Chem 206D. A. Evans
Matthew D. Shair
Monday,
September 30, 2002
http://www.courses.fas.harvard.edu/~chem206/
a73 Reading Assignment for week
A. Carey & Sundberg: Part A; Chapter 3
Conformational Analysis: Part–3
Chemistry 206
Advanced Organic Chemistry
Lecture Number 6
Conformational Analysis-3
a73 Cyclopropane
a73 Conformational Analysis of C4 → C8 Rings
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
size of ring Ht of Combustion(kcal/mol) Total Strain(kcal/mol) Strain per CH2(kcal.mol) "angle strain"deviation from 109°28'
34
56
78
910
1112
1314
15
499.8656.1
793.5944.8
1108.31269.2
1429.61586.8
1743.11893.4
2051.92206.1
2363.5
27.526.3
6.20.1
6.29.7
12.612.4
11.34.1
5.21.9
1.9
9.176.58
1.240.02
0.891.21
1.401.24
1.020.34
0.400.14
0.13
24°44'9°44'
0°44'-5°16'
Eliel, E. L., Wilen, S. H. Stereochemistry of Organic Compounds Chapter 11, John Wiley & Sons, 1994.
a73 Baeyer "angle strain" is calculated from the deviation of the
planar bond angles from the ideal tetrahedral bond angle.
a73 Discrepancies between calculated strain/CH2 and the "angle
strain" results from puckering to minimize van der Waals or
eclipsing torsional strain between vicinal hydrogens.
a73 Why is there an increase in strain for medium sized rings even
though they also can access puckered conformations free of
angle strain? The answer is transannular strain- van der Waals
interactions between hydrogens across the ring.
Conformational Analysis of Cyclic Systems
de Meijere, "Bonding Properties of Cyclopropane & their Chemical Characteristics"
Angew Chem. Int. Ed. 1979, 18, 809-826 (handout)
Snyder, J. P. JACS, 2000, 122, 544.
H
H
H
H
H
H
Nonbonding
Ph
O H
H
Me
Me
C
R
O
Cyclopropane: Bonding, Conformation, Carbonium Ion StabilizationEvans, Kim, Breit Chem 206
Cyclopropane
a73 Necessarily planar.
a73 Subtituents are therefore eclipsed.
a73 Disubstitution prefers to be trans.
υ = 3080 cm-1
? = 120 °
a73 Almost sp2, not sp3
Walsh Model for Strained Rings:
a73 Rather than σ and σ* c-c bonds, cyclopropane has sp2 and p-type
orbitals instead.
side view
σ–1 (bonding)
σ (antibonding) σ (antibonding)
pi (antibonding)
pi (bonding) pi (bonding)
3
Carbocation Stabilization via Cyclopropylgroups
A rotational barrier of about 13.7 kcal/mol is observed in
following example:
NMR in super acidsδ(CH
3) = 2.6 and 3.2 ppm
R. F. Childs, JACS 1986, 108, 1692
1.464 ?
1.409 ?
1.534 ?
1.541 ?
1.444 ?
1.302 ?
1.222 ?
1.474 ?
1.517 ?
1.478 ?
X-ray Structures support this orientation
de Meijere, "Bonding Properties of Cyclopropane & their Chemical Characteristics"Angew Chem. Int. Ed. 1979, 18, 809-826 (handout)
H
H H
H
H H
H
H
H H
H
H H
H
H
H
H
H H
H H
HHH
H
H
H
HH
H
Me
Me
H
eq
ax ax
eq
ax
eq
eq ax
H
H
H
H
H
H
H
H
H
H
X
(MM2)
(MM2)
X
X
Evans, Kim, Breit Chem 206
Cyclobutane
? = 28 °
a73 Eclipsing torsional strain overrides increased bond angle strain by puckering.
a73 Ring barrier to inversion is 1.45 kcal/mol.
a73 G = 1 kcal/mol favoring R = Me equatorial
a73 1,3 Disubstitution prefers cis diequatorial to trans by 0.58 kcal/mol for di-bromo cmpd.
a73 1,2 Disubstitution prefers trans diequatorial to cis by 1.3 kcal/mol for diacid (roughly equivalent to
the cyclohexyl analogue.)
