Anchimeric Assistance

When the solvolysis rates of alkyl halides and sulfonate esters are measured, some curious
influences of neighboring substituents are observed. For example, ethyl chloride, neopentyl
chloride (2,2-dimethylpropyl chloride) and 2,2,2-triphenylethyl chloride are all 1º-alkyl chlorides,
which hydrolyze in wet formic acid to mixtures of alcohols and olefins (SN1 & E1 mechanisms).
The reaction rates for ethyl chloride and neopentyl chloride are nearly identical, but the triphenyl
compound reacts 60,000 times faster. Equations for the latter two solvolyses are shown in the
following diagram. It is apparent that in both cases an initially formed 1º-carbocation has
rearranged prior to product formation, as depicted by clicking on the diagram. However, the
increased rate of the phenyl substituted compound is perplexing, especially in view of the
greater electronegativity of phenyl groups relative to methyl (note that diphenylacetic acid is
over nine times more acidic than isobutyric acid). To explain the unexpected reactivity of 2,2,2-
triphenylethyl chloride it is proposed that the pi-electrons of a suitably oriented phenyl group
assist the 1º-chloride ionization by bond formation from the side opposite the C-Cl bond, as
shown by clicking on the diagram a second time. This intramolecular interaction corresponds to
the last example in the previous section, and is similar to an intramolecular SN2 reaction. The
resulting phenonium ion would immediately open to a 3º-carbocation, in which the assisting
phenyl group has shifted to an adjacent position. In this manner a neighboring aromatic ring
accelerates the rate-determining (endothermic) ionization step, an influence called anchimeric
assistance (Greek: anchi = neighbor).
The following energy profiles for these reactions illustrate the sequence of events. Both
reactions begin by an initial rate-determining ionization step, the transition state of which is
colored pink. The activation energy for this step is larger for neopentyl chloride because it leads
to a discrete 1º-carbocation. On the other hand, the ionization of triphenylethyl chloride
proceeds with assistance from a neighboring phenyl group, and the resulting phenonium ion
immediately opens to a very stable diphenyl 3º-carbocation. The second step in the neopentyl
chloride solvolysis is a rapid rearrangement of the 1º-carbocation to an isomeric 3º-carbocation.
The transition state for this rearrangement is colored green. In both cases, the 3º-carbocation
intermediate finally disproportionates to a mixture of substitution and elimination products. The
essential difference is that the ionization transition state for neopentyl chloride suffers all the
disadvantages associated with the generation of a 1º-carbocation; whereas, the transition state
for ionization of triphenylethyl chloride is lowered in energy by its phenonium-like character.

Anchimeric assistance not only manifests itself in enhancement of ionization, but also influences
the stereochemical outcome of reactions. The acetolysis of diastereomeric 3-phenyl-2-butanol
derivatives provides an example. This alcohol has two chiral centers, and therefore has four
stereoisomers in the form of two pairs of enantiomers. The diastereomeric configurations are
called erythro and threo, according to their correlation with the tetroses erythrose and threose.
As a rule, erythro isomers may assume an eclipsed conformation in which identical or similar
substituents on the two stereogenic sites eclipse each other. Threo isomers cannot assume
such a conformation. In the following diagram, a tosylate derivative of one enantiomer of each
diastereomer is drawn as a Fischer projection. These isomers were solvolyzed in hot acetic acid
solution, buffered with sodium acetate, and the configurations of the resulting acetate esters
were determined. As expected from a SN1 process, some E1 elimination product was also
obtained. Remarkably, each diastereomer is converted to its equivalent diastereomeric acetate
(retention of configuration). Furthermore,the erythro compound retains its enantiomeric purity;
whereas the threo tosylate gives racemic acetate and is itself racemized during reaction. If an
open carbocation intermediate were formed in these reactions, mixtures of erythro and threo
acetates would be expected from both tosylates, but only trace amounts of the opposite
diastereomer were found among the products.

By clicking on the diagram the controlling influence of phenyl group anchimeric assistance will
be demonstrated. First, the molecule assumes a conformation in which the phenyl substituent is
oriented anti to the tosylate group. Next, a pair of pi-electrons from the benzene ring bonds to
C2 as the tosylate anion departs, generating a phenonium intermediate (in brackets). The
intermediate from the erythro tosylate is chiral, but that from the threo tosylate is achiral (note
the plane of symmetry bisecting the three-membered ring). In each case C2 & C3 are
constitutionally equivalent, and nucleophilic attack by acetate anion takes place equally well at
either position (green and light blue arrows). As a result of equal rates of product formation by
acetate bonding to C2 & C3, the achiral threo intermediate yields a 50:50 (racemic) mixture of
threo enantiomers: (2R,3S) from the blue arrows and (2S, 3R) from the green arrows. In
contrast, acetate bonding to C2 & C3 of the erythro intermediate produces the same enantiomer
of the erythro product (2S,3S). Since the initial ionization to phenonium intermediates is
reversible, we are not surprised to find that unreacted erythro tosylate is unchanged; whereas,
unreacted threo tosylate is racemized.

