be broken up ! The staggered conformer has a better orbital match between
into its component destabilizing interactions. bonding and antibonding states.
Incremental Contributions to the Barrier. ! The staggered conformer can form more delocalized molecular
Eclipsed atoms " E (kcal mol -1) orbitals.
Structure
J. P. Lowe was the first to propose this explanation
ethane 3 (H!H) +1.0 kcal mol -1 "A Simple Molecuar Orbital Explanation for the Barrier to Internal
Rotation in Ethane and Other Molecules"
propane 2 (H!H) +1.0 kcal mol -1 J. P. Lowe, JACS 1970, 92, 3799
1 (H!Me) +1.4 kcal mol -1 Me
Me Estimate the rotational barrier about the C1-C2 bond
Me in isobutane
D. A. Evans Acyclic Conformational Analysis: Butane Chem 206

Butane
Relationship between !G and Keq and pKa
Using the eclipsing interactions extracted from propane & ethane we should
! G° = –RT Ln K be able to estimate all but one of the eclipsed butane conformations
Recall that: or
Me Me
! G˚ = –2.3RT Log10K H H H
H eclipsed
staggered H
C C conformation
conformation H H
!E=?
At 298 K: 2.3RT = 1.4 (!G in kcal Mol–1 ) Me Me
H

! G˚298 = –1.4 Log10Keq Eclipsed atoms ! E (kcal mol -1)

1 (H"H) +1.0 kcal mol -1
Since pKeq = – Log10Keq 2 (H"Me) +2.8 kcal mol -1
# E est = 3.8 kcal mol -1

The estimated value of +3.8 agrees quite well with the value of +3.6
reported by Allinger (J. Comp. Chem. 1980, 1, 181-184)

! G˚298 = 1.4 pKeq

n-Butane Torsional Energy Profile

Hence, pK is proportional to the free energy change HH

H
H
E2 C
Keq pKeq !G˚ E1
H Me
H MeMe
1.0 0 0 H
C
energy

10 –1 –1.4 Me
H H
H
H
Me
100 –2 –2.8 kcal /mol H H C
+5.1
H Me
C
H H Me G Barrier?
+3.6
Me A
+0.88
Ref = 0
D. A. Evans Acyclic Conformational Analysis: Butane Chem 206

Butane continued Me Me Me
H H H Me Me H
From the torsional energy profile established by Allinger, we should be able to Nomenclature for C
C C
extract the contribution of the Me"Me eclipsing interaction to the barrier: staggered conformers: H H H H
H H
Me H H
H Me trans or t gauche(+) gauche(-)
H Me H Me
staggered C
H eclipsed or (anti) or g+ or g-
C
conformation Me H conformation Conformer
H population 70% 15% 15%
H H
! E = +5.1 kcal mol-1 at 298 K:
(Klyne, Prelog, Experientia 1960, 16, 521.)
Let's extract out the magnitide of the Me–Me interaction RR

2 (H!H) + 1 (Me!Me) = +5.1 C

1 (Me!Me) = +5.1 – 2 (H!H) 0°

R R
R R
1 (Me!Me) = +3.1 C C
-60° sp +60°
Incremental Contributions to the Barrier. sc sc
Eclipsed atoms " E (kcal mol -1)

2 (H!H) +2.0 ac ac
+3.1 R -120° +120° R
1 (Me!Me) ap
R C C

Eclipsed Butane R
conformation 180°

R
From the energy profiles of ethane, propane, and n-butane, one may extract
C
the useful eclipsing interactions summarized below:
R
Hierarchy of Eclipsing Interactions n-Butane
Torsion angle Designation Symbol Conformer
-1
X Y ! E kcal mol Energy Maxima 0 ± 30° ± syn periplanar ± sp E2
X Y Energy Minima +60 ± 30° + syn-clinal + sc (g+) G
H H +1.0
+120 ± 30° + anti-clinal + ac E1
H C C H +1.4 180 ± 30° antiperiplanar ap (anti or t) A
H Me -120 ± 30° - anti-clinal - ac E1
H H Me Me +3.1 -60 ± 30° - syn-clinal - sc (g-) G
D. A. Evans Acyclic Conformational Analysis: Pentane Chem 206

n-Pentane
The double-gauche pentane
Rotation about both the C2-C3 and C3-C4 bonds in either direction (+ or -):
conformation
Me Me

