D. A.

Evans

Conformational Analysis: Part3

Chem 206

http://www.courses.fas.harvard.edu/~chem206/

Conformational Analysis of Cyclic Systems

Three Types of Strain: Prelog Strain: van der Waals interactions Baeyer Strain: bond angle distortion away from the ideal Pitzer Strain: torsional rotation about a sigma bond Baeyer Strain for selected ring sizes

Chemistry 206 Advanced Organic Chemistry

Lecture Number 6

"angle strain" size of ring Ht of Combustion Total Strain Strain per CH2 (kcal/mol) (kcal.mol) deviation from 10928' (kcal/mol) 3 4 5 6 7 8 9 10 11 12 13 14 15 499.8 656.1 793.5 944.8 1108.3 1269.2 1429.6 1586.8 1743.1 1893.4 2051.9 2206.1 2363.5 27.5 26.3 6.2 0.1 6.2 9.7 12.6 12.4 11.3 4.1 5.2 1.9 1.9 9.17 6.58 1.24 0.02 0.89 1.21 1.40 1.24 1.02 0.34 0.40 0.14 0.13 2444' 944' 044' -516'

Conformational Analysis-3
! Conformational Analysis of C4 ! C6 Rings

! Reading Assignment for week A. Carey & Sundberg: Part A; Chapter 3

Eliel & Wilen, "Stereochemistry of Organic Compounds, "Chapter 11, Configuration and Conformation of Cyclic Molecules, Wiley, 1994 Ribeiro & Rittner, "The Role of Hyperconjugation in the Conformational Analysis of Methylcyclohexane and Methylheterocyclohexanes" J. Org. Chem., 2003, 68, 6780-6787 (handout) de Meijere, "Bonding Properties of Cyclopropane & their Chemical Characteristics" Angew Chem. Int. Ed. 1979, 18, 809-826 (pdf)

Eliel, E. L., Wilen, S. H. Stereochemistry of Organic Compounds Chapter 11, John Wiley & Sons, 1994.

! Baeyer "angle strain" is calculated from the deviation of the planar bond angles from the ideal tetrahedral bond angle. ! Discrepancies between calculated strain/CH2 and the "angle strain" results from puckering to minimize van der Waals or eclipsing torsional strain between vicinal hydrogens. Problem: Rationalize the regioselectivity of the following reduction
H H

NaBH4
O

O OH

D. A. Evans

Friday, September 30, 2005

Stork, JACS, 1979, 7107.

Evans, Kim, Breit

Cyclopropane: Bonding, Conformation, Carbonium Ion Stabilization

Cyclopropane
H

Chem 206

Carbocation Stabilization via Cyclopropylgroups

H H H

! Necessarily planar. ! Subtituents are therefore eclipsed. ! Disubstitution prefers to be trans.

" = 120 ! Almost sp2, not sp3 ! = 3080 cm-1

Me

A rotational barrier of about 13.7 kcal/mol is observed in following example:

H

Me

NMR in super acids !(CH3) = 2.6 and 3.2 ppm

Walsh Model for Strained Rings:

! Rather than ! and !* c-c bonds, cyclopropane has sp2 and p-type orbitals instead.

! (antibonding) H " (antibonding) Nonbonding

side view

! (antibonding)

" (bonding)

" (bonding)

!1 (bonding) de Meijere, "Bonding Properties of Cyclopropane & their Chemical Characteristics" Angew Chem. Int. Ed. 1979, 18, 809-826 (handout)
de Meijere, A.; Wessjohann, L. "Tailoring the Reactivity of Small Ring Building Blocks for Organic Synthesis." Synlett 1990, 20. (pdf)

Evans, Kim, Breit

145-155
ax eq eq eq eq ax ax ax

Conformational Analysis: Cyclic Systems-2

Cyclobutane
H

Chem 206
H H H H H H H H H H H H H H H H

Cyclopentane
H H H H H H H H H H H H H

! Eclipsing torsional strain overrides increased bond angle strain by puckering. ! Ring barrier to inversion is 1.45 kcal/mol.