Anchimeric Assistance by Other Neighboring Groups

The ability of the pi-electrons in a suitably oriented, neighboring benzene ring to facilitate C-X
ionization, where X is a halogen or a sulfonate ester, was described in the previous section.
Other aromatic rings, such as naphthalene, furan and thiophene, may function in a similar
manner, as may the pi-electrons of double and triple bonds. The following diagram shows three
examples of neighboring double bond interaction, the first being one of the most striking cases
of anchimeric assistance on record. The use of dashed lines to show charge delocalization is a
common practice. The text box below the diagram provides additional commentary concerning
these examples.

Reaction (1) illustrates a class of compounds called 'nitrogen mustards'. The alkylating character of these
compounds is similar to that of their sulfur analogs.

Reaction (2) shows a similar case in which ring expansion occurs.

Reaction (3) shows the rates of cyclization for a series of omega-bromo alkyl amines. In the absence of
base, stable cyclic ammonium salts are formed. Bases convert these salts to their corresponding cyclic
secondary-amines.
Anchimeric assistance by triple bonds is not as effective as that from double bonds, in part because vinyl
cations are not very stable. Nevertheless, neighboring triple bonds may capture carbocation species if
water or other nucleophiles are available to trap the resulting vinyl cation.

Reaction (1) shows one such example. Trifluoroacetic acid is used as the solvent because trifluoro
acetate anion is less nucleophilic than acetate ion. Poor yields of these products are found when acetic
acid is the solvent.

Reaction (2) depicts an interesting cyclization initiated by the 1º-end of an allylic cation.

Reaction (3) extends this cyclization application three fold, creating six new chiral centers and three
new rings. It comes from an extensive study of polyene cyclizations by William S. Johnson. Water
destroys the trapped ethylene carbonate cation.

Reaction (1) is an example of a 'mustard compound'. The symmetrical dichloro compound designated by
R is called mustard gas, and was used as a chemical warfare agent in World War I. Such compounds are
powerful alkylating agents, and react with and damage a variety of biological nucleophiles by cross-
linking them.

Reaction (2) shows how the accelerating influence of sulfur changes as the distance from the leaving
group increases. The exceptional facility with which three-membered ring intermediates are formed
reflects the small bond angle preferred by divalent sulfur (ca. 90 degrees).

Reaction (3) confirms the stereoelectronic requirement of a trans-anti relationship of the sulfur atom to
the leaving group. Sulfur is more electronegative than hydrogen, so its inductive effect renders the cis-
chlorosulfide less reactive than cyclohexylchloride.

Reaction (1) shows important differences in the anchimeric influence of oxygen compared with sulfur
(previous example 2). This is a consequence of the larger bond angle preferred by oxygen (ca. 105
degrees). Consequently, a five-membered ring intermediate is most rapidly formed.

Reaction (2) shows preferential five-membered ring formation in transannular assistance.

Dinitrobenzoate C is rapidly hydrolyzed to the eight-membered cyclic alcohol plus some rearranged
unreactive ester. Deactivation of solvolysis in the other isomers is due to the inductive effect of the
ether oxygen.

Reaction (3) shows anchimeric assistance by a neighboring acetate ester. Again, the stereoelectronic
requirement for a trans-anti relationship is demonstrated. The cyclic intermediate shown here may be
trapped if a small amount of water is present. The trapped species, shown in the gray shaded box,
breaks down to the monoacetate of the cis-1,2-diol.
Reaction (1) illustrates a class of compounds called 'nitrogen mustards'. The alkylating character of these
compounds is similar to that of their sulfur analogs.

Reaction (2) shows a similar case in which ring expansion occurs.

Reaction (3) shows the rates of cyclization for a series of omega-bromo alkyl amines. In the absence of
base, stable cyclic ammonium salts are formed. Bases convert these salts to their corresponding cyclic
secondary-amines.

Examples of other neighboring group perturbations, including non-bonding electron pair

assistance by neighboring sulfur, oxygen and nitrogen atoms will be displayed above by clicking
the appropriate button under the diagram. The text box commentary will change to suit the
examples. In most of the cases involving heteroatom assistance, an "onium" intermediate is
formed, in which the heteroatom is charged. Adjacent halogen atoms may also stabilize
carbocations, as noted earlier with respect to trans-anti additions to cyclic alkenes. Functional
rearrangement by way of halonium intermediates has also been reported. For example, a
chloroform solution of the diaxial 2-bromo-3-chlorosteroid, shown on the left below,
spontaneously rearranges to the more stable diequatorial 2-chloro-3-bromo isomer drawn on
the right. The rearrangement is reversible and proceeds by way of the cyclic bromonium ion
written in brackets.