THE QUATERNARY SALTS OF HEXAMETHYLENE- TETRAMINE.

VIII. MISCELLANEOUS SUBSTANCES CONTAINING ALIPHATIC- ALLY BOUND HALOGEN AND THE HEXAMETHYLENE-

TETRAMINIUM SALTS DERIVED THEREFROM.

BY WALTER A. JACOBS AND MICHAEL HEIDELBERGER.

(From the Laboratories of The Rockefeller Institute for Medical Research.)

(Received for publication, Bpril 30, 1915.)

In this paper we wish to present a number of substances which could not be logically incorporated with the previous papers. These are derivatives of a number of simple alkyl halides and halogenacyl esters. Several chloroacetylamino compounds are also described.

EXPERIMENTAL.

(1) Miscellaneous alkyl derivatives.

Oxyethylhexamethylenetetraminium iodide. 1 mol. of iodoethyl alcohol was added to a solution of 1 mol. of hexamethylene- tetramine in dry chloroform. The mixture was filtered from a small amount of precipitate that separated almost immediately, and allowed to stand for two days in a warm place. The salt crystallized in the form of needles. It melts at 157” with decom- position and is very soluble in water.

0.1622 gm. of substance required 5.25 cc. AgN08 Solution I.1 Calculated for CsH170N11: I = 40.64 per cent.

Found: I = 40.74 per cent.

y-Chloropropylhexamethylenetetraminium bromide. Trimethy- lene chlorobromide and hexamethylenetetramine reacted slowly in dry, boiling chloroform. Additional quantities of the quater- nary salt may be obtained by continued boiling of the mother

I1 cc. = 0.00352 gm. Cl; 0.00793 gm. Br; 0.01259 gm. T

465

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from

466 Salts of Hexamethylenetetramine

liquors. The salt forms irregular micro-prisms which are very soluble in water. When rapidly heated, it turns yellow above 140” puffs up slightly, and finally melts with decomposition at 180-3”’

0.2456 gm. of substance required 8.23 cc. AgN03 Solution I. Calculated for C9HlsN&lBr: Br = 26.86 per cent.

Found: Br = 26.58 per cent.

y-Oxypropylhexamethylenetetraminium iodide. This was prepared from 18.6 grams of trimethylene iodohydrin and 14 grams of hexa- methylenetetramine in dry chloroform at room temperature. The portion (4 grams) that separated on standing over night was contaminated with hexamethylenetetraminium iodide, but the fraction (10 grams) separating during the next few days was free from this impurity.

0.2009 gm. of substance required 11.4 cc. AgN03 Solution II.2 Calculated for C9HlsONJ: I = 38.92 per cent.

Found: I = 37.79 per cent.

Cetylhexamethylenetetraminium iodide. This was prepared in chloroform solution. The salt was recrystallized from absolute alcohol. It softens at 131’ and melts gradually as the tempera- ture is raised, liquefying completely and evolving gas at 157”. It is insoluble in cold water.

0.1940 gm. of substance required 7.58 cc. AgNOs Solution II. Calculated for C&H45NJ: I = 25.77 per cent.

Found: I = 26.00 per cent.

Phenylethyl iodide. Phenylethyl chloride, prepared according to Barger;3 was treated with an excess of a normal solution of sodium iodide in dry acetone and boiled for four hours. The mix- ture, from which sodium chloride had separated, was poured into water and the precipitated oil taken up with ether. The ethereal solution was washed successively with dilute sodium bisulphite solution, water, sodium carbonate solution, and water. After drying over calcium chloride the ether was evaporated off. The residual oil was fractionated in vacua, the portion boiling at 104.5-30.5” at 28 mm. being used directly for the preparation of the quaternary salt.

2 1 cc. = 0.00186 gm. Cl; 0.004192 gm. Br; 0.006657 gm. I. 3 G. Barger: Jour. Chm. Sot., xcv, p. 2194, 1909.