145-155°
a73 A single substituent prefers the equatorial position of the flap of the envelope (barrier ca. 3.4 kcal/mol, R = CH
3).
Cyclopentane
C2 Half-ChairCsEnvelope
a73 Two lowest energy conformations (10 envelope and 10 half chair conformations C
s 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.
a73 Since there is no "natural" conformation of cyclopentane, the ring conforms to minimize interactions of any substituents present.
a73 1,2 Disubstitution prefers trans for steric/torsional
reasons (alkyl groups) and dipole reasons (polar groups).
CsEnvelope
Conformational Analysis: Cyclic Systems-2
CsEnvelope
a73 A carbonyl or methylene prefers the planar position of the half-chair (barrier 1.15 kcal/mol for cyclopentanone).
a73 1,3 Disubstitution: Cis-1,3-dimethyl cyclopentane 0.5 kcal/mol more stable than trans.
H
HH
H O NaBH4
O O
O
OEt
O
O
H
H
H
H
NaBH4
O
OEt
OH
H
H
H
H
OH
H
OH
H
HH
H
O O
"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.
Methylenecyclopentane and Cyclopentene
hydrolyzes 13 times faster than
Strain trends:
> >
a73 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.
k6
k6
k5 = 23
95.5:4.5 keto:enol 76:24 enol:keto
Brown, H. C., Brewster, J. H.; Shechter, H. JACS 1954, 76, 467.
Brown, H. C.; Ichikawa, K. Tetrahedron 1957, 1, 221.
Conan, J-Y.; Natat, A.; Priolet, D. Bull. Soc. Chim., Fr. 1976, 1935.
≈
Examples: Chair
Half-Chair
Boat
Twist Boat
+5.5
10.7-11.5
+1.0–1.5
Cyclohexane Energy Profile (kcal/mol)
Inverted Chair
Evans, Kim, Breit Chem 206Conformational Analysis: Cyclic Systems-3
k5
E = 0
E = +5.5
E = +6.5-7.0
The barrier: +10.7-11.5
+5.5
R
H
C
HH
MeH Me
H
R
H
C
C
Me
H
H H
H
H
CMe
Me
Me
H
H HH
H
R
H
H MeH
H
SiMe
Me
Me
H
H
R
H MeMe
H
SnMe
Me
Me
H
Me MeMe
H
Monosubstituted Cyclohexanes: A Values
Keq ?G° = –RTlnK
eq
a73 The A– Value, or -?G°, is the preference of the substituent for the equatorial position.
a73 Me - axial has 2 gauche butane interactions more than Me-equatorial.Expected destabilization: ≈ 2(0.88) kcal/mol = ~1.8 kcal/mol;
Observed: 1.74 kcal/mol
A Values depend on the relative size of the particular substituent.
1.74 1.80 2.15 5.0
Evans, Breit Chem 206Conformational Analysis: Cyclic Systems-4
A–Value
The "relative size" of a substituent and the associated A-value may not correlate. For example, consider the –CMe
3 and –SiMe 3 substituents. While the –SiMe 3substituent has a larger covalent radius, is has a smaller A-value:
4.5-5.0 2.5 1.1A–Value
Can you explain these observations?
a73 The impact of double bonds on A-values:
Lambert, Accts. Chem. Res. 1987, 20, 454
R = Me
substituent A-value(cyclohexane)
0.8 1.74
R = OMe 0.8 0.6
R = OAc 0.6 0.71
??G°
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.
Chem 206D. A. Evans Bond Lengths and A-Values of Methyl Halides
C–Cl: 1.79 ? C–Br: 1.95 ? C–I: 2.16 ?C–F: 1.39 ?