! = 28

CsEnvelope

C2 Half-Chair

CsEnvelope

! Two lowest energy conformations (10 envelope and 10 half chair conformations Cs favored by only 0.5 kcal/mol) in rapid conformational flux (pseudorotation) which causes the molecule to appear to have a single out-of-plane atom "bulge" which rotates about the ring.

(MM2)

! Since there is no "natural" conformation of cyclopentane, the ring conforms to minimize interactions of any substituents present.

CsEnvelope (MM2)

H H

H H

H H

! !G = 1 kcal/mol favoring R = Me equatorial

! 1,3 Disubstitution prefers cis diequatorial to trans by 0.58 kcal/mol for di-bromo cmpd.

! A single substituent prefers the equatorial position of the flap of the envelope (barrier ca. 3.4 kcal/mol, R = CH3). ! 1,2 Disubstitution prefers trans for steric/torsional reasons (alkyl groups) and dipole reasons (polar groups). Me Me X

X ! 1,3 Alkyl Disubstitution: Cis-1,3-dimethyl cyclopentane 0.5 kcal/mol more stable than trans.

! 1,2 Disubstitution prefers trans diequatorial to cis by 1.3 kcal/mol for diacid (roughly equivalent to the cyclohexyl analogue.)

H H

! A carbonyl or methylene prefers the planar position of the half-chair (barrier 1.15 kcal/mol for cyclopentanone). X

Evans, Kim, Breit

Conformational Analysis: Cyclic Systems-3

Chem 206

Methylenecyclopentane and Cyclopentene

Strain trends: > > ! Decrease in eclipsing strain more than compensates for the increase in angle strain.

Relative to cyclohexane derivatives, those of cyclopentane prefer an sp2 center in the ring to minimize eclipsing interactions.

"Reactions will proceed in such a manner as to favor the formation or retention of an exo double bond in the 5-ring and to avoid the formation or retention of the exo double bond in the 6-ring systems." Brown, H. C., Brewster, J. H.; Shechter, H. J. Am. Chem. Soc. 1954, 76, 467.

Examples:
H H H H H H H H O O NaBH4 H

H OH

k6

H H H

NaBH4

H H OH H

k6 = 23 k5

k5

Brown, H. C.; Ichikawa, K. Tetrahedron 1957, 1, 221.

hydrolyzes 13 times faster than

Conan, J-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim., Fr. 1976, 1935.
O O OEt OH O OEt

95.5:4.5 keto:enol

76:24 enol:keto

Brown, H. C., Brewster, J. H.; Shechter, H. JACS 1954, 76, 467.

"Total Synthesis of the Antifungal Macrolide Antibiotic (+)-Roxaticin," Evans, D. A.; Connell, B. T. J. Am. Chem. Soc., 2003, 125, 10899-10905

Me O Me Me Me O
27

Me O

Me OTBSO
22

Me O
18

O Me Me OX Me
63%
27

OTBSO
22

O
18

XO
12

O Me O X = C(CH2)4

XO
12

OX Me

X = CMe2
<10%

PPTS, rt, MeOH.

PPTS, rt, MeOH.

OH Me
27

OH

OH
22

OH

OH

16

Me2CH O

O
2

HO
12

OH

Roxiticin

Me

hydrolyzes 13 times faster than

Conan, J-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim., Fr. 1976, 1935.

Zaragozic Acid C Synthesis

J. Leighton, J. Barrow JACS 1994, 116, 12111-12112
HO O

OH
3

OH

CO2H OH
5 7 1

HO R HO2C HO2C
5

OH

H
3

OH CO2H OH

O CO H 2 HO

tBuO C 2

CO2tBu OBn
5

MgBr
1

tBuO C 2

O TBSO

CH2Cl2:THF 78 C Ph

CO2tBu OBn
5 7

3 steps 86%
Ph

tBuO C 2

CO2tBu
7 5

OTBS
1

76%

H HO

O OBn

O H

Chelate Control

OTBS

91% 3 steps
OPMB Li Me Bn
tBuO C 2

CO2tBu OTBS
7

O
tBuO C 2

2 steps 70%

tBuO C 2

CO2tBu OTBS
7 5

65%

Ph Me

O H tBuO C OBn 2

tBuO C 2

CO2tBu OTBS OH
5

Me OR Bn Ph O O HO2C HO2C HO
5 7

Zaragozic acid C
OH OAc
1 4'