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from

W. A. Jacobs and M. Heidelberger 467

Phenylethylhexamethylenetetraminium iodide. The crude iodide reacted very slowly with hexamethylenetetramine in boiling chloroform. After several hours the mixture was diluted with more chloroform to dissolve unchanged base and filtered. An additional quantity was obtained by concentrating the filtrate and again boiling for several hours. The salt forms pale yellow cubes. When heated, it turns yellow and melts with decomposi- tion at 159”.

0.2128 gm. of substance required 5.71 cc. AgS03 Solution I. Calculated for C1JLN41: I = 34.11 per cent.

Found: I = 33.75 per cent.

The following substance was prepared since the publication of our fi.rst paper,4 in which the compound properly belongs:

o-Iodoben~ylhexamethylenetetraminium bromide. An equimo- lecular amount of o-iodobenzyl bromide was added to a warm so- lution of hexamcthylenetetramine in dry chloroform. The salt soon began to crystallize in the form of spherical aggregates of minute crystals. After several hours these were washed well wit,h dry chloroform and dry acetone and were then pulverized and warmed with dry acetone in order to remove traces of te- naciously adhering iodobenzyl bromide. The salt is sparingly soluble in water, but dissolves more readily than the p-isomer. It effervesces and turns yellow at 173-5”.

0.1822 gm. of substance (Kjeldahl) required 16.65 cc. 6 HCl. 0.2767 gm. of substance required 11.52 cc. AgN03 Solution II. Calculated for CL3H18NIBrI: N = 12.82 per cent; Br = 18.29 per cent.

Found: N = 12.80 per cent; Br = 17.45 per cent.

(2) Esters of monohalogen acids.

Carbethoxyethylhexamethylenetetraminium iodide. Equimolec- ular quantities of P-iodopropionic acid ethyl ester and hexa- methylenetetramine were boiled in dry chloroform. The salt separated as a yellowish oil. This was seeded with a few crys- tals obtained by treating a portion with dry acetone and rub- bing, causing solidification of the entire product. After con- tinuing the boiling for one hour the precipitate of glistening

4 This Jow&, xx, p. 659, 1915.

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from

468 Salts of Hexamethylenetctramine

leaflets was filtered off and washed thoroughly with dry chloro- form. The salt dissolves readily in water and melts with de- composition at 137-8”.

0.2046 pm. of substance required 5.71 cc. AgN03 Solution I (:alculated for C1~H~~O&I: I = 34.45 per cent.

Found: I = 35.14 per cent.

sec.-Octyl bromoacetate. 40 grams of bromoacctyl bromide were carefully adcled to 25 grams of sec.-octyl alcohol, with cool- ing. The mixture was then heated on the water bath until the evolution of hydrobromic acid ceased. The residue was frac- tionated in vacua. The ester boils at 137” (corrected) at 18 mm. and possesses an odor resembling that of the alcohol.

0.1737 gm. of substance required 13.08 cc. AgKO, Solution II. Calculated for ClaH190213r: Br = 31.83 per cent.

Found: Br = 31.58 per cent.

With hexamethylenctetramine this product yielded a gelatinous salt which could not be crystallized.

Bornyl bromoacetute and hexamethylenetetramine. Equimolec- ular amounts of the components were boiled in dry chloroform for one-half hour, filtered from the small amount of precipitated material, and treated with dry acetone. The solution gradually set to a thick mass of crystals of the salt. These were filtered off and washed with dry acetone. The compound sinters above 170” and melts at 178-81”. It is difficultly soluble in water.

0.2002 gm. of substance required 4.83 cc. AgX08 Solution I. Calculated for C18H3102N4Br: Br = 19.24 per cent.

Pound: Br = 19.14 per cent.

Menthyl 6romoacetate5 and hexamethylenetetramine. The salt was prepared in the same way as the bornyl compound, using dry ether as the precipitant instead of acetone. It melts at 153-4” and is somewhat difficultly soluble in water.

0.2021 gm. of substance required 4.95 cc. AgNOa Solution I. Calculated for CJ13302N4Br: Br = 19.15 per cent.

Found: Br = 19.43 per cent.

