J. 0. HALFORD AND ROBERT hl. FITCH
3 354 [CONTRIBUTION FROM
THE
Vol. 85
CHEMISTRY DEPARTMENT, UNIVERSITY OF MICHIGAN, ANN ARBOR,MICH]
Stability of Di- and Trimethyl-l,5-benzodiazepines and their Salts BY J. 0. HALFORD A N D ROBERT hf. FITCH RECEIVED SEPTEMBER 11, 1962 Introduction of a third methyl group a t the 3-position of 2,4-dimethyl-l,5-benzodiazepine slightly destabilizes the base and causes somewhat greater destabilization of the monohydrochloride. In the 1-position the third methyl group completely destabilizes t h e base and severely destabilizes the salt. From these effects, which appear t o reflect energetically small steric strains, it follows t h a t the apparently stable dirnethylbenzodiazepine and its monohydrochloride have minimal competitive stability. The cation, however, is stabilized by 55-60 kcal./mole of delocalization energy, a n amount comparable t o the assignable resonance energy of naphthalene or quinoline.
Colorless 2,4-dimethyl-1,j-benzodiazepine and its The original structure assignment by Thiele and deep purple, almost black, monohydrochloride were Steimmig was strongly indicated by the visible color originally synthesized b y Thiele and Steimmig' by of the cation and is fully supported by the ultraviolet rapid precipitation reactions a t room temperature from and infrared spectra. The lack of selective ultraviolet o-phenylenediamine and acetylacetone. Both base absorption by the diazepine bases is inconsistent with and salt are stable in moist air and in moderately strong alternative structures. The benzodiazepine cation, acidic or basic solutions a t ordinary temperatures. but not the free base, shows an N H stretching frequency Warming with acid, however, effects decomposition to in the infrared. 2-methylbenziinidazole and acetone. Gaseous HCl Benzimidazolines have not appeared as intermeconverts the monohydrochloride to a colorless dihydrodiates or end products. The fragmentation observed chloride which readily drops the second HC1 in aquein some preparations and in the hydrolytic decomous solution or in the solid state. position to a benzimidazole and a ketone indicates that the 3-acylbenzimidazoline structure is unstable. In contrast to the behavior of %,4-dimethyl-l,t5The monodeuteriochloride obtained by rapid precipibenzodiazepine, the usual experience has been that tation from a benzene solution of the 2,4-dirnethyl base azepines and diazepines resist synthesis and appear by gaseous DCl shows both the N H and N D freto be unstable structures. We find, however, t h a t a quencies but not the CD frequency. I t is possible third methyl group a t position 1 or 3 causes moderate under these conditions t h a t individual cation units to severe steric destabilization of the base and salt. have deuterium on one nitrogen and protium (ordiAfter verifying the results of Thiele and Steimmig, Vaisman' synthesized 2,3,4-trimethyl-l,5-benzodiaze-nary hydrogen) on the other. A scale model of the 2,3,3,-l-tetramethyl-l,j-benzopine from o-phenylenediamine and methylacetylacediazepine which Vaisman failed to obtain shows penetone (3-methylpentane-2,4-dione).His attempt to tration of one of the 3-methyl groups into the benzene synthesize a tetramethyl derivative from the diamine a-orbital region. The resultant strain is evidently and dimethylacetylacetone produced a yellow base not relieved by the assumption of a more nearly which formed a red hydrochloride but was not a benzoplanar conformation. If the failure of the tetramethyldiazepine. Barltrop, Richards, Russell, and Ryback3 benzodiazepine to appear is due to the energetic rather have reported the synthesis of a series of 1,5-benzothan the kinetic factor, it follows that the energy rediazepines and related derivatives of 3,B-diaza-4,3quired to strain the diazepine ring into the planar conbenzotropone. formation is considerable, probably 5 kcal.: mole or We have verified prior reports on the 2,4-dimethylmore. Since this strain should be offset by increased and 2,,9,1-trixnethyl-l,,?benzodiazepines and on the attempted synthesis of 2,3,3,4-tetraniethyl-l,5benzo-interaction of the C N bonds with the ring, the net strain without interaction, pertinent to a later discusdiazepine. The yield of crude 2,3,3-trimethyl-1,5 sion, would be larger, probably of the order 10 kcal. :mole. benzodiazepine is lower (0070) under comparable I t is likely that a monoanil is first formed and subconditions than t h a t of 2,1-dimethyl-1,j-benzodiazepine sequently removed by one of two cyclizations, to the (83%) and the crude triniethyl derivative contains benzimidazole or to the benzodiazepine. If the substantial amounts of 2-methylbenzimidazole. We ratio of specific rates of the two ring closures is not have carried out the expected hydrolytic decomposisensitive to the level of methyl substitution, the relation of the triniethyl derivative to 2-methylbenzimidtive amounts of benzimidazole and benzodiazepine azole and methyl ethyl ketone. Cnder the same formed could still be sensitive to the thermodynamic conditions Vaisman's yellow base and red salt do not factors controlling the equilibrium concentrations of decompose. diazepine, diazepine salt, and