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 Advanced Organic Chemistry

Lecture Number 4
BH3, THF O Me Me OCH2Ph H2O2, -OH

The product ? Stereoselection: 8/1

Conformational Analysis-1
! !

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 rationalize the stereochemical outcome as indicated in the directions.
Me

Ethane, Propane, Butane & Pentane Conformations Simple Alkene Conformations

TsO CO2Me C4H9

LiNR2

The product ? Stereoselection: >40:1

! Reading Assignment for week A. Carey & Sundberg: Part A; Chapters 2 & 3
R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070 Conformation Design of Open-Chain Compounds (handout)

Problem 722. Carbonium ion A has been calculated to be 38 kcal/mol more stable than carbonium ion B (Jorgensen JACS 1985, 107, 1496). The profound stabilization of carbonium ions by silicon in this fashion is referred to as the "beta-silicon effect". For example, the SN1 solvolysis reaction of 1 is 10+12 times as fast as the corresponding reaction of 2. The solvolysis of 2 leads to the olefin. For a good review see: Lambert Acc. Chem. Res. 1999, 32, 183-190

R3Si vs R3 C

CH2 A

CH2

CH2 B

CH2

The Ethane Barrier Problem

F. Weinhold, Nature 2001, 411, 539-541 "A New Twist on Molecular Shape" (handout) F. M. Bickemhaupt & E. J. Baerends, Angew. Chem. Int. Ed. 2003, 42, 41834188,"The Case for Steric Repulsion Causing the Staggered Conformation in Ethane" (handout) F. Weinhold,, Angew. Chem. Int. Ed. 2003, 42, 4188-4194,"Rebuttal of the BikelhauptBaerends Case for Steric Repulsion Causing the staggered Connformation of Ethane" (handout)
Me3C H 1 SiMe3 H H
Solvolysis (CF3CH2OH)

Me k1 k2 Me3C H 2 H H

OCOCF3

= 2.4 x 10+12

OCOCF3

Part A: Identify the HOMO LUMO interactions in the SN1 reactions of 1 and 2.

1-LUMO 1-HOMO

2-LUMO 2-HOMO

D. A. Evans

Monday, 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 CH Bonds

H C H C
! CH HOMO

H
C C

!* CH LUMO

!" CH

! CH

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

! CH HOMO !" CH

H
C

H
C

!* CH LUMO ! CH

Following this argument one might conclude that:

For purposes of analysis, each eclipsed conformer may be broken up into its component destabilizing interactions. Incremental Contributions to the Barrier. Structure ethane propane Eclipsed atoms " E (kcal mol 3 (H!H) 2 (H!H) 1 (H!Me)
-1)

! The staggered conformer has a better orbital match between bonding and antibonding states. ! The staggered conformer can form more delocalized molecular orbitals. J. P. Lowe was the first to propose this explanation
"A Simple Molecuar Orbital Explanation for the Barrier to Internal Rotation in Ethane and Other Molecules" J. P. Lowe, JACS 1970, 92, 3799

+1.0 kcal mol -1 +1.0 kcal mol -1 +1.4 kcal mol -1

Me Me Me

Estimate the rotational barrier about the C1-C2 bond in isobutane

D. A. Evans

Acyclic Conformational Analysis: Butane

Chem 206
Butane

Relationship between !G and Keq and pKa

Recall that:

! G = RT Ln K
or

Using the eclipsing interactions extracted from propane & ethane we should be able to estimate all but one of the eclipsed butane conformations
H H Me Me C H H H H Me H

! G = 2.3RT Log10K

staggered conformation

C H Me

eclipsed conformation
!E=?

At 298 K:

2.3RT = 1.4 (!G in kcal Mol1 ) ! G298 = 1.4 Log10Keq

Eclipsed atoms 1 (H"H) 2 (H"Me)

! E (kcal mol -1) +1.0 kcal mol -1 +2.8 kcal mol -1

Since

pKeq = Log10Keq

# 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)

! G298 = 1.4 pKeq

Hence, pK is proportional to the free energy change

n-Butane Torsional Energy Profile

H H HH C MeMe H C H

Keq 1.0 10 100

pKeq 0 1 2

!G 0 1.4 2.8 kcal /mol

E1 H H Me H C H Me H H Me A
Ref = 0

E2

energy

H H

Me C

+3.6

Me Me G

+5.1 Barrier?

