Page 294 - Academic Press Encyclopedia of Physical Science and Technology 3rd Organic Chemistry

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240 Physical Organic Chemistry

+

on nitrogen, to produce RC( O)NH . In this intermediate (169 or 169 ,X = Cl or Br) with sodium hydroxide gave
3
there is no longer any partial double-bond character to im- the same 4:1 mixture of 2,2- and 2,3-dimethylbutanoic

pede C N rotation. Then when one of the three hydrogens acids (170, 170 ) from any of the four different reactants.
is returned to solvent, one possibility is that the original This is evidence for reaction via trimethylcyclopropanone
(171) as intermediate. Moreover, when that intermedi-
H E may remain in the amide but be transferred to the H Z
site, to produce 163. For electron-donating R the exchange ate was synthesized independently [from dimethylketene,
−
was found to occur by a more circuitous mechanism. Pro- (CH 3 ) 2 C C O, and diazoethane, CH 3 CH N + N ], it
tonation on oxygen forms RC( OH) NH , which can produced that same 4:1 mixture when treated with NaOH.
+
2
lose either of the two NH to produce two stereoisomeric
RC( OH) NH as intermediates. Reversal of these two * Cl -H + * Cl -Cl - *
steps then regenerates the amide, but with one of its NH O O - O
H
groups exchanged. However, those NH exchange only 166 168 OH -
with solvent, without exchanging with each other. Thus
* * H + *
the two mechanisms could be distinguished by comparing OH + OH OH
O O O -
intramolecular exchange with intermolecular, since only
14
14
167-α- C 167-β- C
via RC( O)NH is there opportunity for intramolecular
+
3
exchange. O O - O - O O OH
or OH OH OH +
X X
169 169' 171 170 170'
The reaction of 172 in acetate buffer to form 173 shows
somesimilaritytotheFavorskiirearrangement.Ithadbeen
thought to occur by elimination of HCl simultaneous with
ringopeningtoform174asapresumedintermediatethatis
then hydrolyzed further. However, when 174 was prepared
independently and subjected to the buffer conditions, it
F. Decarboxylation was unreactive. Indeed, the hydrogen that is removed in
this mechanism is much less acidic than the adjacent one
α,β-Unsaturated carboxylic acids, RCH CHCOOH, de-

carboxylate to alkenes, RCH CH 2 , plus CO 2 .Yet indicated in 172 , analogous to 166. If, instead, that more
(CH 3 ) 3 CCH CHCOOH does not show this reactivity. acidic proton is removed, the resulting enolate anion 175
−
This is a clue that a γ hydrogen is required. The accepted can lose Cl . The resulting 176 is isomeric to a cyclo-
mechanism involves acid-catalyzed isomerization of the propanone, like 168 or 171, but with an open zwitterionic
structure to avoid angle strain. Addition of hydroxide fol-
α,β-unsaturated acid (164)tothe β,γ -unsaturated acid
lowed by protonation produces 177. This next loses HCl
(165), which can undergo a concerted decarboxylation.
and opens the central ring to form a tautomer of the final
Three further pieces of evidence are that α,β-unsaturated
173. Support for this mechanism was obtained by labeling
acids do isomerize to the β,γ -unsaturated acid faster than
the CCl 2 carbon and showing that it acquires H.
they decarboxylate, β,γ -unsaturated acids do undergo de-
carboxylation with isomerization (similar to the concerted
Cl
decarboxylation of β-keto acids, RCOCH 2 COOH), and Cl Cl - OH
-HCl OH
deuterium is incorporated into the γ position when the ? O buffer O
reaction is carried out with acid OD. H O
172 174 173
G. α-Haloketones
Cl Cl Cl
The Favorskii rearrangement is the conversion of an Cl -H + Cl -Cl - +

α-halo ketone, RR CX COR , in alkali to a car- -

O O - O
boxylic acid, RR R C COOH (or ester). Reaction of H

172' 175 176
14
14
2-chlorocyclohexanone-2- C(166, ∗= C) produces
OH -
cyclopentanecarboxylic acid (167) with the label dis-
H Cl
tributed equally between Cα and Cβ. This is evidence H Cl
-HCl H +
for a symmetric intermediate, the cyclopropanone 168,
O O O -
which can open in two ways. Similarly, reaction of 2-halo- H O HO
O
2-methyl-3-pentanone or 2-halo-4-methyl-3-pentanone 177