O H tBuO C O 2 Ph Me

94%

Me

0:10:1 CH2Cl2:TFA:H2O, 18 h R = PMB R = Ac (89%)

H
3

O CO2H

Ph Me

Evans, Breit

Conformational Analysis: Cyclic Systems-4

Chem 206

Monosubstituted Cyclohexanes: A Values

R H

A Values depend on the relative size of the particular substituent.

H H H H Me H H H Me Me H Me Me Me H

Keq
H

!G = RTlnKeq

! Meaxial has 2 gauche butane interactions more than Meequatorial. Expected destabilization: ! 2(0.88) kcal/mol = ~1.8 kcal/mol; Observed: 1.74 kcal/mol
Me H C H H H H Me H H C Me H C H

AValue

1.74

1.80

2.15

5.0

The "relative size" of a substituent and the associated A-value may not correlate. For example, consider the CMe3 and SiMe3 substituents. While the SiMe3 substituent has a larger covalent radius, it has a smaller A-value:
Me C Me H Me Si Me H Me Sn Me H

! The A Value, or -!G, is the preference of the substituent for the equatorial position.

Me

Me

Me

AValue

4.5-5.0

2.5
Can you explain these observations?

1.1

! The impact of double bonds on A-values:

Lambert, Accts. Chem. Res. 1987, 20, 454
R H H R

substituent R = Me R = OMe R = OAc

!"G 0.8 0.8 0.6

A-value (cyclohexane) 1.74 0.6 0.71

The Me substituent appears to respond strictly to the decrease in nonbonding interactions in axial conformer. With the more polar substituents, electrostatic effects due to the trigonal ring carbon offset the decreased steric environment.

Evans, Breit

Conformational Analysis: Cyclic Systems-5

Chem 206

Impact of Trigonal Carbon

! Let's now compare look at the carbonyl analog in the 3-position
Me H O O
Me

Polysubstituted Cyclohexane A Values

H Me

! As long as the substituents on the ring do not interact in either conformation, their A-values are roughly additive 1,4 Disubstitution: A Values are roughly additive.
Me Me Me Me

!G = 1.36 kcal/mol versus 1.74 for cyclohexane

! Let's now compare look at the carbonyl analog in the 2-position
Me Me3C O H base epimerization Me3C O H Me

!G = 0 kcal/mol

Me Me

Me

!G = 2(1.74) = 3.48 kcal/mol

!G = 1.56 kcal/mol versus 1.74 for cyclohexane

However, the larger alkyl groups do not follow the expected trend. Can you explain? (see Eliel, page 732)
CHMe2 Me3C O H base epimerization Me3C O H CHMe2

1,3 Disubstitution: A Values are only additive in the trans diastereomer

H X H Me H Me H X

!G = A(Me) A(X)

The cis Isomer

H H X Me H Me X H

!G = 0.59 kcal/mol versus 2.15 for cyclohexane

CMe3 Me3C O H base epimerization Me3C O H CMe3

The new interaction!

For X = Me
H H Me Me H H H H Me Me

!G = 1.62 kcal/mol versus 5.0 for cyclohexane

+ 0.88

+ 0.88

!G = 2(.9) + 1(+3.7)= 5.5 kcal/mol + 3.7

Evans, Breit

Conformational Analysis: Cyclic Systems-6

Let's now consider vicinal substitution
Me H

Chem 206

Let's now consider geminal substitution

Me Ph Ph Me

Case 1:
Me

H Me H

Me

The prediction:

!G = A(Ph) A(Me) !G = +2.8 1.7 = +1.1 kcal/mol

The prediction:

!G = 1 gauche butane 2A(Me) !G = +0.88 2(1.74) = +2.6 kcal/mol

Observed:

!G = 0.32 kcal/mol
Observed:

!G = +2.74 kcal/mol

If the added gauche butane destabilization in the di-equatorial conformer had not been added, the estimate would have been off.