+0.88

D. A. Evans

Acyclic Conformational Analysis: Butane

Chem 206
H H Me Me C H H H H H Me C H H H Me Me Me C H H

Butane continued
From the torsional energy profile established by Allinger, we should be able to extract the contribution of the Me"Me eclipsing interaction to the barrier:
H H Me H H H Me Me C H H

Nomenclature for staggered conformers:

staggered C conformation Me
H

eclipsed conformation

trans or t or (anti) Conformer population at 298 K: 70%

gauche(+) or g+ 15%

gauche(-) or g15%

! E = +5.1 kcal mol-1

Let's extract out the magnitide of the MeMe interaction

(Klyne, Prelog, Experientia 1960, 16, 521.)

RR C 0 R R C -60

2 (H!H) + 1 (Me!Me) = +5.1 1 (Me!Me) = +5.1 2 (H!H) 1 (Me!Me) = +3.1

Incremental Contributions to the Barrier. Eclipsed atoms 2 (H!H) 1 (Me!Me) " E (kcal mol +2.0 +3.1
R
-1)

R C

sp sc sc

+60

ac
R C 180 R -120

ac
+120 R C R

ap
Eclipsed Butane conformation

From the energy profiles of ethane, propane, and n-butane, one may extract the useful eclipsing interactions summarized below: Hierarchy of Eclipsing Interactions
Torsion angle

C R
Designation syn periplanar + syn-clinal + anti-clinal antiperiplanar - anti-clinal - syn-clinal Symbol sp + sc (g+) + ac ap (anti or t) - ac - sc (g-)

X
X Y

Y H

! E kcal mol +1.0 +1.4 +3.1

-1

Energy Maxima Energy Minima

0 30 +60 30 +120 30 180 30 -120 30 -60 30

n-Butane Conformer E2
G E1 A E1 G

H
H

H H

C H

H Me Me Me

D. A. Evans

Acyclic Conformational Analysis: Pentane

Chem 206

n-Pentane
Rotation about both the C2-C3 and C3-C4 bonds in either direction (+ or -):
Me Me H Me H
g+g+ g+t

The double-gauche pentane conformation

The new high-energy conformation: (g+g)

Me H Me Me
tg-

H Me
g+g-

Me H

H Me

Me H

Me Me H

t,t

Me Me Me H H

H
g-g-

Estimate of 1,3-Dimethyl Eclipsing Interaction

X Y

Me
tg+

Me H

Me
g-t

g-g+

G = +5.5 kcal mol -1

G = X + 2Y where: X = 1,3(MeMe) & Y = 1,3(MeH) 1,3(MeH) = Skew-butane = 0.88 kcal mol-1 1,3(Me-Me) = G 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

R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070 Conformation Design of Open-Chain Compounds (handout)

Lactol & Ketol Polyether Antibioitics

O Me O OH H Me Me OH O H O O Me OH Et Et OH Me

R Me R Me Me Me

R'

R'
or

Me
g-g-

Me

HO R

Me H H Me
tt

H R R' H Me
or

Me

Me

Et

R'

R !
tg

Me

R'

Ferensimycin B, R = Me Lysocellin, R = H The conformation of these structures are strongly influenced by the acyclic stereocenters and internal H-bonding

Me H H R'

H H R H
gt

Consequences for the preferred conformation of polyketide natural products

Analyze the conformation found in the crystal state of a bourgeanic acid derivative!

Alborixin R = Me; X-206 R = H Internal H-Bonding

Me Me R O C OH Me OH H Me O OH O OH OH O Me Me Me H O Me Me OH O Et Me OH

OH Me Me Me Me

O OR
O

Bourgeanic acid

Metal ion ligation sites (M = Ag, K)

Me Me O C O O R Me OH H Me O OH O OH OH O Me Me Me H O Me Me OH O Et Me OH

D. A. Evans

Conformational Analysis: Ionophore X-206/X-rays

Chem 206

X-ray of Ionophore X-206 ! H2O

Internal H-Bonding
Me Me O C O OH Me OH H Me O OH O OH OH O Me Me Me H O Me Me OH O Et Me OH

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

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

"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
Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf)

The 1,2-Dihaloethanes
X
H C H H H H H C H H

X X

X = Cl; !H = + 0.91.3 kcal/mol X = Br; !H = + 1.41.8 kcal/mol X = F; !H = 0.6-0.9 kcal/mol

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: (CX)

CH3H

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

Increasing !"-acceptor capacity

best acceptor

!-anti-bonding States: (CX)

For the latest views, read Alabugin & Zeidan, JACS 2002, 124, 3175 (pdf)
CH3F CH3Cl CH3Br

Your Thoughts on the trend shown below:

