3562
SAMUEL D. GOLDBERG, WM.F. RINGKAND PAULE. SPOERRI [CONTRIBUTION FROM
THE
DEPARTMENT OF CHEMISTRY OF
THE
VOl. 61
POLYTECENIC INSTITUTE OF BROOKLYN 1
Preparation of Aminobenzoic Acid Esters of Substituted Monoalkylamino Alcohols' BY SAMGEL 17. GOLDBERG. WILLIAM F. RINGKAND PAULE. SPOERRI
In previous papers, the preparation2 and the ketone. 7,8 With ethylmagnesium iodide there is pharmacological propertiesa of two new series of obtained P-chloro-a,a-diethylethanol which on reanesthetic compounds were described. acting with n-butyl- and i-butylamines yields The result of the pharmacological work on these the corresponding amino alcohols. Wheii methylmagnesium iodide is used, these compounds suggested the investigation of the properties of a series of esters in which the side two methods of preparation serve as alternative chain was limited to two carbon atoms, one car- methods for making 0-chloro-a,a-dimethylethanol. bon atom carrying two alkyl substituents, thus Experimental forming a branched side chaiii. fi-Ethylamino-a,a-diethylethanol, HOC(CH&CHnThe preparation of a series of P-alkylamino-a, NHC2H,.-In a 250-cc. pressure bottle was placed 31.4 g a-dimethylethanols, HOC(CH3)2CHaKHR,where (0 23 mole) of a 33% aqueous solution of monoethylamine R represents an alkyl group, was therefore under- and 100 cc of water. To this was added 20 g. (0.18mole) the bottle immediately of ~-chloro-~~,a-dimethylethanol, taken. stoppered and shaken occasionally during the next twentyThe preparation of these amino alcohols re- four hours. The reaction mixture was treated with sohd quired the use of /?-chloro-a,a-dimethylethanolsodium hydroxide and cooled, the upper layer extracted which was synthesized according to the methods with ether, the yther layer separated and dried over anhydrous sodium sulfate. The ether was evaporated and of Krassuski4 and Michael and L e i g h t ~ n using ,~ the residue distilled. Two fractionations of the distillate the addition of hypochlorous acid to isobutylene. gave 12 g. (56%) of a water-white liquid with a slight amThe P-chloro-a, a-dimethylethanol together with moniacal odor, boiling at 152- 153'. an excess of a primary amine in a suitable Preparation of the Other Members of this Series.solvent was refluxed for several hours and then The preparations of the 6-methyl- and B-ethylamino-a,acarefully fractionated. The average yield of 0- dimethylethanols were carried out as described above The higher members of this series of amino alcohols, alkylamino-a, a-dimethylethanol was 52%. namely, the P-n-propyl-, p-i-propyl-, 0-n-butyl-, piThe p-nitrobenzoic acid esters of the amino al- butyl-, p-n-amyl- and 6-i-amylamino-a,a-dimethylethcohols were obtained through the condensation of anols were prepared in a slightly different manner. 