04 Conformational Anal 1

Chem 206D. A. Evans Acyclic Conformational Analysis-1

The product ?Stereoselection: 8/1H2O2, -OH

BH3, THF

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.

Me

OCH2Ph

Me

O

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.

The product ?Stereoselection: >40:1

TsOCO2Me

C4H9

Me

LiNR2

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

A

CH2 CH2R3Si

vs

B

CH2 CH2R3C

Part A: Identify the HOMO–LUMO interactions in the SN1

reactions of 1 and 2.

1-LUMO

1-HOMO

2-LUMO

2-HOMO

Me3C

H

SiMe3

OCOCF3

HH

1

Me3C

H

Me

OCOCF3

HH

2

Solvolysis (CF3CH2OH)

k1

k2

= 2.4 x 10+12

D. A. EvansMonday, September 25, 2006

http://www.courses.fas.harvard.edu/colgsas/1063

Chemistry 206

Advanced Organic Chemistry

Lecture Number 4

Conformational Analysis-1

! Ethane, Propane, Butane & Pentane Conformations

! Simple Alkene Conformations

! Reading Assignment for week

A. Carey & Sundberg: Part A; Chapters 2 & 3

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

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, 4183-4188,"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 Bikelhaupt–Baerends Case for Steric Repulsion Causing the staggered

Connformation of Ethane" (handout)

Chem 206D. A. Evans Acyclic Conformational Analysis-1

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

Incremental Contributions to the Barrier.

+1.0 kcal mol -1

1 (H!Me)

2 (H!H)

3 (H!H)

propane

ethane

" E (kcal mol -1)Eclipsed atomsStructure

For purposes of analysis, each eclipsed conformer may be broken up into its component destabilizing interactions.

Ethane Rotational Barrier: The FMO View

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.

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

!* C–HLUMO

! C–HHOMO

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

! C–HHOMO

!* C–HLUMO

! C–H

!" C–H

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

!" C–H

! C–H

Following this argument one might conclude that:

C C

C CC

H

C

H

C C

HH

H H

H

H

Me

Me

Me

! 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

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

Chem 206D. A. Evans Acyclic Conformational Analysis: Butane

! G˚ = –2.3RT Log10K

! G° = –RT Ln K

Relationship between !G and Keq and pKa

Recall that: or

! G˚298 = –1.4 Log10Keq

At 298 K: 2.3RT = 1.4 (!G in kcal Mol–1 )

pKeq = – Log10KeqSince

pKeq

0–1–2

0–1.4

1.010100

!G˚Keq

! G˚298 = 1.4 pKeq

–2.8 kcal /mol

Hence, pK is proportional to the free energy change

! E = ?

eclipsed conformation

staggered conformation

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

Butane

Me

C

Me

CH

H HH H H

HH

Me

Me

Eclipsed atoms ! E (kcal mol -1)

+1.0 kcal mol -11 (H"H)

+2.8 kcal mol -12 (H"Me)

# 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)

+3.6

+5.1

+0.88Ref = 0

G

E1

E2

n-Butane Torsional Energy Profile

H

C

Me

HHH

Me

C

Me

H H

H

Me

H

Me

C

Me

H

C

H

H

HH

HH

H

Me

Me

ene

rgy

A

Barrier?

Acyclic Conformational Analysis: ButaneD. A. Evans Chem 206



! E = +5.1 kcal mol-1

From the torsional energy profile established by Allinger, we should be able toextract the contribution of the Me"Me eclipsing interaction to the barrier:

Butane continued

Me

C

H

CH

H MeH Me H

HMe

H

H

Let's extract out the magnitide of the Me–Me interaction

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

1 (Me!Me) = +5.1 – 2 (H!H)

1 (Me!Me) = +3.1

+3.1

Incremental Contributions to the Barrier.

