Sept. 3 , 1936
ALKALINE CLEAVAGE
[CONTRIBUTION FROM
THE
4323
O F CY-~~RYLBENZOINS
CHEMISTRY DIVISION,OAKRIDGENATIONAL LABORATORY, A N D THE DEPARTMENT OF CHEMISTRY, UNIVERSITY O F TENNESSEE]
A Reinvestigation of the Alkaline Cleavage of a-Arylbenzoins’ BY JEROME F. EAST HAM,*"^
JAMES
E. H U F F A K E RVERNON ,~~ F. RAAEN*’ AND CLAIRJ. COLLINS*’ RECEIVEDNOVEMBER 30. 1955
A reinvestigation of the work of Sharp and Miller (ref. 7 ) has disclosed that the “a-o-tolylbenzoin” (supposedly compound V) described by these and other investigators (ref. 10) is, in fact, or-phenyl-2-methylbenzoin ( X I X ) . I n addition to compound X I X , the addition of o-tolylmagnesium bromide to benzil yields authentic a-a-tolylbenzoin (V) . The structures of XIX and V were proven by chemical means. Compound V, upon treatment with boiling, ethanolic alkali is converted t o a-phenyl-2-methylbenzoin ( X I X ) which, in turn, is cleaved t o benzhydrol and o-toluic acid. The additions of m-tolyl and of p-tolylmagnesium bromide to benzil have been shown also to yield both the normal and the rearranged a-arylbenzoins. Carbonyl-labeled a-phenylbenzoin undergoes alkaline cleavage to benzhydrol and benzoic acid with 3‘3, rearrangement of the carbon-14 label; whereas under similar conditions, labeled a-anisoylanisoin (XXIXa) is incompletely cleaved and undergoes 667, rearrangement. The mechanism of the alkaline cleavage of triarylketols is discussed. HO 0 0 OH In previous papers3 several examples of acidI 11 alkali It 1 catalyzed rearrangements of the carbon skeleton PhC-CPh Ph2CHC-CPh2 ---+ 1 TT of the 1,1,2-triphenylethyl system have been disII cussed. Both single and multiple-labeling techCHPh2 PhlCHCOOH + Ph2CHOH (1) I 111 IV niques with carbon-14 have been fruitful in studying the mechanisms of (a) the Wagner-Meerwein other a-substituted benzoins7 (V, V I and VII, rearrangement of 1,2,2-triphenylethanol and its equation 2). Our interest in these rearrangements d e r i ~ a t i v e s ~; ~ “(b) * ~the semi-pinacolic dehydro- was derived from certain anomalies in the stoichiombromination of 2-brom0-1,1,2-triphenylethanol~~ ; etry8 reported by Sharp and Miller, and from (c) the pinacol rearrangement of triphenylethylene their statement7 that “detection of rearrangement glyco13c; and (d) the deamination of 1,1,2-tri- is impossible” during the alkaline cleavage of CYphenyI-2-aminoethan01.~~ The present paper is phenylbenzoin (XV). The extent of rearrangeconcerned with the base-catalyzed rearrangements ment during alkaline cleavage of a-phenylbenzoin of 1,1,2-triphenyl-2-ketoethanol HO 0 (a-phenylbenzoin, XV) and re1 11 Alkali lated compounds. PhC-CPh v PhCHOH + PhCOOH and ArCOOH + Ph2CHOH (2) I Rearrangements of a-ketoalXI I\‘ Ar cohols (acyloins and benzoins) v, .ir = o-toiyi YIII, Xr = o-tolyl X I I , Xr = o-tolyl I X , r\r = nz-tolyl XIII, -%r = 9%-tolyl are known to occur in the presVI,Ar = m-tolyl X , Ar = p-tolyl XI\’, Ar = p-tolyl