5 S. Smiles: Jour. C’hem. Xoc., lxxxvii, p. 454, 1905.

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from

W. A. Jacobs and 34. Heidelberger 469

Phenyl bromoacetate and hexanaethylenetetramine. Mannich and Drauzburg” prepared the corresponding salts with phenyl chloro- acetate and phenyl iodoacetate. As we found the former to be unsuitable for preparation on a large sca.le and as the latter proved to be insoluble in water, the bromide was prepared. The quaternary salt separates rapidly from a boiling solution of the components in dry chloroform. As precipitated, it contains chloroform of crystallization which was removed by boiling the product with dry acetone. It melts at 149-50” with decom- position, and is easily soluble in water.

0.2262 gm. of substance required 6.40 cc. rlgS0, Solution I Calculated for C14H190&-aRr: Br = 22.51 per cent.

Found: ,Br = 22.45 per cent.

Tribromo-p-cresyl bromoacetate. Tribromo-p-cresol was dis- solved in normal sodium hydroxide solution and treated, drop by drop, with chilling and shaking, with 1.1 mols. of bromoacetyl bromide. The oil which remained after making the mixture alkaline crystallized on rubbing. Recrystallized twice from ab- solute alcohol, it forms cream-colored prisms which soften at 60” and melt at 60.5-1.5” (corrected). The ester is more difficultly soluble in alcohol, methyl alcohol, and ligroin than in the other organic solvents.

0.1394 gm. of substance (Carius) gave 0.224’7 gm. RgBr. Calculated for C9He02Br,: Br = G8.64 per cent.

Found: Br = 68.60 per cent.

The hexamethylenetetraminium salt of the ester was found to bc insoluble in water and was not obtained in a state of purity.

o-Nitrophenyl bromoacetate. This substance was prepared in the same way as the preceding ester. Recrystallized twice from absolute alcohol, in which it is less soluble than in ether, benzene, and chloroform, it melts at 55.5-6.” (corrected) with slight pre- liminary softening.

0.2794 gm. of substance (Kjeldahl) required 11.30 cc. & HCl. 0.1777 em. of substance gave 0.1270 gm. AgBr. Calculated for C8H604NBr: N = 5.39 per cent; Br = 30.74 per cent.

Found: N = 5.G7 per cent; Br = 30.41 per cent.

G C. Mannich and IV. Drauzburg: Chem. Zentralbl., Ixxxiii, pt. ii, p- 1817, 1912.

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from

470 Salts of Hexamethylenetetramine

o-Xitrophenyl bromoacetate and hexamethylenetetramine. The salt separates practically quantitatively when a solution of the components in dry chloroform is boiled for twenty minutes. It forms slightly grayish micro-prisms which melt with decomposi- tion at 149-50”. Its aqueous solution decomposes rapidly with separation of o-nitrophenol. Moist air also exerts a hydroiytic action. The corresponding chloride was prepared by Mannich and Drauzburg.G

0.1216 gm. of su,bstance required 3.06 cc. .IgSOs Solution I. Calculated for C1JI180~S~Br: I3r = 19.97 per cent.

Found: 13r = 19.9G per cent.

Benxeneaxo-fi-naphthyl chloroacetde. 4.2 cc. of chloroacetyl chloride were added to a solution of 12.4 grams of benzeneazo-fi- naphthol in toluene. The mixture was boiled for nine hours and was then evaporated to small bulk. Separation of the ester was made more complete by the addition of ligroin. Yield: 6.7 grams. Recrystallized from absolute alcohol, it forms orange, felted needles which melt at 127-8” (corrected). It is very soluble in benzcnc, ether, and acetone, and dissolves in sulphuric acid with a purplish red color.

0.1310 gm. of substance gave 11.0 cc. S (750 mm. and 27.5’). Calculated for ChH,,OsS&l: K = 9.07 per cent.

Found: K = 8.G3 per cent.