+2.0

1 (Me!Me)

2 (H!H)

" E (kcal mol -1)Eclipsed atoms

Eclipsed Butaneconformation

From the energy profiles of ethane, propane, and n-butane, one may extractthe useful eclipsing interactions summarized below:

Hierarchy of Eclipsing Interactions

! E kcal mol -1

+1.0

+1.4

+3.1

C C

X Y

H

H

H

H

X Y

H H

H Me

Me Me

Nomenclature for staggered conformers:

CH

H H

H

Me

Me

CH

H Me

H

H

Me

C

H

Me H

H

H

Me

trans or tor (anti)

gauche(+)

or g+

gauche(-)

or g-

Conformer population at 298 K:

70% 15% 15%

R

C

R

R

C

R

R

CR

sp

sc

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

sc

acac

ap

CR

R

C

RR

C

R

R

0°

+60°

+120°

180°

-60°

-120°

Torsion angle Designation Symbol

0 ± 30°

+60 ± 30°

+120 ± 30°

180 ± 30°

-120 ± 30°

-60 ± 30°

± syn periplanar

+ syn-clinal

+ anti-clinal

antiperiplanar

- anti-clinal

- syn-clinal

± sp

+ sc (g+)

+ ac

ap (anti or t)

- ac

- sc (g-)

Energy Maxima

Energy Minima

E2

G

E1

A

E1

G

n-ButaneConformer

Acyclic Conformational Analysis: PentaneD. A. Evans Chem 206

n-Pentane

Me Me

H H

H H

Me H

H H

H Me Me H

H Me

H H

Me Me

Me Me

Me MeMe Me

Me

Me Me

Me

Rotation about both the C2-C3 and C3-C4 bonds in either direction (+ or -):

tg+g-g+

g-t

g-g-

tg-

g+g-

g+t

g+g+t,t

Δ G° = +5.5 kcal mol -1

Estimate of 1,3-Dimethyl Eclipsing Interaction

The double-gauche pentane conformation

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

X Y

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-11,3(Me!Me) = + 3.7 kcal mol -1

3.1

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.

~ 3.7 ~3.9 ~ 7.6

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

Me Me MeMe Me MeMeMe

Acyclic Conformational Analysis: Natural ProductsD. A. Evans Chem 206

The syn-Pentane Interaction - Consequences

R R'

Me Me

R R'

Me Me

R R'

H MeMe H

Me Me

R' HH R

R Me

H R'Me H

Me R'

R HH H

!

!

tt g-g-

tg gt

or

or

Consequences for the preferred conformation of polyketide natural products

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

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

Me

Me Me

OH

Me

O

OR

Bourgeanic acid

Ferensimycin B, R = MeLysocellin, R = H

Lactol & Ketol Polyether Antibioitics

R

HO O O

O

Me Me

OH O

Et

Me

HOHO

Me Me

Me OH Et

Et

OHH

Me

The conformation of these structures are strongly influenced by the acyclic stereocenters and internal H-bonding

Alborixin R = Me; X-206 R = H

O O O O

OHMe

Me

Me

OH

Me Me

OC

Me

OH

OHOH

O

O

EtOH

Me

H

MeOH

Me

MeH

R

Internal H-Bonding

O O O O

OHMe

Me

Me

OH

Me Me

OC

Me

O

OHOH

O

O

EtOH

Me

H

MeOH

Me

MeH

R

Metal ion ligation sites (M = Ag, K)

M

D. A. Evans Chem 206Conformational Analysis: Ionophore X-206/X-rays

O O O O

OHMe

Me

Me

OH

Me Me

OC

Me

OH

OHOH

O

O

EtOH

Me

H

MeOH

Me

MeH

Internal H-Bonding

X-ray of Ionophore X-206 ! H2O

"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.

O O O O

OHMe

Me

Me

OH

Me Me

OC

Me

O

OHOH

O

O

EtOH

Me

H

MeOH

Me

MeH

R

Metal ion ligation sites (M = Ag, K)

M

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

Chem 206D. A. Evans The Gauche Effect

The 1,2-Dihaloethanes

X = Cl; !H° = + 0.9–1.3 kcal/mol

X = Br; !H° = + 1.4–1.8 kcal/mol

X = F; !H° = – 0.6-0.9 kcal/mol

Observation: While the anti conformers are favored for X = Cl, Br, the gaucheconformation is prefered for 1,2-difluroethane. Explain.

X

C

X

H

HH

H

H

C

X

H

HH

X

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

best acceptorIncreasing !"-acceptor capacity

!-anti-bonding States: (C–X)

CH3–H

CH3–CH3

CH3–NH2

CH3–OH

CH3–F

For the latest views, readAlabugin & Zeidan, JACS 2002, 124, 3175 (pdf)

best acceptor

Increasing !"-acceptor capacity

!-anti-bonding States: (C–X)

CH3–F

CH3–Cl

CH3–Br

For the latest views, readAlabugin & Zeidan, JACS 2002, 124, 3175 (pdf)