ence of alkali.? Alkali is known Ar = Pto1Y1 also to cleave these systems to carbinols and acids.j (XV) has now been determined by the series of reIn some cases rearrangement and cleavage reac- actions outlined in Chart I. By the method of tions occur consecutively in the same medium, B i l t ~benzhydryl ,~ phenyl ketone-CI4 was converted a phenomenon illustrated by equation 1 and first HO 0 observed by Curtin and Leskowitz.6 These workers KOH i n demonstrated the rearrangement by isolation of Ph2C-C*Ph __ -+ P h n 6 H O H + Ph6OOH MeOH a-hydroxydibenzhydryl ketone (11), diphenylXI-, 2.16 IVa, 0.065 XIa, 2.10 acetic acid (111) and benzhydrol (IV) from treatment of a-benzhydrylbenzoin (I) with alkali. Sharp and Miller have made the claim that rearrangements occur during the alkaline cleavage of ___f
I
(1) This paper is based in part upon work performed under Contract No. W-7405-eng-20 for t h e Atomic Energy Commission. This paper is P a r t VI1 in t h e Molecular Rearrangement Series P a r t VI, H. J. Schaeffer and C . J . Collins, THISJOURNAL, 78, 124 (1956), and contribution No. 149 fron t h e Department of Chemistry, University of Tennessee. (2) (a) Research Participant a t Oak Ridge National Laboratory, June-September, 1954 and 1955; (b) University of Tennessee; (c) Oak Ridge National Laboratory (3) (a) W. A Bonner and C . J. Collins, THISJ O U R N A L , 76, 5372 (1953); (b) C. J . Collins and W. A Bonner, ibid., 75, 5379 (1953); (c) C . J. Collins and W. A. Bonner, ibid., 77, 92, 6725 (1955); (d) W. A. Bonner and C . J. Collins, ibid., 77, 99 (1955); (e) C. J. Collins, i b i d . , 77, 5517 (1955); ( f ) H . J . Schaeffer and C. J. Collins, 6th Annual Southeastern Regional Meeting of t h e American Chemical Society, Birmingham, Alabama, 1954. (4) T h e acyloin rearrangement has been extensively applied with steroids. F o r several examples see C. W. Shoppee and E. Shoppee in Rodd’s “Chemistry of Carbon Compounds,” Vol. I I E , Elsevier Publishing Co., London, 1953, p. 925. ( 5 ) S. F. Acree, A m . Chenz. J . , 29, 588 (1903). (6) D. Y .Curtin and S. Leskowitz, THISJ O U R N A L , 7 3 , 2633 (1951); c f . also D. I’.Curtin a n d A Bradley, & b i d . ,76, 5778 (19.54).
HO
I
OH
1
Ph2C-C*HPh XYI
KMn04
+
Ph2C=0 Ph*COOH XVII, 0.005 XIa, 2.17 CHART1“ a Molar radioactivity of compounds expressed as millicuries. ___f
to carbonyl-labeled a-phenylbenzoin ( X W . This product X V was shown to be discretely labeled by conversion to 1,2,2-triphenylethylene-1-Cl4 glycol (XVI) followed by permanganate oxidation of the glycol to non-radioactive benzophenone (XVII) and labeled benzoic acid (XIa). Alkaline cleavage of the keto1 (XV, 2.16 mc./mole) with potassium ( 7 ) D. B. Sharp and E. L. Miller, i b i d . , 74, 5643 (1952). ( 8 ) For example, alkaline cleavage of 28.3 moles of benzoin itself was reported t o yield 32.3 moles of acids, benzoic and formic. This is a yield of 113%. (9) H . Biltz, B e y , 32, 03.5 (1899).