Oxyethyl anisate (oxyethyl p-methoxybenxoate). 6.2 grams of ethylene glycol were dissolved in 30 grams of pyridine and chilled in a. freezing mixture. After slowly adding a solution of 17 grams of anisoyl chloride in 15 cc. of dry chloroform, the mix- ture was allowed to stand at room temperature for one hour. It was then poured into iced 25 per cent sulphuric acid and shaken out with chloroform. The oil remaining after concentration was fractionated in vacua. 10 grams of the oxyethyl anisate distilled at 161-2” at 0.75-0.85 mm. When redistilled it boiled at 149-50” (corrected) at 0.4 mm.

0.1147 gm. of substance gal-c 0.2569 gm. CO2 and 0.0624 gm. HzO. Calculated for CloHl~Oj: C = 61.19 per cent; H = 6.17 per cent.

Found: C = 61.11 per cent; H = 6.09 per cent.

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from

W. A. Jacobs and M. Heidelberger 471

Ethylene anisate. The undistilled residue obtained in the fractionation of the oxyethyl anisate solidified on cooling. Re- crystallized twice from acetic acid, it forms prisms which melt at 117-7.5” with slight preliminary softening. It is difficult,ly soluble in cold absolute alcohol and ether, easily in bcnzenc ant1 chloroform.

0.1161 gm. of substance gal-e 0.2787 gm. CO2 and 0.0547 gm. HzO. (‘nlculatcd for C1811,800: C = 65.41 per cent; H = 5.49 per cent.

Found: C = 65.48 per cent; H = 5.27 per cent.

ChZoroacetyZoxyethyZ anisate. ClCH&XOCH&H~OOCC,H40CH,. A solution of 13.5 grams of crude oxyethyl anisate in 15 cc. of dry benzene was warmed with 7.5 grams of chloroacetyl chloride. After the evolution of hydrochloric acid had ceased the residue was fractionated in vacua. The principal fraction boiled at 170-5” at 0.5 mm. and solidified on standing. Recrystallized successively from dry ether and absolute alcohol with the aid of a freezing mixture, it melts at 45.5-6.5” (corrected). It is very soluble in benzene and chloroform.

0.2822 gm. of substance required 19.39 cc. AgN03 Solution II. Calculated for C12H130&1: Cl = 13.01 per cent.

Found: Cl = 12.75 per cent.

Chloroacetyloxyethyl a&sate and hexamethylenetetramine. Equi- molecular amounts of the components were boiled for one-half hour in dry chloroform, after which the solution was concentrated and filtered from a small amount of hexamethylenetetraminium chloride. The salt was then precipitated as a viscous oil by means of dry ether. The supernatant liquid was poured off and t,hc oily salt dissolved in cold absolute alcohol. Ether was added until crystallization began, after which the mixture soon set to a solid mass. The salt was filtered off, washed, and placed in a desiccator as quickly as possible, owing to its hygroscopicity. When heated, it softens above 70” and gradually melts until it is completely fluid at 90”. It is easily soluble in water, alcohol, chloroform, and acetone.

0.1383 gm. of substance required 3.5 cc. AgNOI Solution I. Calculated for &H250eN&1: Cl = 8.59 per cent.

Found: Cl = 8.91 per cent.

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from

472 Salts of Hexamethylenetetramine

(S) Miscellaneous amine and hydraxine derivatives.

w-Chloroacetylaminoacetophenone. 20 grams of w-aminoaceto- phcnone hydrochloride were dissolved in about 150 cc. of mater and covered with about 100 cc. of toluenc. After adding 11 cc. of chloroacetyl chloride, 150 cc. of two-normal potassium hy- droxide were added in small amount,s, with vigorous shaking and cooling. The chloroacetyl derivat’ive soon separated and was filtered off, washed with water and toluene, and recrystallized, with bone-blacking, from dilute alcohol. Yield: 11.5 grams. It forms micaceous scales melting at 124-6.5” with preliminary softening. It is difficultly soluble in the cold in benzene, toluene, and ether, and dissolves very readily in chloroform.

0.2289 gm. of substance (Kjeldahl) required 11.15 cc.& HCl. (‘alculated for C1,H,,O~NCl: N = 6.62 per cent.