The 1,2-Dihaloethanes
X
H H C H H H H C H H

best acceptor

X X

Increasing !"-acceptor capacity

X = Cl; H = + 0.91.3 kcal/mol X = Br; H = + 1.41.8 kcal/mol X = F; H = 0.6-0.9 kcal/mol

D. A. Evans

Stabilized Eclipsed Conformations in Simple Olefins

Butane versus 1-Butene
Me

Chem 206

Simple olefins exhibit unusal conformational properties relative to their saturated counterparts
Propane versus Propene
109 H H H H Me H H H H H 120 CH2

staggered conformation

H C H H

Me H

H H

C H H

Me Me

eclipsed conformation

! G = +4 kcal mol-1

Me

Hybridization change opens up the CCC bond angle

H CH2 C H H H C H CH2 H

staggered conformation

CH2 C H H H

H H

Me CH2 C H

eclipsed conformation

" = 50

! The Propylene Barrier

! G = 0.83 kcal mol-1

"=0

staggered conformation

The Torsional Energy Profile ! = 50 ! = 180

H H H H C H H C Me H Me H C H H C

+2.0 kcal/mol

eclipsed conformation

!=0

H C H H +1.32 kcal H C H H C H Me H +1.33 kcal

New (de)stabilizing effect

H C H Me

H H X H C H H X C H H
stabilizing conjugation between !"CX & #CH
!=0

+0.49 kcal

! = 120
! = 180

Conforms to ab initio (3-21G) values: Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035.

! Acetaldehyde exhibits a similar conformational bias

O H H H H Me H H O H H H H O Me Me H H O Me

K. Wiberg, JACS 1985, 107, 5035-5041 K. Houk, JACS 1987, 109, 6591-6600

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

Evans, Duffy, & Ripin

5

Conformational Barriers to Rotation: Olefin A-1,2 Interactions

5

Chem 206

1-butene
H H H C C Me H H
4

2-propen-1-ol
H H H C C OH H H

E (kcal/mol)

E (kcal/mol)

0 -180

-90

90

180

! (Deg)
The Torsional Energy Profile ! = 50
Me H H H C H C H H H C H

0 -180

-90

90

180

! (Deg)
! = 180
H C Me H

The Torsional Energy Profile

H H

H C H C

OH H

! = 60
HO H H C H H C H H

! = 180

!=0
C H Me H C

H H H

+1.32 kcal
H H C H C

Me H H

+1.33 kcal

! = 120
C H C

OH H H

+2.00 kcal

!=0
H
! = 180

H H H

+0.49 kcal
!=0

! = 120

+1.18 kcal

C HO !=0

+0.37 kcal
! = 180

Conforms to ab initio (3-21G) values: Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035.

Evans, Duffy, & Ripin

5

Conformational Barriers to Rotation: Olefin A-1,2 Interactions-2

Chem 206

2-methyl-1-butene
4

2-methyl-2-propen-1-ol
4

H H H C C Me

H Me
H H H C C OH H Me

E (kcal/mol)

E (kcal/mol)

0 -180

-90

90

180

! (Deg)
The Torsional Energy Profile ! = 180 H
H H C H C Me Me

0 -180

-90

90

180

! (Deg)
The Torsional Energy Profile ! = 180 ! = 60
HO H C H C Me H H H H C H C OH Me

! = 50
Me H H C H C Me H

! = 120
OH

!=0
C H Me !=0 H C

! = 110
H Me H

+1.39 kcal
H H C H C

Me Me H

+2.68 kcal

!=0
H C H HO C

H Me H

+1.16 kcal

H H

+2.01 kcal
Me

C H

C H

+0.06 kcal

+0.21 kcal
! = 180

! = 180

!=0

Evans, Duffy, & Ripin

Conformational Barriers to Rotation: Olefin A-1,3 Interactions

Chem 206

(Z)-2-pentene
4

(Z)-2-buten-1-ol
4

H Me H C C OH

H H

H Me

E (kcal/mol)

E (kcal/mol)

C Me

!
2

0 -180

-90

90

180

0 -180

-90

90

180

! (Deg)
H Me C H Me C H H

! (Deg)
The Torsional Energy Profile !=0
Me C H HO C H H H Me

The Torsional Energy Profile !=0

! = 180
H C H C H OH H

+3.88 kcal

! = 180 ! = 90
Me Me H C H C H H Me H H C H C Me H

+1.44 kcal
Me

! = 120
OH C H C H H

+0.86 kcal

+0.52 kcal
! = 180

H !=0

!=0

! = 180

Values calculated using MM2 (molecular mechanics) force fields via the Macromodel multiconformation search.

Review: Hoffman, R. W. Chem. Rev. 1989, 89, 1841.