95% the amino alcohols with p-nitrobenzoyl chloride ethyl alcohol was used as a solvent for the reactants in an aqueous alkaline medium. The tempera- and the mixtures refluxed from three to twenty-four hours ture of this reaction must be maintained between The reaction mixture was acidified with concentrated hydrochloric acid and vacuum distilled almost to dryness 30 to 40' for optimum yields. The nitro esters To the cold residue in the flask was added cold 3074 are all yellow solids. sodium hydroxide solution and the same procedure used These nitro esters were reduced with tin and for the purification In Table I are summarized the phyyical constants of hydrochloric acid to the anesthetic amino bases. this series of amino alcohols, the molecular refraction The hydrochlorides of the higher members of (using Eisenlohr'sq atomic refraction values) and the the series of the amino bases were in all cases very analyses of the picrates. The picrates were crystallizeJ viscous yellow oils; the sulfates, on the other hand, from either benzene or xylene. The nitro esters are prepared by condensing the amino were all white crystalline solids. Two members of another series of amino alco- alcohols with p-nitrobenzoyl chloride as follows: p-i-Butylamino-a-diethylethyl p-Nitrobenzoate, (iso)hols were prepared utilizing the reaction between C~HsNHCHsC(CHa)zCOOCtHaNO2.-To 10 g. (0.039 a Grignard reagent and a chloro ester6or a chloro mole) of p-isobutylamino-a,a-dimethylethanoland 5 g (1) Submitted in partial fulfillment of the requirements for the degree of Master of Science in Chemistry, June, 193G, by William F Ringk. ( 2 ) Samuel D Goldherg and Willet P Whitmor?. 'rm5 JOURXAL 69, 2280 (1937). (3) David I Abramson and Samuel D Goldhers, J Pharrnacol , 63, 69-87 (1938). (4) K Krassuski, J prakf Chem., [2] 76, 241 (1907) (5) A. Michael and V L. Leiphton, B o . , 39, 2157 (19061, J. Prakt Chsm , [2] 64, 103 (1901) (6) E Susskind, Ber , 39, 226 (1906)
of sodium hydroxide in 250 cc of water was added with stirring 13 g. (0.07 mole) of powdered p-nitrobenzoyl chloride in one amount. The temperature of the reaction was controlled so that it did not go above 40". An oil was soon formed which finally solidified after one-half (7) Tiffeneau, Compl. r e n d , 134, 775 (1902) (8) Henry, r b r d , 142, 131, 494 (1906), Rec Irau. chim., 86, 1-1) (1900). (9) Bisenlobr, 2 physik. C h t m . , 7 6 , 585 (1910), 89, 429 (1914).
AMINOBENZOIC ACIDESTERS O F MONOALKYLAMINO ALCOHOLS
Dec., 1939
3563
TABLE I
8-ALKYLAMINO-CZ,CZ-DIMETHYLETHANOLS (RHNCHzC(CH&0H) Alkyl group
Methyl Ethyl n-Propyl z-Propyl %-Butyl i-Butyl n-Amyl ;-Amyl
B.p oc:'
sp. gr.
142-143 152-153 169-171 158-160 186-187 180-181 205-208 202-204
0 . 887523 . 877719 . 864619 .852819 .858620 .849O20 .854320 858019
n-Butyl 216-220 i-Butyl
214-216
.
ltsD
1.4338 1.4344 1.4335 1.4288 1.4362 1.4309 1.4388 1.4380
MR
MR
M. p. of picrates, O C .
Calcd.
Found
137-138 132-133 128- 129 166-167 121.5-122.5 138-139 109-110 145-146
30.361 34.979 39.597 39.597 44.215 44.215 48.833 48.833
30.212 34.742 39.417 39.586 44.175 44.201 48.933 48.645
Formula
Analyses of picrates Carbon, % Hydrogen, % Calcd. Found Calcd. Found
39.76 41.62 43.33 43.33 44.92 44.92 46.39 46.39
39.87 41.81 43.18 43.22 45.01 44.68 46.53 46.56
,9-Alkylamino-a,a-diethylethanols (RHNCHZC(C2H6)~0H) 1.4433 127-128 53.451 53.182 CiaHz608N4 47.76 47.87 a t 23°C. .862126 1.4410 130.5-131.5 53.451 52.973 C I B H ~ ~ O B 47.76 N~ 47.91
0.8629*'
4.82 5.20 5.56 5.56 5.88 5.88 6.19 6.19
4.84 5.41 5.69 5.54 5.97 6.22 6.29 6.45
6.47 6.68 6.47 6 . 7 0
TABLE I1
,~-ALKYLAMINO-CY-DIMETHYLETHYL p-NITRO-AND p-AMINOBENZOATES Alkyl group
Nitro esters, m. P.. OC.
n-Propyln-Butyl&Butyl-
108-109 87-88 130-131
n-Amyl-
107-109
&Amyl-
112-113
i-Butyl-
. .. ..