4324
J. F. EXSTHAM, J. E. HUFFAKER, V. F. RAAENA N D C. J . COLLINS
hydroxide in methanol produced benzhydrol (IVa, 0.07 mc./mole) and benzoic acid (XI, 2.10 mc./ mole). From these data it can be seen that rearrangement during the alkaline cleavage of aphenylbenzoin occurs to the extent of only a few per cent. I n two of the cases reported by Sharp and Miller (the rearrangements of VI and VII)' uncharacterized oils were used as starting materials. A third a-arylbenzoin, however, was a crystalline material of m.p. 116-11i0, presumed from its mode of formation to be a-o-tolybenzoin (17). This material had been prepared by the addition of 0tolylmagnesium bromide to benzil by Roger and McGregor,'O who cleaved the product with alkali (equation 3 ) to obtain o-toluic acid (XII) and benzHO
11
11
PhC-CPh
XVIII
phenylbenzoin (Fig. 1) shows the steric inhibition of resonance expected for the 2-methyl group.'? The structure V of the isomer of m.p. S2-S8O follows from the reactions outlined in Chart 111. This product IT has been reduced to a glycol (XXXIII) which in turn has been oxidized to 2methylbenzophenone (XXIV) and benzoic acid (XI). The ultraviolet spectrum (Fig. 1) of this product V, a-o-tolylbenzoin, is quite distinct from that of its isomer XIX, a-phenyl-2-methylbenzoin, but similar to that of phenylbenzoin. Upon treatment with alkali, a-o-tolylbenzoin undergoes rearrangement to a-phenyl-2-methylbenzoin ( X I X ) , which is cleaved to benzhydrol ( 1 1 7 ) and to otoluic acid ( X I I ) without further rearrangement. From the foregoing results it seems likely that the
0
0 0
H0 o-C;H;hlgBr
--*
Ph~-CPh
-
Vol. 78
CHa
0
CH,
I
I
u
llkali
p112A-d-b
or
+ Ph?CHOH
L+I
11
~
CH 3
A,--COOH
SIX
(3)
I\-
SI1
hydro1 (IV), rather than the expected phenyl-o- additions7 of m-tolylmagnesium bromide and of tolylcarbinol and benzoic acid. Sharp and Miller p-tolylmagnesium bromide to beiizil proceed with repeated the Grignard preparation and cleavage some rearrangement, and that the product in each reaction with the same results as Roger and I l k CH:J Ho 0 11 11 Gregor (6s. ref. 6). The foregoing facts led us to I1 F;o the conclusion t h a t the material of m.p. 116-117" PhC-CPh Ph?&-COCHa / is not a-o-tolylbenzoin (V) but is instead an isomer, a-phenyl-2-methylbenzoin (XIX), l 1 ITe have now repeated the addition of o-tolylmagnesium bromide XI-111 ss SSI to benzil, and have confirmed this conchsion. I n (a) 1, o - ~ j ~ , ~ [ g(b) ~ r1, ~ - C ~ H ~ h i g (c) B r 1, PhMgBr several experiments we obtained yields (SOYo or 2, I € , 0 2, H ~ O less) of the previously isolated compound7Zlo of m.p. 1 1 6 - 1 1 ' 7 O which has now been shown to possess structure XIX. However the major portion (as the -k---.,"i minor O of the reaction product, not previously isolated, is an isomer of m.p. 82-53', and possessing strucHO 0 ture The structure XIX of the isomer of Ph?C-C II - o m.p. 116-117" follows from the reactions outlined in Chart 11. Thus, this minor reaction product X I X from (a) addition of o-tolylmagnesium bromide t o SIX benzil, is the same as the product from (b) addition CrOa of o-tolylmagnesium bromide to methyl benzilate .iCOH LiAtH, and (c) addition of phenylmagnesium bromide to 2-methylbenzil. This product X I X has been reduced to a known glycol (XXII)13and oxidized to benzophenone (XVII)' and o-toluic acid ( X I I ) . H o YH CH3 The ultraviolet spectrum of this product X I X , Ph2C-CH--I/ I;MllO< / --COH a-phenyl-2-methylbenzoin, compared with that of + Ph2C=0 T