Found: iY = 6.83 per cent.

w-Chloroacetylaminoacetophenone and hexamethylenetetramine. d chloroform solution of the components was boiled for one-half hour, evaporated to small volume, filtered from the slight preeipi- tat’e, and treated with dry acetone. The salt separated as an oil which rapidly solidified, forming micro-platelets with a faint yellow-green tinge. Tt melts at 149-50” to an orange tar, is solu- ble in chloroform, and dissolves readily in water and alcohol.

Calculated for C16H2&N&1: Cl = 10.08 per cent. Found: Cl = 10.00 per cent.

/\ (CH3)2N \-/\cHNHcocH

-/-\/ 2

c1

(CH,) A \-, (I)

Chloroacetylbis - [ p-dimethylaminophenyl] - methylamine (chloro - acetylleucoauramine) (I). 8 grams of leucoauramine were dis- solved in a mixture of benzene and toluene, 75 cc. of two-normal sodium hydroxide added, and then, drop by drop, 3 cc. of chloro- acetyl chloride dissolved in toluene. Transitory colors developed, first green, then blue, then brown-violet, the color disappearing almost, entirely in each case on shaking. Toward the end of t,hc operation the chloroacetyl derivative started to crystallize

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from

IV. A. Jacobs and A/r. Heidelberger 473

out. To make this complete one-half volume of ligroin was added and the mixture allowed to stand in the ice box over night. The product was filtered off, washed well with mater, and re- crystallized from 95 per cent alcohol, forming almost colorless plates and needles which take on a greenish blue tinge on exposure to the air. Yield: 7 grams. The compound dissolves in acetic acid with a blue color, in sulphuric acid with a faint yellow color, and is readily soluble in chloroform and acetone, but insoluble in ether. It melts to a deep green liquid at 1644.5” (corrected) with slight gas evolution.

0.2442 gm. of substance (Kjeldahl) required 20.9 cc. & HCl. Calculated for G9Hz10N,C1: N = 12.16 per cent.

Found: N = 11.99 per cent.

Chloroacetylleucoauramine and hexamethylenetetramine. Equi- molecular amounts of the components were boiled in dry chloro- form solution for one and one-quarter hours. The olive-yellow solution was evaporated to small bulk and treated cautiously with dry acetone, causing the separation of the salt first as an oil. A portion of this was removed, rubbed up with acetone and ether, and crystallized by chilling. On seeding the main portion with this and slowly continuing the addition of dry acetone, the entire product was obtained in the crystalline state. After warm- ing for one hour with dry acetone the salt still had a faint yellow color. It melts at 175” to a thick yellow liquid which decom- poses at 179”. It is difficultly soluble in water but dissolves readily upon the addition of dilute acids.

0.3188 gm. of substance required 6.67 cc. AgNO, Solution I. Calculated for C&H360NEl: Cl = 7.30 per cent.

Found: Cl = 7.36 per cent.

Chloroacetyltriphenylmethylamine (chloroacettriphenylmethyla- mide) . 11.7 grams of crude triphenyImethylamine were obtained by passing dry ammonia into a mixture of 20 grams of triphenyl- methyl chloride and 20 grams of naphthalene at 130”, taking up with ligroin, filtering off the ammonium chloride, saturating the filtrate with dry hydrochloric acid, suspending the resulting precipitat’e in dry benzene, passing in dry ammonia, again filter- ing, and evaporating the filtrat,e to dryness. The amine was

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from

474 Salts of Hexamethylenet,etramine

taken up in benzene and chloroacetylated as in the previous cases, completing the precipitation of the chloroacetyl derivative by means of ligroin. The compound was filtered off, washed with water, and recrystallized from acetic acid, forming snow-white, interlaced hairs. Yield: 5.9 grams. When recrystallized again from toluene and heated in a tube sealed at both ends it melts at 201-2.5” (corrected). The substance dissolves readily in chloro- form, less easily in benzene and hot acetic acid, and with difficulty in absolute alcohol. It gives a yellow color with sulphuric acid, deepening to a dark orange-brown on addiCon of a drop of aqueous potassium dichromate solution.