F A-value: 0.25–0.42 Cl A-value: 0.53–64 Br A–value: 0.48-0.67 I A-value: 0.47–0.61
Chem 3D Pro (Verson 5.0)
CMe3
H
O
Me3C
CHMe2
H
O
Me3C
Me
H
O
Me3C
Me
H
O
H
Me
O
H
Me
O
Me3C
H
CMe3
O
Me3C
H
CHMe2
O
Me3C
Me
Me
Me
Me
H
X
Me
H
X
H
Me
H
H
Me
Me
H
Me
Me
MeMe
Me X
HH
Me H
XH
Me Me
HH
H
H
Evans, Breit Chem 206Conformational Analysis: Cyclic Systems-5
a73 Let's now compare look at the carbonyl analog in the 3-position
The impact of trigonal Carbon
?G° = –1.36 kcal/molversus –1.74 for cyclohexane
a73 Let's now compare look at the carbonyl analog in the 2-position
?G° = –1.56 kcal/molversus –1.74 for cyclohexane
?G° = –0.59 kcal/molversus –2.15 for cyclohexane
However, the larger alkyl groups do not follow the expected trend. Can you explain? (see Eliel, page 732)
?G° = –1.62 kcal/mol versus –5.0 for cyclohexane
Polysubstituted Cyclohexane A Values
1,4 Disubstitution: A Values are roughly additive.
?G° = –2(1.74) = –3.48 kcal/mol
1,3 Disubstitution: A Values are only additive in the trans diastereomer
?G° = 0 kcal/mol
a73 As long as the substituents on the ring do not interact in either conformation, their A-values are roughly additive
?G° = A(Me) – A(X)
The new interaction!
For X = Me
+ 3.7
+ 0.88+ 0.88
?G° = 2(.9) + 1(+3.7)= 5.5 kcal/mol
base epimerization
base epimerization
base epimerization
A
Me
Ph
C
B
Me
Ph
D
EtO
O
n-C4H9 H
OH
H MeMe
H
H
Me
Me
HH
LiNR2
MeI
Me
Me
H
H
EtO
MeO
n-C4H9 H
OH H
Me
MeH
H
Evans, Breit Chem 206Conformational Analysis: Cyclic Systems-6
Let's now consider geminal substitution
?G° = A(Ph) – A(Me)The prediction:
?G° = +2.8 – 1.7 = +1.1 kcal/mol
Observed: ?G° = –0.32 kcal/mol
Hence, when the two substituents are mutually interacting you can predict neither the magnitude or the direction of the equilibrium. Let's analyze this case.
?G° = +2.8 ?G° = –0.32
Allinger, Tet. Lett. 1971, 3259
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.
Let's now consider vicinal substitution
?G° = 1 gauche butane – 2A(Me)The prediction:
?G° = +0.88 – 2(1.74) = +2.6 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 1:
Case 2:
D. Kim & Co-workers, Tetrahedron Lett. 1986, 27, 943.
diastereoselection 89:11
Problem:Can you rationalize the stereochemical outcome of this reaction?
Note the difference in the Ph substituent in A & B.
Me
H
O
Me
H
H
O
Me
H
O
Me
H
N
Me
HH
H
N
Me
H
H
N
Me
HH
H
Me
N
H
MeH
O
H
Me
N
H
Me
H
O
H
Me
O
H
Me
N
H
MeH
O
OH
Me
N
Me
N
H
O
O
Me
H
O
OMe
H
O
O
H
Me
N Me
N H
Evans, Breit Chem 206Conformational Analysis: Cyclic Systems-7
Heteroatom-Substituted 6-Membered Rings
??G° = 1.74 kcal/mol
Reference:
G° = 2.86 kcal/mol
??G° = 1.43 kcal/mol
??G° = 1.95 kcal/mol
G° = 2.5 kcal/mol
??G° = 1.6 kcal/mol
??G° = 1.9 kcal/mol
A-Values for N-Substituents in Piperidine
??G° = 0.36 kcal/mol
The Reference:
??G° = 3.0 kcal/mol
a73 Hydrogen is "bigger" than the N–lone Pair.
a73 The A-value of N–substituents is slightly larger than the corresponding cyclohexane value. Rationalize
??G° = 4.0 kcal/mol
??G° = 0.8 kcal/mol
a73 The indicated distance is 2.05 ?. The analogous H–H distance in
Cyclohexane is 2.45 ?