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

The 1,2-Dihaloethanes

X = Cl; ΔH° = + 0.9–1.3 kcal/molX = Br; ΔH° = + 1.4–1.8 kcal/molX = F; ΔH° = – 0.6-0.9 kcal/mol

X

C

XH

HH

H

H

C

XH

HH

X

Your Thoughts on the trend shown below:

Stabilized Eclipsed Conformations in Simple OlefinsD. A. Evans Chem 206

! The Propylene Barrier

CH

CH2

H

H

H

CH

CH2

Heclipsed

conformation


+2.0 kcal/mol

H

K. Wiberg, JACS 1985, 107, 5035-5041

X C H

H

H

H

K. Houk, JACS 1987, 109, 6591-6600

New (de)stabilizing effect

stabilizing conjugation between !"–C–X & #–C–H

X C H

H

H

Butane versus 1-Butene



! G° = +4 kcal mol-1

Me

C

H

CH

H MeH Me H

HH

H

Me



! G° = –0.83 kcal mol-1

Me

CCH

HCH2CH2

HH

Me

H H

" = 0" = 50

+1.33kcal

+1.32 kcal

+0.49 kcal

! = 180

! = 120

! = 50

! = 0

! = 180! = 0

The Torsional Energy Profile

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

HC

HC H

H

HH

CH

C H

H

H

HC

HC H

H

H

Me Me

H

HC HC

H

H

MeMe

! Acetaldehyde exhibits a similar conformational bias

O

HH

H H

O

MeH

H H

O

HMe

H H

O

MeMe

H H

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

Simple olefins exhibit unusal conformational properties relative to their saturated counterparts

H Me

H H

HH

109°H CH2

HH

H

120°

Propane versus Propene

Hybridization change opens up the C–C–C bond angle

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

0

1

2

3

4

5

-180 -90 0 90 180

+1.33kcal

+1.32 kcal

+0.49 kcal

! = 180

! = 120

! = 50

! = 0

! = 180! = 0


! (Deg)

E (

kcal/m

ol)

1-butene

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

Me

H H

C HCH

H

HC

HC H

H

HH

CH

C H

H

H

HC

HC H

H

H

Me Me

H

HC HC

H

H

MeMe

!

0

1

2

3

4

5

-180 -90 0 90 180

! = 180! = 0

! = 0

! = 60

! = 120

! = 180

+1.18 kcal

+0.37 kcal

+2.00kcal

E (

kcal/m

ol)


2-propen-1-ol

! (Deg)

HC

HC H

HH

OH

OH

HO

HC

HC H

H

H

OH

HO

H

H

C HCH

H

H

C HCH

H

H

H

C HCH

H

!

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

0

1

2

3

4

5

-180 -90 0 90 180

! (Deg)

2-methyl-1-buteneE

(kca

l/m

ol)

+2.68kcal

+1.39 kcal

+0.06 kcal

! = 180

! = 110

! = 50

! = 0

! = 180! = 0


HC

HC Me

H

H

HC

HC Me

H

H

HC

H

Me

H H

C MeCH

H

C Me

H

H

Me

Me

H

HC MeC

H

H

Me

Me

!

0

1

2

3

4

5

-180 -90 0 90 180

! (Deg)

2-methyl-2-propen-1-ol

E (

kcal/m

ol)


! = 0 ! = 180

! = 0

! = 60

! = 120

! = 180

+0.21 kcal

+1.16 kcal

+2.01kcal

HC

HC Me

HH

OH

OH

HO

HC

H

H

C MeH

OH

HO

H

H

C MeCH

H

H

H

C MeCH

H

H

H

C MeCH

H

!

Chem 206Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,3 Interactions

0

1

2

3

4

5

-180 -90 0 90 180

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

(Z)-2-pentene

! (Deg)

E (

kca

l/m

ol)


! = 0 ! = 180

! = 0

! = 90

! = 180+3.88 kcal

+0.52kcal

Me

H H

C HCMe

H

Me

HC

MeC H

H H

Me

Me

H

H

C HCMe

H

H

H

C HCMe

H

!

0

1

2

3

4

5

-180 -90 0 90 180

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

(Z)-2-buten-1-ol

! (Deg)

E (

kca

l/m

ol)

+0.86kcal

+1.44 kcal

! = 180

! = 120

! = 0

! = 180! = 0


HC

MeC H

H

H

HC

Me

HC

MeC H

HH

OH

C H

H

H

HO

OH

H

HC HC

Me

H

OH

!

04 Conformational Anal 1

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