Case 2:
H Me Me OH H OH H H Me Me

The conformer which places the isopropyl group equatorial is much more strongly preferred than would be suggested by A- Values. This is due to a syn pentane OH/Me interaction.
Problem: Can you rationalize the stereochemical outcome of this reaction?
O EtO n-C4H9 LiNR2 MeI H EtO n-C4H9 O Me

diastereoselection 89:11
D. Kim & Co-workers, Tetrahedron Lett. 1986, 27, 943.

Evans, Breit

Conformational Analysis: Cyclic Systems-7

Chem 206

Heteroatom-Substituted 6-Membered Rings

! A-values at the 2-position in both the O & N heterocycles are larger than expected. This is due to the shorter CO (1.43 ), and CN (1.47 ) bond lengths relative to carbon (CC; 1.53 ). The combination of bond length and bond angle change increases the indicated 1,3-diaxial interaction (see eq 1, 4).

A-Values for N-Substituents in Piperidine

H N

The Reference:
N H

!G = 0.36 kcal/mol

Me H

Reference:

H Me

Me N N

!"G = 1.74 kcal/mol

! Hydrogen is "bigger" than the Nlone Pair.

Me

!G = 3.0 kcal/mol

Me H O Me O

H Me

! The A-value of Nsubstituents is slightly larger than the corresponding cyclohexane value. Rationalize

(1)

!"G = 2.86 kcal/mol

H H O H H Me O Me

(2)

O Me

!"G = 1.43 kcal/mol

(3)

!"G = 1.95 kcal/mol

Me H

H H N H H H N H H H Me N Me H Me

(4)
N

H Me

!"G = 2.5 kcal/mol

(5)
H

N Me

!"G = 1.6 kcal/mol

(6) H N

!"G = 1.9 kcal/mol

Evans, Breit

Conformational Analysis: Bicyclic Ring Systems

Chem 206

Estimate the energy difference between the two methyl-decalins shown below.
Me Me

Hydrindane Ring System (6/5)

H H

flexible

rigid
H H

Decalin Ring System (6/6)

H H

!G = 0.5 kcal/mol (at 23 C) !G = 0.0 kcal/mol (at ~200 C)

rigid
! The turnover to favor the cis fusion results from the entropic preference for the less ordered cis isomer.

mobile

H H

The 5-5 Ring System

H H
H H

favored

2.4 kcal/mol

Relative !G

!G = +6.4 kcal/mol
Let's identify the destabilizing gauche butane interactions in the cis isomer
H
H H Me H
A B

3
H

Gauche-butane interactions
2

Me
A B

H
C D

H
C D

4 1

C1 ! C2 C1 ! C3 C4 ! C3 "G(est) = 3(0.88) = 2.64 kcal/mol

A/B Trans

A/B Cis

Rationalize the conformational flexibility of a A/B Trans vs. A/B Cis Steroid!

Evans, Breit

Conformational Analysis: Axial vs Equatorial Reactivity

! SN2 Reactions (Displacement with PhS)
H Me3C OTs Me3C

Chem 206

Different reactivity for axial and equatorial substituents

Axial substituents are more hindered, thus less reactive in many transformations ! Acetylation with Ac2O/Py
H OH OH H

OTs H

k rel

31

k rel
Me3C

1
H OH Me3C

0.13

OH H

The axial diastereomer is not always slower reacting: ! Alcohol Oxidation with Cr(6+)
H Me3C OH Me3C OH H

k rel

0.27

! Acid-catalyzed esterification
H CO2H CO2H H

k rel

1
Me Me H OH Me Me Me

3.2
Me OH H

k rel

1
H

0.04
CO2H CO2H Me3C H

k rel

3.36

k rel

Me3C

The rate-determining step is breakdown of the chromate ester. This is an apparent case of strain acceleration

0.05

! Ester Saponification
H Me3C CO2Et Me3C CO2Et H

For a more detailed discussion of this topic see: Eliel, E. L., S. H. Wilen, et al. (1994). Stereochemistry of Organic Compounds pp 720-726

k rel

20