(1)
(2)
(3)
(4)
(5)
(6)
2.05 ? 2.45 ?
a73 A-values at the 2-position in both the O & N heterocycles are larger than
expected. This is due to the shorter C–O (1.43 ?), and C–N (1.47 ?) bond
lengths relative to carbon (C–C; 1.53 ?). The combination of bond length and
bond angle change increases the indicated 1,3-diaxial interaction (see eq 1, 4).
Me
Me
H
H
H
O
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
HMe
H H
R
DC
BA A B
Me
H
H
H
H
H
C
H
H
HMe
HH
R
D
Evans, Breit Chem 206Conformational Analysis: Bicyclic Ring Systems
Conformations of Bicyclic Ring Systems
The steroid nucleus provided the stimulation for the development of conformational analysis, particularly of polycyclic ring systems. D. H. R. Barton
was awarded a Nobel prize in 1969 for his contributions in this area.
2.4 kcal/mol 0 Relative ?G°
rigid
Decalin Ring System (6/6)
mobile
Let's identify the destabilizing gauche butane interactions in the cis isomer
1
2
3
4
Gauche-butane interactions
C1 C2
C1 C3
C4 C3
?G°(est) = 3(0.88) = 2.64 kcal/mol
Estimate the energy difference between the two methyl-decalins shown below.
Hydrindane Ring System (6/5)
flexible rigid
?G° = –0.5 kcal/mol
a73 The turnover to favor the cis fusion results from the entropic preference for the less ordered cis isomer.
The 5-5 Ring System
favored
A/B CisA/B Trans
Rationalize the conformational flexibility of a A/B Trans vs. A/B Cis Steroid!
1
4 7
11
10
13
14
17
?G° = +6.4 kcal/mol
see Elier, p 780
Me3C CO2Et
H
Me3C
CO2Et
H
TS
TSMe3C CO2H
H
TSMe3C
CO2H
H
CO2H
HCO2H
H
H
OHMe
Me
Me
OH
HMe
Me
Me
Me3C OH
H
Me3C
OH
H
Me3C OH
H
Me3C
OH
H
OH
H OH
H
Me3C OTs
H
Me3C
OTs
H
Evans, Breit Chem 206Conformational Analysis: Axial vs Equatorial Reactivity
The axial diastereomer is not always slower reacting:
Different reactivity for axial and equatorial substituents
a73 Acetylation with Ac2O/Py
k rel 1 0.13
1 0.27
1 0.04
1 0.05
Axial substituents are more hindered, thus less reactive in many transformations
k rel
a73 Acid-catalyzed esterification
k rel
k rel
a73 Ester Saponification
20 1k rel
a73 Alcohol Oxidation with Cr(6+)
1 3.2k rel
1 3.36k rel
The rate-determining step is breakdown of the chromate ester. This is an apparent case of strain acceleration
a73 SN2 Reactions (Displacement with Ph–S–)
1 31k rel
GSReference Case
?G ref?G A
?GA > ?G ref
??G°
??G > ??G°
?GB < ?G ref
?G B
??G°
??G < ??G°
Steric Hindrance and Steric Assistance
GS GS
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
Evans, Breit Chem 206Conformational Analysis: Cylcoheptane
See Eliel, page 762+
Cycloheptane
Chair (2.16 kcal/mol) Twist-Chair (0 kcal/mol)
Boat (3.02 kcal/mol) Twist-Boat (2.49 kcal/mol)
Hendrickson, J. B. JACS 1961, 83, 4537.
Olefins are preferentially orientated to eliminate eclipsing interactions.