Me H H Me
g+g- The new high-energy conformation: (g+g–)
H Me Me H
g+t
Me Me tg- Me Me

H H Me Me H H Estimate of 1,3-Dimethyl Eclipsing Interaction

t,t Me
g+g+ g-g-
Me

Me Me H Me Y
Me H X

H H g-t
tg+
g-g+

Δ G° = +5.5 kcal mol -1

Δ G = X + 2Y where:

X = 1,3(Me−Me) & Y = 1,3(Me−H)

1,3(Me−H) = Skew-butane = 0.88 kcal mol-1
1,3(Me-Me) = ΔG – 2Y = 5.5 –1.76 = + 3.7 kcal mol-1
1,3(Me!Me) = + 3.7 kcal mol -1

Estimates of In-Plane 1,2 &1,3-Dimethyl Eclipsing Interactions

Me Me Me Me Me Me Me Me

3.1 ~ 3.7 ~3.9 ~ 7.6

It may be concluded that in-plane 1,3(Me!Me) interactions are Ca +4

kcal/mol while 1,2(Me!Me) interactions are destabliizing by Ca 3 kcal/mol.
D. A. Evans Acyclic Conformational Analysis: Natural Products Chem 206

The syn-Pentane Interaction - Consequences Lactol & Ketol Polyether Antibioitics

R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070
Conformation Design of Open-Chain Compounds (handout)
Me Me Me Me
O OH O
Et
R R' R R' Me Me HO O O O
! or OH H H Me OH Et
R Me Me Et OH
Me Me Me H H Me H R R' H
tt g-g-
Ferensimycin B, R = Me
R R' R Me Me R' Lysocellin, R = H
! or
Me Me Me H H R' H H R H
tg
The conformation of these structures are strongly influenced by the
gt
acyclic stereocenters and internal H-bonding

Consequences for the preferred conformation of polyketide natural products

Alborixin R = Me; X-206 R = H

Analyze the conformation found in the crystal state of a bourgeanic acid derivative!
Internal H-Bonding
Me Me Me Me
Me R
OH
H
Me
OH O O O O O O
H OH OH Me
C Me OH Me OH O
Me Me
OR O OH
OH
Et
Me Me Me
Bourgeanic acid

Metal ion ligation sites (M = Ag, K)

Me Me Me Me
Me R
OH
H
Me
O O O O O
H OH OH Me
C Me OH Me OH O Me
O O
OH
M Et
D. A. Evans Conformational Analysis: Ionophore X-206/X-rays Chem 206

X-ray of Ionophore X-206 ! H2O X-ray of Ionophore X-206 - Ag+ - Complex

Internal H-Bonding
Me Me Me Me
Metal ion ligation sites (M = Ag, K)
Me
OH
H Me Me Me
Me Me R Me
O O O O O OH
H OH OH Me H
C Me OH Me OH O Me
Me
O OH O O O O O
OH H OH OH Me
Et C Me OH Me OH O Me
O O
OH
M Et

"The Total Synthesis of the Polyether Antibiotic X-206". Evans, D. A.; Bender,
S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506-2526.
D. A. Evans The Gauche Effect Chem 206

The 1,2-Dihaloethanes Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf)
X H
H H H H X = Cl; !H° = + 0.9–1.3 kcal/mol
C C X = Br; !H° = + 1.4–1.8 kcal/mol
H H H X X = F; !H° = – 0.6-0.9 kcal/mol
X X
Observation: While the anti conformers are favored for X = Cl, Br, the gauche
conformation is prefered for 1,2-difluroethane. Explain.

Relevant Article: Chem. Commun 2002, 1226-1227 (pdf)

!-anti-bonding States: (C–X)

For the latest views, read
CH3–H Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf)
CH3–CH3
CH3–NH2

CH3–OH

CH3–F
Increasing !"-acceptor capacity best acceptor

Your Thoughts on the trend shown below:

!-anti-bonding States: (C–X)
For the latest views, read
Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf) The 1,2-Dihaloethanes
CH3–F
X H
CH3–Cl H H H H X = Cl; ΔH° = + 0.9–1.3 kcal/mol
CH3–Br best acceptor C C X = Br; ΔH° = + 1.4–1.8 kcal/mol
H H H X X = F; ΔH° = – 0.6-0.9 kcal/mol
Increasing !"-acceptor capacity X X
D. A. Evans Stabilized Eclipsed Conformations in Simple Olefins Chem 206

