June 5 , 1955
NOTES
pressure while any other nitroamine would be capable only of intermolecular hydrogen bonding. Experiment showed that sublimation was effective in separating the isomers a t 120" without decomposition. When a gentle current of air was drawn through the sublimation tube, separation time was reduced to four to six hours. Since temperatures higher than are obtainable in steam distillation are used and the product is obtained nearly pure and dry, sublimation furnishes a more rapid and elegant method for the separation of aminonitropyridines. The apparatus for this work has been described. Table I summarizes the information obtained on total yield and percentage of each isomer obtained from the nitration of 2-aminopyridine, 2-amino-32-ammethylpyridine, Z-amino-4-methylpyridine, ino-5-meihylpyridine and 2-amino-6-methylpyridine. The nitration and separation of isomers was carried out as described in the Experimental portion of the paper. No claim of originality in the nitration procedure is made, the aim being to combine what proved to be the most useful steps in already published ~ o r k . l - ~ , j -In ~ this way, a general method of syntheses for compounds of this type has been devised. TABLE I SITROAMISES PREPARED Starting pyridine
%Amino 2-Ainino-3-niethyl 2-Amino-4-methyl 2-Amino-5-methyl 2-Amino-&methyl
Isomeric nitro product
3-Sitro 5-Kitro 5-Sitro 3-Sitro 5-Xitro 3-IYitro 3-iYitro 5-A'itro
Yield,
~I.P Tndi.,
'C.
vidual
163- 164 188 236 131-136 220 190 141 187
20 0 63 1 90 0 22 3 47 3 335 21 2 46 4
cZ Total
83 1 90 0 69 6 333
70 6
Experimental Nitration Procedure.-As indicated, this method was used for 2-arninopyridine and all the 2-aminopicolines. 2Aminopyridine (25.3 g., 0.27 mole) was dissolved cautiously in 50 ml. of concd. sulfuric acid (d. 1.84). Vigorous stirring and cooling were used t o keep the temperature below 20". T o this solution, cooled to 5-10', was added dropwise 40 ml. of a 1 : 1 mixture of concd. sulfuric acid ( d . 1.84) and concd. nitric acid ( d . 1.42). During this addition, solution temperature was maintained below 20'. If the intermediate pyridylnitramine was desired, the solution was poured over ice at this point and the pyridylnitramine ( m . p . 185-189° dec.) collected. If the nitroamines were desired, the solution was warmed cautiously. At 35-40', t h e exothermic rearrangement of the nitramine t o nitroamines caused a sudden increase in temperature. m'hen this initial rise had subsided, the solution was held a t 50" for four hours to complete the rearrangement. The solution was then poured over ice and neutralized with concd. ammonia (250 ml., d . 0.90). The precipitate of 2ainino-3-nitropyridiiie and 2-amino-5-nitropyridine was collected by suction filtration and dried in a vacuum oven at 70". Sublimation.-The apparatus used and its operation has been d e ~ c r i b e d . ~A charge of 20-60 g. can be handled. Six hours is generally sufficient for complete separation.
-
(4) I,. N. Pino and W. S. Zehrung, J. Chem. Educnlioiz, 31, 476 ( 1 954). ( 5 ) G . R. Lappin and F. B. Slezak, THISJ O W R N A L , 72, 2806 (1950). ( 6 ) 0 . Seide, -7. Rliss. Phvs C h ~ i ? ?.?or., . 5 0 , 531 (1920); C. A , , 18, 1497 (1924). (7, 0. Seiclr, I ~ v v 57B, , 701, IS02 (1924).
3155
IYhen the separation is complete, the residual isomer can be recrystallized from dilute alcohol and the sublimed isomer vxshel out of the condensing tube with acetone and the acetone evaporated t o give a pure crystalline product.
CARSEGIE HALLOF CHEMISTRY ALLECHESY COLLEGE
MEADVILLE, PESSA.