9' / phC-e-
!\
YH3
/ \; 3
/
(10) R. Roger and A . McGregor, J . C h c m So;., 4 4 2 1 1 0 3 4 ) . (11) W. E. Bachmann, THISJ O U R K A L , 64, 2112 (19321). (12) T h e yields of the normal addition product V and the abnormal addition product XIX may vary considerably. I n one experiment, for example, V was formed in G G 7 , yield, whereas there was no significant amount (less than 1%) of t h e abnormal product XIX, as demonstrated by the carbon-14 dilution technique [R.H . Mayor and C. J . Collins, ibid.,73, 171 (1951)l. This experience was repeated in several other cases of t h e addition of phenyl or substituted phenyl Grignard reagents t o b e n d or t o substituted b e n d s . For example, in t h e addition of phenyl-C"-magnesium bromide t o benzil, one experiment yielded e-phenylbenzoin which possessed a statistical distribution of the label among t h e three phenyl groups; another experiment yielded a-phenylbenzoin which had been formed without rearrangement I t is not possible t o s t a t e a t present how these rearrangements are controlled, or whether they occur during the Grignard addition, ur in t h e subsequent work up. T h i s rearrangcment reaction i s being investigated and will be t h e suhiect of a forthcoming paper. !13) R KagFr :in
D Ilcddon ind R' G l3rnsn
i
i i r 5 i o 1 ~b 4 1
75, 3i I I
Sept. 5 , 1956
ALKALINE CLEAVAGE 0
HO
1
OH
HO
/I
PhC-CPh
I
LiXlH4
4325
@.-ARYLBENZOINS
OF
1
PhC-CHPh 4.4
d - C H ,
&CHB V
XXXIII
z
PhC
‘‘3
I-
o 0.8C
+PhCOOH
I
Ph2C-C
11
‘0
1
3
PhzCHOH
XIX
+
CHARTI11
rooH 0
5
0.4
1
I1
HO
II
PhC-CPh
~
0
I 1 + PhC-CPh 2 , H20 1
1, ArMgX
-
1 _____ -1
0.2
oxidation the 2,4dinitrophenylhydrazone of benzophenone was prepared. l 5 The Grignard reactions 0 0
-
W 1
XI1
1x7
0.6
o
I
I
--+
a
XI
CH,
CHa
W
LL
XXIV
Ho
1.0
0
220
(XP) .\\ \ a - g - T o l y l b e n z o i n (P) \ a - Phenyl-2-rnethylbenzoin(XIX) a -Phenylbenzoin
240
230
0 OH
I
ll
and Arc-CPh
I
Air
260
250
270
200
W A V E L E N G T H , rnp
Fig. 1.
(4)
Ph VI, Br = v-tolyl XXY, - i r = m-tolyl YII, Xr = p-tolyl XXYI, Xr = p-tolyl
XVIII
of equation 4 must therefore have proceeded with some rearrangement. The yield of benzophenone derivative was less than lOy0in each case. An exact measure of the extent of rearrangement in the addition of P-tolylmagnesium bromide to b e n d was obtained by reduction of the crude product to a mixture of glycols, equation 5. The unrearranged glycol XXVII could be isolated from the
0
II
XIa, 1.12
h
OH
I
a
CH3
0
II + HOC4r
*
XrCOH 9rzC=0 1.13 1.12 CHARTIVa Molar radioactivity expressed as millicuries.
HO XXVII
J. ~ r 0 3
J. coz * ll
‘
0
I I1 Arc-CXr I Xr*
0
OH
HO
I1
.-lrC-CXr
LiAlH4 VI1 and XXYI __ --.) OH OH
I 1 PhC-CHPh
0
0
0.00
oe
HO
XX\-III
mixture by crystallization. The rearranged glycol XXVIII was shown by the isotopic dilution technique12to constitute 7.575 of the mixture. One more example of the alkaline rearrangement-cleavage reaction has been studied, that of a-anisylanisoin XXIX. It seemed likely that the decreased reactivity of the carbonyl group in this case would slow the cleavage reaction (6) and allow the rearrangement reaction ( 7 ) to proceed to a greater extent. Labeled anisylanisoin (XXIXa) was prepared as shown in Chart IV and a sample treated with methanolic alkali for six hours. (15) Conditions for oxidation were those used by Sharp and Miller’ on t h e mixed products of alkaline cleavage of these oils. p-Benzoylbenzoic acid subjected t o these conditions did not undergo decarhoxylation.