the monoanil precursor. Conductometric titration yields accurate consistent This equilibrium hypothesis suggests possible imequivalent weights for the diazepine bases and an provement of the chance of obtaining the missing 2 , 3 . equivalent weight of ,274 for Vaisman's yellow base. 3,4-tetramethyl base by displacement of the equilibBase strength constants, obtained with the glass elecrium toward the diazepine base or salt by removing trode in approximately 0.02 molal aqueous solution, water as it forms. Therefore, with benzene substiare 3.1 X l o p 7 for 2,3,4-trimethyl-l,5-benzodiazepinetuted as solvent, we have pumped out water during the And 1.1 X 10pq for "4-dimethyl-1 ,j-benzodiazepine. reaction. This procedure, tried out with 2,3,4-triWith the hydrogen electrode, a t higher concentration, methyl-1 ,j-benzodiazepine, increases the yield of crude Schwarzenbach and Lutz? measured Kg = 10Y9J product from A5 to %yo,a result which supports the for the latter compound. equilibrium hypothesis. As might be expected, however, from the estimated strain energy, the revised (1) J. Thiele a n d C.. Steirnrnig, B p i . . , 40, 9Y,,i (1907). procedure still fails to produce the missing tetramethyl ( 2 ) S. V a i s m a n , T r u d y I n s t . Rliiin. Khni.ikov. Cosirdavsl. Unit'., 6 , 67 (1940). base. 1 3 ) J A. B a r l t r o p , C G. Richards. D . M Russell, and G. Kyback, The correct choice between the taut,omeric 1H and J . C h P m S o c . , 1132 (lY59). 3 H structures for the base and cations has been evi, A c l a , 23, 1147 (1940). ( 4 ) C.. S c h w a r z e n h a c h a n d K. I,utz, H P ! ~Chiin.
Nov. 5, 1963
DI-
AND
TRIMETHYL-1 ,5-BENZODIAZEPINES
dent from the outseti and has received subsequent experimental s ~ p p o r t . ~The , ~ base and dication are taken to have minimally strained nonplanar 3H dianil forms while a planar resonance-stabilized 1H structure can be assigned to the singly charged cation. Vaisman's projected but apparently unstable tetramethyl base would have to be a dianil which could not be protonated to a 1H cation. With the pertinent atomic porbital axes in the bases inclined at more than 60' in parallel planes, styrene-like interaction with the benzene ring should be small and is probably negligible. Strong selective absorption by the cation in the visible and ultraviolet suggests a delocalized orbital system which implies a planar conformation for the entire bicyclic skeleton. In order to stabilize this conformation, the delocalization energy, relative to a hypothetical planar cation with localized double bonds in both rings, should be large enough to compensate for tautomerization and strain terms, and will include the benzene resonance energy for a total above 50 kca1.1 mole. We have extended the series of methylated 1,sbenzodiazepines to include the cation of the 1,2,4trimethyl-l,5-benzodiazepine,obtained in two steps from acetylacetone and N-methyl-o-phenylenediamine. Reaction under the conditions used by Thiele and Steimmig produces the intermediate anil, 4-N-(omethylaminophenyl)-iminopentanone-2,contaminated with 1,2-dimethylbenzimidazole,but yields no diazepine salt. Attempted cyclization of the monoanil in hydroxylic solvents produces transitory color suggesting cyclization, but results in practically complete conversion to 1,2-dimethylbenzimidazole. The cyclization occurs, however, a t lower temperatures in benzene with HCl present, and with simultaneous removal of water under reduced pressure. The crude diazepine salt, the residue after evaporation of the solvent under reduced pressure, eludes direct purification by recrystallization or sublimation. In the other cases, purified salt was obtained by precipitating the base and reconverting to the hydrochloride. Here, the base, which would have to assume the less stable 1H enamine form, is not obtained. Instead, the attempt to precipitate a diazepine base from the crude salt yields a mixture of the monoanil precursor and 1,2-dimethylbenzimidazole. The mean equivalent weight of the crude salt, by conductometric titration in water, is 234. If the only impurity is uncyclized monoanil salt, this indicates 30 to 40% cyclization. The ultraviolet absorption, however, after adjustment of intensities, is almost identical, in alcohol, with that of the 2,3,4-trimethyl1,j-benzodiazepine hydrochloride, indicating much more nearly complete cyclization. Both the visible absorption and the main double ultraviolet maximum a t 263, 269 mp show clearly the presence of a high relative concentration of a benzodiazepine salt. A secondary maximum appears in the trimethylbenzodiazepine salt spectra a t 237 mp, b u t is less intense and lies a t a lower wave length () I e T a r , ibtd, 83, 1014 (1961) ( I ) f a ) 11 I? Augnod a n d G H Williams, r h e i n RPT, S7, 123 t I 9 5 7 ) . ( h ) C Walling, "Tree Radicals in S o l u t i o n , " J o h n Wiley a n d Sons. I n c , New Y o r k , S V I 1957. p p 482-486 ( 2 ) ickerman a n d G R Verrnnnt, J . A m Ciivin . C o r , 84, 41.50
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(8) R T l f o r r i q o n . J 11.i2 (1962)
C a z e s . S Sarnkoff, a n d C A
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