Tortional Strain and Stereoelectronic effects
• Strain due to eclipsing of bonds- Molecules generally prefer staggered arrangement of
groups (see earlier)
-Geometric constraints that force eclipsing interactions at both ground and in transition states
would increase energy, the latter resulting in increase in energy of activation for a reaction.
Consider hybridization changes, for example.
sp2 to sp3 and vice versa changes in cyclohexanone and cyclopentanonesp2 to sp3 is more favored in cyclocyclohexanone (why?)
Example: NaBH4 reductions in cyclohexanone is 23 times faster than in cyclopentanone.
How about sp3 to sp2? - more favored in cyclopentane systems.
Two opposing effects:
• More relief of strain in cyclopentane system (approx. 3 kcal/mol more enthalpy of
activation in cyclohexane than in cyclopentane)
• Resistance to bond angle expansion more in cyclopentane, which likes to have a bond angle
of 108o. It does not like to go to 120o needed by sp2 hybridized orbital.
(Relief of strain is more important, hence faster reaction in cyclopentane in going from sp3 to sp2)
Carbonyl reactivity in cyclohexanones
Because of the chair conformation, axial/equatorial approaches to C=O group are different.
-small nucleophiles approach from axial side
-large nucleophiles from equatorial side
Results with bulky reagents easy to rationalize- small nucleophiles more difficult.
For bulky reagents axial attack increases van der Waals strain, for example 1,3-interactions.
Bürgi-Dunitz angle (109o from the plane of the carbonyl) Acc. Chem. Res. 1983, 16, 153.
Tetrahedron, 1974, 30, 1563.
Explanations for axial preference of small nucleophiles
1. Product development control- i.e., the equatorial product is more stable hence the TS
leading to it is lower in energy. Not valid since the transition states for these reactions are
early and resemble more the starting material than the product (see Hammond postulate)
2. Tortional strain argument
Axial attack relieves some tortional strain (eclipsing interaction between the CO and the C2
and C6 carbon-hydrogen bonds).
Equatorial attack increases tortional strain, because the oxygen must move through a fully
eclipsed arrangement (C-O and C2-H) before the product assumes a stable conformation
Stereoelectronic arguments
(a) Klein (Tetrahedron 1974, 30, 3349)
C-C interacts with C=O * and distorts C=O* so that the * has greater coeffient on the axial
side. Since nucleophilic attack involves electron donation into this orbital axial attack is
preferred. (incidentally, there is some controversy regarding C-C donation vs C-H donation.
Cieplak effect relays on better C-H donation as stated below. Generally C-C donation is
thought to be better though. (For a discussion see Eliel, ‘Stereochemistry of Organic
Compounds’ p. ).
(b) Cieplak (J. Am. Chem. Soc. 1981, 103, 4540)
C-H bonds are better than C-C bonds in electron donation (cf. hyperconjugation) and there are
C-H bonds in the axial orientation.
Stereochemistry in bicyclo[2.2.1]heptane systems
BH3, R CO3H, H2/Pd all exo preferred
• 5,6-H‘s block endo approach
• Greater tortional strain (???) in endo approach - Developing eclipsing interaction?
Addition of methyl group to the bridge head results in increased amounts of endo selectivity.
Hydride reduction of bicyclo[2.2.1] heptanones
•exo major
• same effect as before for methyl substitution
Ring forming reactions - Baldwin’s rules
Smith (a very good description with lot of examples): Organic Synthesis, P. 601-611.
J. Chem. Soc., Chem. Commun. 1976, 734.
(Special case of enolates)Tetrahedron, 1982, 38, 2939.
A general guide: 5>6>3>7>4>8-10.
Eschenmoser (1970) proposed collinear approach of nucleophiles for SN2-type reactions.
Relative rates of ring closure:
Rates of reaction governed by Gibb’s Free Energy of activation, more negative the value the
faster the reaction.
H# higher positive for 3, 4-membered rings compared to 5, 6.
More positive enthalpy means- less reactive (strain?)
However, S# is least negative for 3-carbon ring formation
- comparable for 4, 5, and 6 carbon ring formation.
- becomes more negative as ring size increases above 7
H# - reflects strain; S# probability of bringing together the reactive endgroups. ( more
negative as ring size increases; increased contribution to the TS# portion of free energy)
Combination of enthalpy and entropy is best for 5 and 6 membered ring formation.
Other factors (solvent effects, geometric or stereoelectronic, especially orbital symmetry effects) may
play important roles
Example of an exception! Formation of cyclopropyl ketones vs cyclopentyl ketones.
Baldwin’s rules were developed to predict ease of ring closure with stereoelectronic
requirements of the transition states.
Applicable to: (a) kinetically controlled reactions; (b) reactions of first row elements; (c) Not
for electrocyclic reactions
Three factors were considered:
(a) ring size;
(b) hybridization of carbon at reaction site (tetrahedral, trigonal, digonal)
(c) relationship of the reacting bond to that of the forming bond (endocyclic or exocyclic)
Certain types were found favorable (Table 3.12 C&S, A, p. 165)
Examples:
1. Nucleophilic substitution
2. Lactonization
5-endo-trig vs. 5-endo-dig
Examples:
Exo-dig processes
Alkylation
Radical Cyclization Reactions