(ioos
Vol. 77
EMJLH. WHITE [CONTRIBUTION h-0. 1262 FROM
THE STERLING
CHEMISTRY LABORATORY, YALE UNIVERSITY]
The Chemistry of the N-Alkyl-N-nitrosoamides.
I. Methods of Preparation
BY EMILH. WHITE RECEIVEDDECEMBER 23, 1954 Two new methods for the nitrosation of X-alkylamides have been developed: one using nitrogen tetroxide and the other, a sodium nitrite-acetic anhydride mixture. The limitations of the usual nitrosation methods were determined and a number of N-nitroso derivatives of amides, urethans and sulfonamides were prepared.
During the course of preparation of a number of N-alkyl-N-nitrosoamides required for a study of their thermal decomposition,' the limitations of the usual nitrosation procedures were determined and two new methods were developed. In one of the new methods, a sodium nitrite-acid anhydride mixture is used and in the other the reagent nitrogen tetroxide; the latter method proved to be the most satisfactory for the nitrosation of amides. The methods (A-E) will be discussed in order of their increasing generality.
reduction of nitric acid7 are used to nitrosate the amide. A large excess of the "nitrous fumes" must be used because large amounts of nitric oxide and nitrogen dioxide are lost (nitrogen trioxide is instable a t 0'). Since in practice an impure N-nitroso-N-(sec-butyl)-benzamide was obtained, this method was not investigated further. Method D. Nitrosyl Chloride.-This reagent was first used for the nitrosation of K-arylamides by Hey.a Kitrosy1 chloride, unlike the reagents of methods A and B, was found to be powerful enough to nitrosate N-(sec-butyl) amides. However, the H O O=N 0 method was not extensively used during the course I I/ I_ 11 R-S4-R' --+ R-A-C-R' of this work, since nitrogen tetroxide (method E) Method A. Aqueous Systems.-This method2 was readily available and in addition yielded purer usually involves the acidification of an aqueous products. Nitrosyl bromide was found to be inefsolution of sodium nitrite and the amide. The fective, due largely to the extensive dissociation of reaction is slow (Table I, 40 hr. required a t 0" for the reagent into nitric oxide and b r ~ m i n e . ~ Method E. Nitrogen Tetroxide.'O-The reaction 11). It is restricted to amides of primary carbinamines (RCH2NH2),3and yields products that are of nitrogen tetroxide with amides proved to be a impure compared t o those from methods D and E ; general method for the preparation of nitrosoit is convenient, however, for large-scale nitrosa- amides." The reaction is rapid, 10 min. a t 0" tions of water-soluble amides4 A large excess of 0).-N(Z 0.X-O-iY i o r g . this pritcrdiire failed; the unreacted amide wa? rcco\,ered. C h i n . , 261, 75 (1950); C.C. Addison and R. 'Thompson, J . C k e m . S o r . , (4) Fur amides inwlulile in water. acetic acid-water mixturrt S211 (1949)). T h e symmetrical structure I S w a s assigned to cryscan he iiisd; however, a \lrong acid miist also he present (no nitrosanitrogen tetroxide by J. S. Broadley a n d J . RI. Rolirrtwii. , ticin C B i t b e amide occurred in a mixture of ~ - - ( i i - ! , ~ i t ? l ~ - a c e t a m i [ l ~talline X a l w e , 164, 915 (1949). hiidium nitrite, acetic acid. and water at .io for 16 hr.). (12) This reaction occurs with all strong acids. Acetic acid is ((;) For example, S-(?z-butyl)-p-toluenesulfonamideyielded 5 capable of denitrosation. h u t t h e r a t e is quite low (footnote 1, Table 11. acetyl-N-(n-hutyl)-Ih-toluenesulfonamide. rnns 4 and 1 : . 5. nr. Isan-orth and n. FI. rrCy, .T rhc;lz. Y , , C :IG (i!i,in). See also R. Huisgen, A?i?z.,574, 182 (1951)). (0)
6009
N-ALKYL-N-NITROSO AMIDES : METHODS OF PREPARATION
Nov. 20, 1955
TABLE I N=O
1
S-ALKYL-S-NITROSOAMIDES, R-Y-C-R'
It
0 R'
R
Cmpd.
Methyl Methyl 3,5-Dinitrophenyl 3,5-Dinitrophenyl
n-Butyl Isobutyl n-Butyl Isobutyl
Ib
11 IIId IV
M.p. or b.p.
Yield,
yo
Method
80 73 96 91 95 87' 85'
A A B B E E D E B E
OC. (mm.)