X X I X , Ar
=
H-0 XXX
p-anisyl
OH Ar2C(H
3
+ O\CAr
(6)
OY
o oe iI
I
.irC-C.%r
I
Ar
0
+H@
-+
I1
OH
I
.irC-C:\r
I
Ar
(7)
4326
J. F. EASTHXM, J. E. MUFFAKER,Y.F. KAAENAND C. J. COLLINS
The amount of anisic acid produced during this time was taken as a measure of the extent of cleavage. The neutral residuum, consisting of the cleavage-produced carbinol and uncleaved ketol, was oxidized with chromium trioxide. The activity of the anisic acid produced by oxidation was taken as a measure of the rearrangement in the ketol. The results are summarized in Chart V. Under conHO
0
OH
1
CrOaon
*
+ Ar?C=O neutral residuum 0 938 Molar radioactivity expressed as millicuries. CHART1-L
0
I * + HOC.1r 0.250
ditions which caused the complete cleavage of the triphenyl ketol in two hours, the trianisyl ketol was only 55yo cleaved after six hours. During this time the uncleaved material had approached complete rearrangement (statistical redistribution of the anisyl groups) 66y0 of the way. Rearrangement in the cleaved material had, of course, proceeded to a lesser extent, about 47%.16 To explain the difference between a-phenylbenzoin (XV) and its tri-p-methoxy derivative XXIX it seems useful to compare the rearrangement reaction with the pinacol rearrangement and the cleavage reaction with the benzilic acid rearrangement. Cleavage (equation 6) involves hydroxide attack on the carbonyl group, as in the benzilic acid rearrangement. From its large negative sigma value (Hammett function) a p-methoxy group would be expected to slow such nucleophilic attack, as it does in the benzilic acid rearrangement.': Rearrangement (equation 7) involves migration of an aryl group with its bonding electrons; introduction of a p-methoxy group should facilitate this migration as it does in the pinacol rearrangement. 18,l 9 To explain the difference between a-phenylbenzoin and its two o-methyl derivatives (V and XIX) the mechanisms show; in equations 6 and 7 are similarly useful. stated (Chart 111))the products from treatment Of a-o-tolylbenzoin (V) with alkali are toluic acid and benzophenone, rearrangement products. Rearrangemerit of this arylbenzoin in base obviously occurs (16) Cleavage or oxidation of a triaryl ketol of activity in randomly distributed in t h e aryl groups would yield a n aromatic acid of activity m/3. (17) J. H. Blanksma and W. H. Zaaiger, Rec. trau. chifrz., 67, 883 (1938); J. D . Roberts, D . R. Smith and C . Lee, THISJ O W R X A L , 73, 619 (1951); M . T . Clark, E. C . Hendley and 0. K. Neville, abtd., 77, 3280 (19.55). (18) G . 1%'. U'heland, "Advanced Organic Chemistry," 2nd Ed., 1949, p. 515. John Wiley and Sons, Inc., New York, N . Y., (19) T h e decreased reactivity in the anisoyl type carbonyl need not profoundly affect the rearrangement reaction since all energy lost by interruption of the original carbonyl's conjugation is regained by formation of a n identical new conjugated carbonyl. This is not true in the rleavage reactinn
IroL i S
much more rapidly than does cleavage. The latter reaction (6) with a-o-tolylbenzoin (V) should logically be slowed by steric compression developed by the o-methyl group in the intermediate needed ( c j . XXX) ; the rearrangement reaction ( 7 ) on the other hand should be facilitated b y the steric effect, since migration of a phenyl group (cf. XXXI) would leave the o-tolyl group on a trigonal carbon atom relieving considerable compression. The cleavage' "O of the isomeric a-phenyl-2-methylbenzoin (XIX) without rearrangement follows consistently with this reasoning. In summary, the data collected show that aphenylbenzoin (XV) itself rearranges less during alkaline cleavage than either its tri-p-methoxy derivative XXIX or its a-o-methyl derivative V, but more than its 2-o-methyl derivative XIX. These data on the alkaline treatment of the four aarylbenzoins (V, XV, XIX, XXIX) can be correlated by comparison of their cleavage (equation 6) with the benzilic acid rearrangement and their rearrangement (equation 7 ) with the pinacol rearrangement.