Hydroxymethylene Ketones. IV. Orientation in the Condensation of Methyl n-Hexyl Ketone with Methyl Formate BY E. EARLROYALS AND E. R. C O V I S G T O N ' RECEIVEDSOVEMBER 1'7, 1954
In continuation of our investigations concerning the condensation of unsymmetrical ketones with formic esters,?it was decided to determine the manner in which methyl n-hexyl ketone condenses with methyl formate. We have shown in the present work that methyl n-hexyl ketone condenses with methyl formate in ether solution in the presence of sodium methoxide at both the methyl and the methylene units to give the isomeric hydroxymethylene ketones I and II.3 The presence of both I and I1 in the condensation product was shown by ultimate conversion of I to a-n-amylcrotonaldehyde (IX) and I1 to anonenaldehyde (X) by the reaction sequence of Chart 1. The mixed sodium salts of the hydroxymethylene ketones I and I1 were treated with methanolic hydrogen chloride according to the procedure of Royals and Brannock4 to give a reaction product probably consisting of the isomeric Pketoacetals I11 and 17 and the methoxymethylene ketone IV. Reduction of the mixture with lithium aluminum hydride followed by treatment of the resulting mixture (probably containing VI, VI1 and VIII) with aqueous sulfuric acid gave a mixture of a-n-amylcrotonaldehyde (IX) and a-nonenaldehyde (X). The aldehyde mixture was separated by fractional distillation into three fractions constituting 40, 12 and 48% of the distilled aldehydes. The lower boiling fraction was identified as a-n-amylcrotonaldehyde by the preparation of the semicarbazone, m.p. 169", which showed no m.p. depression on admixture with an authentic sample, m.p. 170". The higher boiling fraction was identified as a-nonenaldehyde by the preparation of a semicarbazone, m.p. 163", which showed no depression on admixture with an authentic sample, m.p. 164-165'. A mixture of the semicarbazones from the lower and higher boiling fractions showed m.p. 137-150". The formation of a-n-amylcrotonaldehyde in appreciable amounts from the above reaction sequence was rather unexpected. Despite the above evidence from m.p.'s of semicarbazones, it seemed de(1) Abstracted from a thesis presented by E. R. Covington t o the Graduate Faculty of Emory University in partial fulfillment of t h e requirements for t h e degree of Doctor of Philosophy, June, 1954. (2) See Papers I , TI and 111, E. E. Royals and K. C. Brannock, THISJ O U R N A L , 76, 3041 (19541,for previous work in this field. (3) It is known t h a t t h e results of condensations between esters and ketones are dependent upon t h e experimental conditions, t h e nature of t h e ester, and the t y p e of basic catalyst used. See, f o r example, R. P. Mariella, i b i d . , 69, 2670 (1917); R . Levine, J. A. Conroy, J. T . Adsms and C. R. Hauser, i b i d . , 67, 1.512 11945). (4) E. E.Royals and K . C Rrannock, i 6 i L 75. 2050 (1953).
II
4
\.I11
sirablc to obtain further evideiice regarding the structures of thc two aldehydes obtained. The higher boiling aldehyde fraction was hydrogenated ovcr platinum black to n-iionyl alcohol whose 1 naphthylurethan, m.p. 61-62', gave no m.p. depression on admixture with an authentic specimen. The lower boiling aldehyde fraction, tentatively identified5 as cu-n-amylcrotonaldehyde, on hydrogenation over platinum black gave 2-ethylhepta1101, m.p. of 1-naphthylurethan 41.5". Since 2ethylheptanol has not previously been reported in the literature, it was necessary to synthesize this material by an unequivocal method. a-Ethyl-heptanoic acid (not previously reported) was prepared by the malonic ester method in 55% over-all yield from diethyl malonate. Lithium aluminum hydride reduction of a-ethylheptanoic acid gave %ethylheptanol in 75% yield. The alcohol gave a l-naphthylurethan, m.p. 43-44', which failed to depress the m.p. of the 1-naphthylurethan of the reduction product of the lower boiling aldehyde fraction. I t is obvious from these results that distinct limitations are placed on the synthesis of pure a,P-unsaturated aldehydes by reaction sequences of the type illustrated in Chart 1 because of the occurrence of both methyl and methylene condensation in the first step. -%nother possible limitation is that in the second step of the synthetic sequence hydroxymethylene ketones resulting from methylene condensation give mixtures of P-ketoacetals