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.

Cyclopropane Rings as Neighboring Groups The cyclopropyl group appears to provide greater anchimeric assistance to the formation of carbocations than any other hydrocarbon group. Cyclopropylmethyl bromide reacts about 40 times as rapidly as allyl bromide in aqueous C2H5OH solution. Cyclopropylmethyl tosylate undergoes solvolysis in acetic acid 90 times as rapidly as benzyl tosylate and 123,000 times as rapidly as ethyl tosylate.

Cyclopropane Rings as Neighboring Groups John D. Roberts examined the products obtained from Cyclopropylmethyl cations formed by diazotization of Cyclopropylmethylamine labeled with 14C at C1. Initial suggestion by Roberts Dissociation of cyclopropylmethyl derivatives results in the formation of “tricyclobutonium” ion, in which the cationic center interacts with the bond linking the two methylene groups of the cyclopropane ring.

Cyclopropane Rings as Neighboring Groups However, tricyclobutonium cations should have equal amount of radioactive label compounds due to the equal distribution on the three methylene groups of the cations. Roberts proposed later the formation of “bicyclobutonium” ion, in which the cationic canter interacts with one neighboring bond of the cyclopropyl ring.

Cyclopropane Rings as Neighboring Groups NMR spectra of several cations formed from cyclopropyl- methyl derivatives in superacid solution showed that ions appear to have structures in which the planes of the cationic carbons bisect the cyclopropane rings. The stability of these “bisected” structures may be attributed to the fact that cationic center can interact with two “bent bonds” of the cyclopropyl ring.

Cyclopropane Rings as Neighboring Groups The effects of substituents on the solvolysis rates of cyclopropylmethyl derivatives suggest that the TS for the reactions are lowest in energy when the developing cationic center can interact with two sides of the neighboring cyclopropyl ring rather than one. More rapid reaction in acetic acid than parent compound

Cyclopropane Rings as Neighboring Groups H.C. Brown demonstrated that a cyclopropyl substituent in para position increase the solvolysis rate of a tertiary benzylic chloride. A single methyl substituent at meta position results in a slight further increase in the rate of reaction. However, a second meta-methyl group markedly decrease the rate, because it forces the TS to adopt a conformation similar to that of ion 26 rather than one similar to the bisected ion 27.

Cyclopropane Rings as Neighboring Groups

Neighboring Alkyl Groups: 2-Norbornyl Cations Anchimeric Assistance by Alkyl Groups: The “Nonclassical” Hypothesis Alkyl groups rarely provide anchimeric assistance to the formation of carbocations. However, alkyl groups can act as effective neighboring groups in the 2-norbornyl system. Solvolysis of exo-2-norbornyl brosylate (28) in acetic acid proceed 350 times as rapidly as solvolysis of its endo isomer 29. 28 yields exclusively exo-2-norbornyl acetate and a completely racemic mixture.

Neighboring Alkyl Groups: 2-Norbornyl Cations Anchimeric Assistance by Alkyl Groups: The “Nonclassical” Hypothesis Winstein and Trifan suggested that C1-C6 bond acts as a neighboring group in reactions of 28, resulting in the formation of the “nonclassical” cation 30. A plane of symmetry Through C4, C5, and C6

Neighboring Alkyl Groups: 2-Norbornyl Cations Anchimeric Assistance by Alkyl Groups: The “Nonclassical” Hypothesis J.D. Roberts studied the rearrangements of 2-norbornyl Derivatives labeled with radioactive carbon at C2.

Neighboring Alkyl Groups: 2-Norbornyl Cations Anchimeric Assistance by Alkyl Groups: The “Nonclassical” Hypothesis Why should an alkyl group provide anchimeric assistance? The C1-C6 bonds in exo-2-norbornyl derivatives are trans to the bonds between C2 and the leaving groups. (2) The norbornyl ring system is quite strained and thus the C1-C6 bond is bent and weak, and its electrons are relatively available to participate in the displacement of a leaving group.