Experimentalz0 a-Phenylbenzoin, Carbonyl-labeled (XV) .-To a hot solution of 8.00 g. of phenyl benzhydryl ketone-CI4 (2.161 nic./mole)21 in 36 ml. of glacial acetic acid in a n open erlenmeyer flask there was added 10.1 ml. of concentrated nitric acid in one portion. The solution was gently boiled in the open flask for 30 minutes during which time considerable nitrogen oxide escaped. The cooled solution was poured onto ice and the resulting mixture was extracted with ether. The ether solution was washed with dilute aqueous base, dried over sodium sulfate and evaporated to leave a yellow oil. The desired product could be leached from this oil with hot hexane leaving an uncharacterized amorphous yellow solid. Dilution of the hot hexane with benzene and slow cooling yielded 6.1 g. of pale yellow crystals, m.p. 84-86 O . Recrystallization gave colorless a-phenylbenzoincurbonyZ-ClJ (XV), m.p. 87.5-89' (reported2z 87-88"), 2.163 mc./mole. Procedure was adapted from t h a t of Bilt~.~ 1, I ,2-Tripbenylethylene-I-C14 Glycol (XVI).--A solution of 0.20 g. of arylbenzoin XS.' (carbonyl-labeled, 2.163 mc./ mole) and 0.1 g. of lithium alutninum hydride in 20 ml. of ether was refluxed for one hour, t o yield l,Z,Z-triphenylethylene-l-C14-glycol (XVI). T h e recrystallized >-ield was 0.18 g., m.p. 166.5-167.5', undepressed by authentic material prepared by addition of phenylmagnesium bromide to benzoin. Oxidation of 0-Pheny1benzoin.-A 0.20-g. sample of the phenylbenzoin (XV, carbonyl-labeled, 2.163 mc./rnole) was dissolved in five ml. of acetic acid and treated with 0.090 P. of chromium trioxide in a few droDs of water. The regulting solution was kept a t 15' for one hour, dllutcd with 20 ml. of water and extracted with ether. The ethcr solution was washed with water, extracted with alkali, dried and evaporated. The residual benzophenone wa\ characterized as its 2,4-dinitrophenylhydrazone, m . p . 239-239.5" (radioactivity assay, ca. 0.005 mc./mole). The aqueous alkaline extract from the oxidation was made acidic with sulfuric acid and extracted with ether. \\'ashing, drying and evaporating the ether left crude cry5tallinc benzoic acid. Recrystallization from water and y b l i m ttiun gave 48 mg. of the pure acid, m.p. 121-123 , 2.1763 tnc./mole. Oxidation of 1 , I ,2-Triphenylethylene-I-Cl4Glycoi.-Tliii oxidation was carried out with permanganate as described (20) Melting points are reported uncorrected. Radioactivity determinations were performed in the usual manner IC. J. Collins, THIS J O U R N A L , 7 0 , 2519 (1948) ] using t h e vibrating-reed electrometer. Assays of individual compounds were reproducible t o approximately i(I7, ..? (111 W. A. Bonner and C. J . Collins. ibid , 76, , 3 7 2 (1!1.53). ( 2 1 ) S fi Arree. Rei., 37, L'iX (1QO4).
.
Sept. 5 , 1956
ALKALINECLEAVAGE OF CY-ARYLBENZOINS
previously.3c~d~eFrom the alkali-insoluble residue was prepared the 2,4-dinitrophenylhydrazone of benzophenone, m.p. 238-239" (undepressed by an authentic sample),