Amino esters,
".%I.'
Amino ester sulfates m. p.. "C.
Formula
Analyses of sulfates Carbon, % Hydrogen, % Calcd. Found Calcd. Found
Nitrogen, % Calcd. Found
CzsH460aN4S CsoH520gN4S CsoHsoOsN4S
56.19 56.37 55.91 56.14 57.51 57.39
7.69 7.94 8.07 8.43 7.99 8 . 3 9
9 . 3 6 9.16 8 . 3 7 8.19 8.95 8.81
CszHuOaNaS
58.72 58.77
8.26 8.23
8.56 8 . 4 6
CsnH~0sNaS 58.72 57.81
8.26 9.02
8.56 7.82
,9-Alkylamino-a-diethylethyl p-Nitro- and p-Aminobenzoates 122-123 131-133 C34He208N& 59.46 59.63 9.04 9.29
8.16 8.03
123-124 138-140 150-153 116-119 lHzO Cryst. 83.5-84.5 142-143 158.5-159.5 93-95 Anhyd. 163-166 1HzO Oil 146-148
hour of stirring. The solid nitro ester was filtered off and washed with water until free of alkali. The nitro ester was recrystallized from benzene, m. p. 130-131". The solid nitro ester was then reduced with tin and hydrochloric acid in the usual manner. All of the esters were made similarly. In Table I1 are given the constants of the nitro and amino esters, as well as the analyses of the amino ester sulfates.
Pharmacology.-A preliminary pharmacological investigation of the sulfates of the 8-n-propyl-, P-n-butyl, 6-i-butyl-, and P-n-amyl-amino-a-dimethylethyl p-aminobenzoates was carried out. As a result of this investigation it was found that this series of anesthetics apparently was too toxic for injection purposes. However, the P-n-amyl derivative showed surface anesthetic activity to a high degree and was therefore tested further.1° Table I11 summarizes the toxicity tests of the sulfate of /3-n-amylamino-a-dimethylethyl p-amino benzoate (abbreviated to n-amyl sulfate), Cocaine and Butyn. In an anesthetized dog, n-amyl sulfate causes a slight reduction in blood pressure and a slight increase in pulse rate upon intravenous injection of (10) We are indebted t o Dr. Donald C. A. Butts of Philadelphia for the pharmacological investigation of this compound.
TABLE I11 SUBCUTANEOUS TOXICITY Concn., Compd. % Animal n-Amyl sulfate 1 White mice Cocaine 1 Whitemice Cocaine 4 White mice 1 White mice Butyn Butyn 5 White mice 1 Guinea pigs %-Amylsulfate
%-Amylsulfate
1
No. .of M. L. D. animals mg./kg. 64 45 41 75-100 19 100-150 26 25-50 26 Approx. 50 43 35-40
Intravenous Toxicity White mice 9 10-15
% died at M. L. D. indicated 10 0-18 0-25 0-12.5 14 0-27 0-100
a 1%solution. The intravenous toxicity for dogs is 20 mg./kg. Corneal anesthesia in the rabbit's eye, using a 1% n-amyl sulfate solution, a 4% cocaine solution and a 2% butyn solution produces anesthesia averaging eighty-seven, sixty-six and seventynine minutes, respectively, when from one to five drops of the solution are instilled into the rabbit's eyes. Immediate anesthesia was produced in all cases and no demonstrable irritations found in any treated eye. n-Amyl sulfate caused practically no mydriasis and no corneal erosion. Application of one drop of a 1% solution of n-amyl sulfate to the cornea of the rabbit's eye produces anesthesia last-
CHARLES F. WLNANS
3564
Vol. 61
ing forty-three minutes while a 0.05% (1:2000) solution anesthetizes for six minutes. n-Amyl sulfate does not alter the intraocular tension of the rabbit’s eye when used in 1% concentrations.