Simple olefins exhibit unusal conformational Butane versus 1-Butene

properties relative to their saturated counterparts Me
H Me H Me
staggered H Me eclipsed
Propane versus Propene C C
conformation H H conformation
109° 120° H
H Me H CH2 H H
! G° = +4 kcal mol-1
H H H
H H Me
H H Me
CH2 CH2
staggered C
H eclipsed
C
Hybridization change opens up the C–C–C bond angle conformation H H conformation
H H H
" = 50 "=0
H ! G° = –0.83 kcal mol-1
! The Propylene Barrier CH2 staggered
C conformation The Torsional Energy Profile
H H
! = 50 ! = 180
H Me
CH2 +2.0 kcal/mol H
H H Me
C H C C H
eclipsed C C H H
H H H
conformation H H
H

!=0 H
New (de)stabilizing effect H +1.33
C C H kcal
H Me Me
H +1.32 kcal
H
H
C C H
H H H ! = 120
+0.49 kcal
X C H H
H X C H !=0 ! = 180
Conforms to ab initio (3-21G) values:
H Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035.
H
stabilizing conjugation between ! Acetaldehyde exhibits a similar conformational bias
!"–C–X & #–C–H
K. Wiberg, JACS 1985, 107, 5035-5041 O O O O
K. Houk, JACS 1987, 109, 6591-6600 H Me H Me
H H Me Me
H H H H H H H H

The low-energy conformation in each of above cases is eclipsed

Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,2 Interactions Chem 206

5 5
1-butene 2-propen-1-ol

4 H H 4 H H
H H
C C H C C H
H H
! Me !
E (kcal/mol)

OH

E (kcal/mol)
3 3

2
2

1
1

0
-180 -90 0 90 180 0
! (Deg) -180 -90 0 90 180
! (Deg)
The Torsional Energy Profile
The Torsional Energy Profile H
! = 50 ! = 180 H OH
C C H
Me H H
H Me
H C C H H
C C H
H H H ! = 60 ! = 180
H H HO
H
!=0 H C C H
H H
H
! = 120
+1.33 H OH
C C H
kcal +2.00
H Me Me kcal
H +1.32 kcal H
C C H
H !=0 H H
C C H H
H H +1.18 kcal H
+0.49 kcal ! = 120 H
H C C H
!=0 ! = 180 HO
H +0.37 kcal
Conforms to ab initio (3-21G) values:
Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035. !=0 ! = 180
Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,2 Interactions-2 Chem 206

5
2-methyl-1-butene 5
2-methyl-2-propen-1-ol
4 H H
H 4 H H
C C Me H
H C C Me
H
!
E (kcal/mol)

3
Me
! OH

E (kcal/mol)
3

2
2

1
1

0
0
-180 -90 0 90 180
-180 -90 0 90 180
! (Deg) ! (Deg)

The Torsional Energy Profile

H The Torsional Energy Profile
Me
! = 180 H C C Me H
OH
H H
! = 180 C C Me
H H
! = 50 ! = 60 H
Me HO

H H
C C Me C C Me
H H H
H
H H ! = 120
! = 110 +2.68 OH +2.01
!=0 kcal kcal
H +1.39 kcal Me H
!=0 +1.16 kcal C C Me
H H H H
H
C C Me C C Me H
H Me H H
H C C Me
H H HO
H +0.21 kcal
+0.06 kcal H
!=0 ! = 180 !=0 ! = 180
Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,3 Interactions Chem 206

5 5
(Z)-2-pentene (Z)-2-buten-1-ol
4 4 H H
Me
C C H
H H H
Me
C C H ! OH
E (kcal/mol)

E (kcal/mol)
3 H 3

! Me

2 2

1 1

0 0
-180 -90 0 90 180 -180 -90 0 90 180

! (Deg) ! (Deg)

H The Torsional Energy Profile The Torsional Energy Profile

Me
C C H !=0 !=0 H
H Me
H
Me
C C H
H HO ! = 180
H
H
Me OH
C C H
H
! = 180
+3.88 kcal H
H
! = 90 Me Me +1.44 kcal ! = 120
C C H
Me H OH
+0.86
Me H Me kcal
C C H C C H
H H H
+0.52
H H H
kcal
!=0 ! = 180 !=0 ! = 180
Values calculated using MM2 (molecular mechanics) force fields
via the Macromodel multiconformation search. Review: Hoffman, R. W. Chem. Rev. 1989, 89, 1841.