and methoxyrnethylene ketones. I t seemed desirable to determine whether such a mixture may be successfully used without separation for the preparation of pure a,P-unsaturated aldehydes in the aliphatic series6 Diethyl ketone was chosen for the test case, since only methylene condensation with iiiethyl formate is possible, and it is known2 that the condensation product is a mixture of P-ketoacetal and methoxymethylene ketone. Lithium aluminum hydride reduction of this mixture and subsequent hydrolysis and dehydration of the product gave pure I-methyl-2-ethylacrolein in 54% yield from the mixed condensation product. ( 5 ) B. Zaar, B r r . Sciriiniriel upid Co. A k l . Ges., 311 (1929); C A . 2 4 , 2107 (1930), has reported the preparation on a-n-amylcrotonaldetiyde t)y ct,ndrriaaLion < i f ncetddehyrlr w i t h 11-heptdldehyds: 110 u ) ~ ! cluLiivc striicturr prixji WI(S 0 8 c r e < l . ( t i ) p, S v i f e r t .in(J IT Srliiriz. I l r i o . tiiiii . A , t u , 3 4 . 7 2 8 ( l ! l > l 1 I I , ~ \ ' C ..ncrc,ifully r ~ : ~ l u c cc~r li - t u i r i u l k ~ , x y i i l r t h y l r i i r ketriiir- i n Llir JIG\ c l i t , h-l formate, 40 g. (0.67 mole), vas c-onrletised with 70 g. (0.55 mole) of methyl n-hexyl ketone in the prcscnce of 27 g. (0.5 mole) of sodium methoxide in 800 ml. of dr>- ether according to the procedure of Royals and Bran11ock.~ The reaction mixture was stirred for 2.3 hours after n-hich time the ether was removed under t h e vacuum from a water aspirator. Methanol, 96 g. ( 3 moles), was added to the residual sodium salts, t h e mixture was cooled to O", and a solution of 28 g. (0.78 mole) of hydrogen chloride in 50 g. ( 1.36 moles) of methanol was added. The reaction mixture was allowed to stand for 1.3 hours, then worked up as described by Royals and Brannock. The product isolated, 11.2 g . (44% yield based on observed saponification equivaient), showed b.p. 100-112° ( 3 mm.), n Z 51.4350, ~ sapon. equiv., 187. The calculated saponification equivalent for the 8-ketoacetal (111or V ) is 202, while t h a t for the mcthoxymethylene ketone ( I V ) is 170. Hence, t h e product consisted of t53% p-ketoacetal and 47% methoxymethylene ketone. Preparation of a Mixture of a-Nonenaldehyde and aAmy1crotonaldehyde.-The mixture of 0-ketoacetals and inethoxymcthylene ketone described above was reduced with lithium aluminum hydride and the resulting crude product \viis hydrolyzed and dehydrated with aqueous sulfuric acid essentially according to the directions of Seifert and The products from four small runs utilizing a total of 6.5 g. of the P-ketoacetal and methoxymethylene ketone mixture Twre combined to give 28.5 g. (58% yield) of a crude mixture of a-nonenaldehyde and a-n-amylcrotonaldehyde. This mixture was fractionallv distilled throueh a Todd coluinii 11 ith monel spiral packing in a n atmosp6ere of nitrogen t o give: ( A ) 7.3 g., b.p. 69-74" (6.5 mm.), n 3 I ~1.4431I .14Bt3; ( B ) 2.2 g., b.p. 74-82' (6 5 mm.); ( C ) 8.8 g , b p . 82--83' (6.5 mm.), n 3 I ~1.4490. Fraction ( A ) was identified as a-n-amylcrotonaldehytic b y formation of a semicarbazone, m.p. 169'. A sample of a n-am>-lcrotonaldehyde was prepared by condensation of acetaldehyde with n-heptaldehyde according t o the procedure of Zaar.5 This material showed b.p. 67" (4.5 m m . 1, ~ 2 ~ ~1.4489, x 1 and gave a sernicarbazone, m.p. 170", which tlid iiot depress the m.p. of the semicarbazorle of fractioii
(ai.
Hydrogenation of 6.6 g. of fraction ( A ) in 25 ml. of cthan01 over 0.1 g. of platinum black in a Parr low pressure hydrogenation apparatus gave 3.5 g. of a n alcohol, b.p. & - 7:Y (:3 mm.), %*'D 1.4310, m.p. of 1-naphthylurcthan 41.5'. The m . p . of a mixture of this 1-naphthylurethan with that of a n authentic sample of the 1-naphthylurethan of 2-ethylheptanol Lprepared as described below, m.p. 43-44') waz 41..5-43.t5 . Fraction ( C ) was identified as e-nonenaldehydc h y forin,+tion of a semicarbazone, the m.g. of which (163") was not depressed by a n authentic sample of a-nonenaldehyde semiThe authentic sample of acarbazone (m.p. 164-165'). iionenaldehyde IVBS prcpui-til by the method of Scanlan and Sivrrn.8 liycli-oge~iu~io~i of 7 g . uf fr:cctiun ( C ) i t i 25 1111. of ethanol I J V V I . 0.1 g. of pl.iti1111111 hl;u>kg a v e 4.S g . o f V - I I ~ I I Y:tleohoI. ~ ' t V i 1 111 1 1 ' s . l I ?
iitlxii . ~ t i t I
Ilrl