From these alcohols, as well as two @-alkylamino-a,a-diethylethanols,by combination with p-nitrobenzoyl chloride and reduction, there has been prepared a series of new esters. A pharmacological study of one ester shows summary it to have interesting surface anesthetic propA series of new @-alkylamino-cy,or-dimethyl- erties. ethanols has been prepared. BROOKLYN, NEWYORK RECEIVED OIXOBER 13, 1939
[A CONTRIBUTION FROM
THE RESEARCE
LABORATORIES OF THE GOODYEAR TIRE& RUBBERC O . ]
Nickel as a Catalyst for the Hydrogenation of Aromatic Halogen Compounds BY CHARLES F. WINANS* The catalytic hydrogenation of o-nitrochlorobenzene over nickel was first attempted by Sabatier and Mailhe’ who, however, obtained aniline hydrochloride as a result of a combined hydrogenation and dehalogenation. Furthermore, Sabatier and Espe12 found that small amounts of halogen compounds did not interfere with the vapor ph&e reduction of benzene provided that some nickel remained in catalytically active form after a portion had been converted to nickel halide in removing the impurity. The simultaneous hydrogenation and dehalogenation of organic compounds has been effected by several workers3 using platinum and palladium catalysts, and certain others have effected hydrogenation without the removal of halogen. Ellis* describes the preparation of a reduced nickel catalyst suitable for the production of chlorinated aromatic amines from the corresponding nitro compounds. Strangely, very little has appeared in the recent literature concerning the use of nickel for the hydrogenation of halogen compounds. The present paper attempts to demonstrate that the hydrogenation of these compounds is a general reaction which is applicable in an efficient and economical process. The success of this conversion depends upon the choice of a stable halide, the use of a temperature below that a t which dehalogenation occurs, and the use of a catalyst with sufficient mass of metal. These conditions have been met in the
* P-t
address: Mellon Institute, Pittsburgh, Pa. (1) Sabatiu and Maiie. Compt. r e d . , 188, 245 (1904). (2) sabstisr and Bspel, Butl, W C . ckinr., ll, 778 (1914). (8) For a fomp&te rbscld of the prior aork in hydrogemtion of wganic holo(lm compounda, Enis, “-tiom of Organic Substances,” M.td., D. Van Nostrpnd CO., Inc., New York, N. Y.,
ioao. *)
P . E 3(19 of Bdaeno 8.
hydrogenation of aromatic halogen compounds at temperatures below 150’ with Raneys nickel. The substituents reducible below 150’ which may be attached to the halogenated aromatic nucleus include the olefinic, acetylenic, nitro, nitroso, cyano, oximino, azido, azo, and carbonyl groups. Anils and hydro-amides may also be treated. It has not been possible to hydrogenate chlorobenzene to chlorocyclohexane, for a t the temperature required to saturate the benzenoid ring halogen was removed giving rise to benzene in small amounts. Benzyl chloride gave some diphenylethane under similar conditions. In the aliphatic series 1-chloropropene, w-chlorostyrene, sym-dichloroethylene, and tetrachloroethylene resisted saturation of the olefin bond. The accompanying table gives the names of hydrogen acceptors and reaction products with physical properties and yields for fourteen different halogen compounds illustrating the behavior of several types. Most of the products were distilled from the reaction mixture. Others were obtained in crystalline form as solid product or hydrochloride derivative. All products were identified by the formation of known characteristic derivatives or by analysis. The relative strength of attachment of chlorine, bromine, and iodine to the aromatic nucleus was demonstrated in the reduction of the halogenated nitrobenzenes. p-Chloronitrobenzene gave rise to p-chloroaniline even at 150’ in nearly quantitative yield. p-Bromonitrobenzene was not quite so stable, but still the predominant product was pbromaniline. o-IOdonitrobenzene was lwgely dehalogenated during reduction to &e, only a small amount of 0-idoadi.m being isolated from (6) Murray Ron*).,
U,S4Patmt 1,648,190, May 10, 1w7.
