7 Neighboring Group Effect and Nonclassical Cations

Substitution with Retention of Configuration SN2 reaction at chiral carbons yield products with inverted configuration. SN1 reaction normally yield at least partially racemized products. However, if b-carbon has a substituent with unshared electron pairs, nuclephilic substitution reactions proceed with retention of configuration. trans-2-iodocyclohexanol

Substitution with Retention of Configuration bromohydrin Stereospecifically inversion Stereospecifically inversion Cyclic bromonium ion

Substitution with Retention of Configuration

Substitution with Retention of Configuration Although cyclic halonium ions are only short-lived intermediates, they have much longer lifetimes in less nucleophilic solvents such as superacids.

Substitution with Retention of Configuration Similar reaction occurred if other atoms that may act as nuclephiles, such as oxygen atoms, are located on carbons linked to carbons bearing leaving groups.

Sulfur and Nitrogen Mustards Anchimeric Assistance Neighboring group effect Retention of configuration (2) Acceleration of rates

Sulfur and Nitrogen Mustards Anchimeric Assistance Like other displacement reactions involving neighboring groups, the substitution reactions of sulfur mustards proceed with overall retention of configuration.

Sulfur and Nitrogen Mustards Anchimeric Assistance Like their sulfur analogs, primary alkyl halides with dialkyl- amino groups on b-carbons under rapid intramolecular reactions to form cyclic ammonium ions which are relative stable and may proceed slowly with weak nucleophiles.

Sulfur and Nitrogen Mustards Effects of Ring Size On the rates of formation of cyclic sulfonium and of cyclic ammonium salts

Sulfur and Nitrogen Mustards Effects of Ring Size On the rates of formation of cyclic sulfonium and of cyclic ammonium salts

Sulfur and Nitrogen Mustards Effects of Ring Size 3-Membered ammonium rings are formed more rapidly than 4- or 7-membered rings. (2) The 5- and 6-membered rings are formed much faster than the 3-membered ammonium salts. However, 3-Membered sulfonium rings are formed faster than sulfonium rings of any other size. - Normal bond angles of divalent sulfur atoms are much smaller than bond angles of trivalent nitrogen atoms.

Trans/Cis Rate Ratios

Trans/Cis Rate Ratios Summary from Table 7.3 trnas-2-bromocyclohexyl brosylate undergoes solvolysis in acetic acid at only one-tenth the rate of cyclohexyl brosylate (2) trnas-2-chlorocyclohexyl brosylate undergoes solvolysis in acetic acid at only one-thousandth the rate of cyclohexyl brosylate (3) The trans isomer reacts more rapidly than the cis isomer (4) The difference in rates between the two isomers is small for 2-chlorocyclohexyl brosylate, indicating that the chlorine atom is not an effective neighboring group

Trans/Cis Rate Ratios Whether in open-chain or cyclic molecules, neighboring group effects will be most evident when the leaving group and the neighboring group can easily be placed in a trans, coplanar arrangement. 4a reacts rapidly when heated in acetic acid, but 4b is quite unreactive under the same conditions.

Trans/Cis Rate Ratios Summary of neighboring group effects

Neighboring Acetoxy Groups The displacement of tosylate by the neighboring acetoxy group yields the cyclic five-membered acetoxonium ion 6 rather than a three-membered ring.

Cyclic Phenonium Ions Participation by Aromatic Rings Displacement of leaving groups can be assisted by neighboring groups with lacking unshared electrons. Donald Cram suggested the formation of cyclic phenonium ions as intermediates

Cyclic Phenonium Ions Participation by Aromatic Rings If the reactions were stopped before they were complete and unreacted 10 and 11 were recovered, 10 was recovered in a completely racemic form, while tosylate 11 had retained its optical activty. Intimate ion pair

Cyclic Phenonium Ions Migration of Aryl Groups The migrations of aryl groups usually yield rearrangement products with inverted configurations at both the migration origins and the migration termini.

Double Bonds As Neighboring Groups The Iso-Cholesterol Rearrangement Double bonds would be expected to participate in displace- ment reactions even more effectively than aromatic rings. Iso-cholesterol rearrangement Cholesteryl tosylate Cyclopropyl ring is formed by displacement of the leaving group with inversion of geometry of the chiral carbon

Double Bonds As Neighboring Groups The Iso-Cholesterol Rearrangement Displacement reactions of cholesteryl tosylate are about 100 times as rapid as reactions of cyclohexyl tosylate. Double bond participates in displacement of the leaving group to form allylcarbinyl (homoallylic) cation.

Double Bonds As Neighboring Groups The Iso-Cholesterol Rearrangement Tosylate 12 was found to react about 1200 times as rapidly as ethyl tosylate. The reaction yielded a cyclopropane derivatives as well as the simple displacement product.

Double Bonds As Neighboring Groups 7-Norbornenyl Cations The largest rate enhancement caused by a neighboring double bond is observed in the solvolysis of anti-7- norbornenyl tosylate (13), which reacts 107 times as rapidly as its syn isomer (14), and 1011 times as rapidly as 7-norbornyl tosylate (15).

Double Bonds As Neighboring Groups 7-Norbornenyl Cations Proposed mechanism intermediate Cyclopropane-like characteristics is formed

Double Bonds As Neighboring Groups 7-Norbornenyl Cations Several factors for the contribution of rapid reaction rate of anti-7-norbornenyl derivatives The developing cation at C7 of the 7-norbornenyl system can interact with center of the double bond having the region of greatest electron density. (2) In norbornenyl ring systems, the five-membered rings are distorted far from planarity, so that C7 is relatively close to the double bond. (3) The cyclic array of three p orbitals containing two electrons in the 7-norbornenyl cation can be regared as a “bishomoaromatic” ring system.

Double Bonds As Neighboring Groups 7-Norbornenyl Cations H.C. Brown suggested that it might be a rapidly equilibrating mixture of cations 16b and 16c.

Double Bonds As Neighboring Groups 7-Norbornenyl Cations Paul G, Gassman tested this possibility by introducing methyl groups onto the double bond of 7-norbornenyl derivative.

Double Bonds As Neighboring Groups 7-Norbornenyl Cations The solvolysis reactions of the anti-7-norbornenyl derivatives 19 yielded products that retained the original anti configurations

Double Bonds As Neighboring Groups 7-Norbornenyl Cations Mixtures of anti and syn-isomers were formed when the substituents were p-dimethylamino or p-methoxy groups

Double Bonds As Neighboring Groups 7-Norbornenyl Cations Aromatic rings fused to anti-7-norbornenyl rings can also participate in displacement of leaving group at C7, although the degree of anchimeric assistance is much smaller than for participation by a double bond.

Double Bonds As Neighboring Groups 7-Norbornenyl Cations Cycloheptatrienyl cations can also act as neighboring groups in the 7-norbornyl system

Double Bonds As Neighboring Groups 7-Norbornenyl Cations 7-Chloronorbornadiene (20) reacts about 750 times as Rapidly as anti-7-chloronorbornene in acetic acid solution. It was originally suggested that both double bonds might Assist in stabilizing the carbocation 21, or that they might Interact with each other as well, in structure 22.