0.3072 gm. of suhstnncc (Kjeldahl) required 9.35 cc. Fc HCl. Calculated for C&&NCl: N = 4.17 per cent..

Found: N = 4.2F per cent.

Chloroacetyltriphenylmethylamine and hexamethylevaetetramine. After boiling for one hour the chloroform solution of the com- ponents was evaporated to small bulk and treated with several volumes of dry acetone. The precipitate of small, transparent cubes was boiled for one hour with dry acetone. When once iso- lated, the salt is difficultly soluble in chloroform. It also dis- solves with difficulty in water and gives a yellow color with sul- phuric acid. When heated it turns yellow at about 150” and melts with decomposition at 194-5”.

0.3173 gm. of substance required 6.27 cc. &SO, Solution I. Calculated for CSTH,,ONSC~: Cl = 7.46 per cent.

Found: Cl = 6.96 per cent.

&Acetyl-a-chloroacetyl-a-phenylhydraxine and hexamethylewtetra- mine. The salt separated from the boiling chloroform solution of the components as long silky needles containing chloroform of crystallizat,ion. This was removed by boiling the compound for one-half hour with dry acetone. The salt melts at 192-3”.

0.1820 gm. of substance required 5.0 cc. Agl\;Oa Solution I. Calculated for C16H2302N&1: Cl = 9.67 per cent.

Found: Cl = 9.67 per cent.

P-Chloroacetyl-a, cu-phenylbenxylhydraxine. 20 grams of a, cY-phen- ylbenzylhydrazine were chloroacetylated in toluene solution in the same way as in the previous examples. As the chloroacetyl

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from

W. A. Jacobs and M. Heidelberger 475

derivative did not separate from the toluene layer, the latter was shaken out first with dilute hydrochloric acid and then with dilute sodium carbonate solution. After the crystallization in- duced by the purification process had ended, the product was filtered off and combined later with an additional amount ob- tained by evaporating the filtrate to small bulk and adding ligroin. The substance was recrystallized by dissolving in hot benzene and adding an equal volume of ligroin. Yield: 17.8 grams. Recrystallized from methyl alcohol, it forms large, irregular crystals melting at 112.5-3.5” (corrected). It is readily soluble in the usual organic solvents, except ligroin.

0.1537 gm. of substance gave 14.25 cc. N (755 mm. and 17’). Calculated for ClbH160N.$l: N = 10.21 per cent.

Found: N = 10.64 per cent.

,&Chloroacetyl-cu, a-phenylbenzylhydrazine and hexamethylenetetra- mine. After the solution of the components in dry chloroform had been boiled for eight hours it was concentrated and treated with several volumes of dry acetone. The salt slowly crystallized out in almost quantitative yield. It melts at 145-6” to an orange liquid. It is readily soluble in water and dissolves in sulphuric acid with a brownish color.

0.2592 gm. of substance required 6.36 cc. AgNO, Solution I. Calculated for C21H&N&l: Cl = 8.55 per cent.

Found: Cl = 8.64 per cent.

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from

Walter A. Jacobs and Michael HeidelbergerSALTS DERIVED THEREFROM

HEXAMETHYLENETETRAMINIUM BOUND HALOGEN AND THE

CONTAINING ALIPHATICALLY MISCELLANEOUS SUBSTANCES

HEXAMETHYLENETETRAMINE: VIII. THE QUATERNARY SALTS OF

1915, 21:465-475.J. Biol. Chem. 

  http://www.jbc.org/content/21/2/465.citation

Access the most updated version of this article at

 Alerts:

  When a correction for this article is posted• 

When this article is cited• 

alerts to choose from all of JBC's e-mailClick here

  ml#ref-list-1

http://www.jbc.org/content/21/2/465.citation.full.htaccessed free atThis article cites 0 references, 0 of which can be

by guest on April 6, 2018

http://ww

w.jbc.org/

Dow

nloaded from