35-37 (0.1) 30-32 (0.1) 63-63.5 dec." 66.5-67 decC 67-67.5 decC
c=o
I.R., pa
5.75 5.81 5.75 5.81
N=O
6.60 6.52 6.59 e
5.84 6.59 Phenyl sec-Butyl V e 5.81 3,s-Dinitrophenyl sec-Butyl VI 5.73 6 .58 Methyl 88, Cyclohexy1 VI1 5.70 6.55 Ethoxyl 79' Cyclohexyl VI11 5.77 6.60 Methyl 88' a-Phenylethyl IX 5 In carbon tetrachloride. n . 2 5 ~ 1.4425. c Recrystallized from an ether-pentane mixture, m.p.'s uncorrected. n.26~ 1.4400. e Present as an unresolved shoulder to the band of the nitro groups a t 6 . 4 4 ~ . The nitrosoamides, for which R = sec-alkyl, decompose a t room temperature (stable for several hr. a t O D )and were not isolated, but rearranged immediately; in each case, the nitrosoamide was shown to be pure from the infrared spectrum. The yields given are the yields of products from the nitrogen elimination (footnote l), a reaction for which the nitrosoamide must be the precursor; therefore, they represent minimum yields.
'
where X = NOs- for method E, C1- for D, NOzfor C, OAc- for B, and possibly NOz- or H20 for ANALYSES'( N-ALKYL-iY-NITROSOAMIDES) method A. The physical constants of the amides Xlolecular Carbon Hydrogen yo Nitrogen, 70 Calcd. FAund Calcd. F o h d Calcd. Found Cmpd. formula used in this work (some of which have not been pre8.39 8.40 19.44 19.26 I C S H ~ N Z O ~49.98 50.30 viously reported) are listed in Table 111. 19.18 8.39 8.15 19.44 49.98 5 0 . 2 0 I1 CiHiiNgOz I n general, nitrosoamides of primary carbinam18.91 18.88 4.08 3.95 44.60 44.88 I11 CiiHiiNdOs ines (I-IV) are stable compounds; ca. 10-15 hr. a t 18.91 18.70 IV CiiHnNiOa 44.60 44.77 4.08 4.13 a Schwartzkopf iMicroanalytica1 Laboratory, Woodside 75' is required for their rearrangement.' Corresponding derivatives of a-phenylethylamine are 77, Long Island, N. Y. less stable, decomposing a t 50°, whereas those of secin a typical run was GO%, whereas in the presence of ondary aliphatic carbinamines (V-VIII) decompose sodium acetatel3 essentially quantitative yields a t 25' (the latter can be isolated a t 0"). NitrosoH O O=N 0 mides of t-carbinamines are very unstable, eliminatI /I I II ing nitrogen a t - 10". RN-CR' 4- "03 TABLE I1
RN-CR' HNOs
+ N,Oc + NaOAc +HOAc + S a x 0 3
Experimental
were obtained. Based on this reversal by strong acids and the instability of nitrosyl bromide, a rapid quantitative method of denitrosation was developed using a system of hydrogen bromide and sodium thiosulfate. l 4 The nitrosation step is probO=N
0
I
11
RX-CR' Br2
+
H
O
I
+ HBr + RN-CR'!I
f NOBr
+ Brz + Na&406
2NOBr I_ 2NO t 21\'a2S203-+- 2SaBr
ably very similar for the five methods used. By analogy to the nitrosation of amines,l6 this reaction can be represented by H
I
O
II
RN-CR'
+ O=KX
--f
O=N
I
0
II
RN-CR'
+ HX
(13) No ot her base was used with nitrogen tetroxide, b u t in method D, pyridine proved t o be as effective as sodium acetate. (14) The sodium thiosulfate may be omitted if nitrogen is passed through t h e system t o remove t h e nitric oxide. V. Braun (Ber., 70B, 979 (1937) has used HC1 and NaHSOa t o effect denitrosation and Angier, e2 at. (THIS JOURXAL, 74, 408 (1952)) have used HC1 and phenol. ( 1 5 ) J. H. Dusenbury and R. E. Powell, THISJOURNAL, 73, 3269 (1951).
Preparation of the Amides.-The acetamides were prepared by a general method described elsewhere,' and the urethans by previously reported procedures.16 The 3,5dinitrobenzamides were prepared from the amines and 3,5dinitrobenzoyl chloride in an excess of pyridine. Since these amides are rather insoluble in common organic solvents, the reaction mixture was poured into a n excess of water and the precipitated amides filtered and dried. The N-(n-butyl)- and the h~-(isobutyl)-3,5-dinitrobenzamides were recrystallized from dioxane and the sec-butyl isomer from a mixture of dioxane and methyl acetate. The nbutyl amide forms a crystalline complex with dioxane. The dioxane can be removed, however, a t 100" and 0.01 mm. The benzamides were prepared by the Schotten-Baumann procedure. The physical properties of the amides are given in Table 111. Nitrosation with an Acetic Anhydride-Sodium Nitrite Mixture (Method B).-A solution of the amide (0,010 mole) in a mixture of acetic acid (10 ml.) and acetic anhydride (50 ml.) was cooled to 0" and 15 g. of granular sodium nitrite (0.22 mole) was added during c u . 5 hr. After 10 hr. a t 0 , the temperature was allowed to rise to 10-15" (during cu. 30 min.) and the mixture poured into a mixture of ice and water. The nitrosoamide was extracted with ether, and the upper phase was washed with water, with a n aqueous solution of sodium carbonate (5'%), with water, and then dried with anhydrous sodium sulfate. The solvent was removed (under vacuum), and depending on the properties of the nitrosoamide, the product was either distilled under vacuum (temp.