Chair-BoatLowest-energy conformation
Cyclooctane
1
7
3
Ring strain originates in eclipsing interactions and transannular van der Waals interactions
Transannular strain
between C3 & C7
Methyl position 1 2 3 4 5
1.8 2.8 >4.5 -0.3 6.1(pseudoeqatorial)(pseudoaxial) (kcal/mol)?G
5
1
7
3
Underside view of boat-chair C3 & C7 eclipsing interactions
3
7
O
X
X
O
Me
O
Me
MeI
LiCuMe2
O
Me
Me
O
Me
Me
Evans, Breit Chem 206Conformational Analysis: Cyclooctane
Cyclooctane continued...
Chair-Boat (BC)Lowest-energy conformation
1
7
3
Transannular strain
between C3 & C7
5
Cyclooctane derivatives
Nu
Nu
Disubstitution occurs at C4 or C6 SN2 occurs at C1 and C5
Carbonyl is positioned at C3 or C7 Olefin is positioned at C3-C4 or
C6-C7
Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 1981.
Chair-Chair (CC) conformation (+1-1.6 kcal/mol)
Boat-Boat (BB) conformation (>+ 8 kcal/mol)
Chair-Boat (CB) conformationreference structure
LINR2 Predict
stereochemistry
a70
a70 Predict stereochemistry
Methyl position 1 2 3 4 5
1.8 2.8 >4.5 -0.3 6.1(pseudoeqatorial)(pseudoaxial) (kcal/mol)?G
H
HO
H
HO
H
HO
H
HO
H
HLiO
H
HLiO
H
HLiO
H
HLiO
H
HLiO
H
HLiO
H
HLiO
H
HLiO
H
ΦR
H
C
HH
Me
Me
ΦO
Φ
56
56
ΦM
56
B
ΦP
56
C
A
Me
Me
CCC∠ 109° 28'
ΦP
ΦO
ΦM
–H2
Φ = 60°
+6°
For ΦP
5656
56
56
56
0*
For ΦM
15°
Φ = 56°
–11°
44°
61
44
15
CCC∠ 111°
61°
[?]
+6°
–41°
–11°
D. A. Evans Chem 206Conformational Transmission
Observation: Relative enolate stability correlates to ring junction stereochemistry
base
ratio: 13 : 87
House, JOC 1965, 30, 1341
base
ratio: 70 : 30
base
ratio: 10 : 90
base
ratio: 92 : 8
Observation: Relative enolate stability seems to be correlated to position of C=C
Readings: Velluz etal, Angew. Chemie, Int Ed. 1965, 4, 181-270
How do we explain the experimental observations shown above?
Let Φ be defined as the torsion or dihedral angle for butane
Φ illustrated may be designated as Φ B.
Let's now consider cyclohexane
Perfect chair real chair
Given cyclohexane with an identified torsion angle ΦR, if ΦR either increases or decreases wht effects in angle change are transmitted to ΦO, ΦM, and ΦP?
ΦR = 56° ΦR = 0°
Operation:
Hence, relative to cyclohexane, the following notation for torsion angle change may be denoted:
[?] = ΦR( 0°) – ΦR( 56°)
R
R
R
R
B
A
R
R
B
H
H
H
H
A
R
R
B
R
R
C
R
H
Me
H
Me
C
R
H
Me
H
Me
H
HO
H
HO
O
OBz
O
Me
OH
Me
Me C5H11
Ac2OTsOH
H
HLiO
H
HLiO
AcO
OBz
O
Me
OH
Me
Me C5H11
H
HLiO
H
HLiO
AcO
OBz
D. A. Evans Chem 206Conformational Transmission-2
Operation:
Operation:
Simple Application: Reinforcing Torsional Effects
versus
Which C=C bond isomer is more stable?
1) C=C will open up ring=B torsion angle
2) Ring B will resist increase in its ring fusion torsion angle
3) Therefore torsion effects are opposed
1) C=C will close down ring=B torsion angle
2) Ring B will accomodate decrease in its ring fusion torsion angle
3) Therefore torsion effects are reinforcing
base
ratio: 10 : 90
base
ratio: 92 : 8
effects reinforcingeffects opposing
effects reinforcing effects opposing
Question: Which is the more stable C=C isomer in the two THC structures?
R. W. Kierstead, JACS 1967, 89, 5934
Question: Which enol acetate is more stable?
or