SULFONIUM DERIVATIVES QP ~ ~ T H I O N I N E
May, 1945
[CONTRIBUTION PBOM THE LANKBNAU HOSPITd
849
RESEARCH INSTITUTE]
Methionine Studies. VII. Sulfoxiium Derivatives' BY GERRITTOENNIES AND JOSEPH J. KOLB (a) Methioninemethylsulfonium acetate may be obtained from an aqueous solution of the iodide by reaction with mercuric acetate. The resulting sirupy evaporation residue corresponds in yield and equivalent weight (acidity, by methylate titrationa) to a monohydrate. On storage in m u 0 it undergoes slow decomposition. 2. 1 Halide Derivatives of N-Acylmethionine. (a) N- ormylmethioninemethylsulfonium Iodide.-To (1) HOOCCH(N"s)CH~CH9CHs RX 50 mM. of methioninemethylsulfonium iodide in 40 cc. of HOQCCH ("2) CHtCHsS(CHz)(R) X- 89% formic acid, 35 cc. of 10.1 M acetic anhydride is added.' After about five minutes a vigorous reaction (2) HOOCCH(NHAC)CH~CH~SCHIR X + occurs whieh must be controlled by cooling. Vacuum disHOOCCH("AC)CH~CH&(CH~)(R) + Xtillation, after several hours of standing, leaves a sirupy (3) HOOCCH(NH~)CH&H,S(CH~)(R) x(CHaCO)*O HCOOH +HOOCCH(NHCH0)- residue. Its solution in 20 cc. of warm methanol deposits CH&HS(CHz) (R) + X- ~CHJCOOH a granular precipitate on gradual addition of 300 cc. of acetone; yield 60-70%. R having been represented by C H c , CHt----CHCH-, The same compound is obtained, in 60% yield, from GHbCH=CHCHand H O O C C H r , X by C1, Br and I, methionine (20 mM. in 16 cc. of formic acid) by acetylaand Ac by CHgCO- and HCO-. tion' (14 cc. of acetic anhydride), followed after half an hour by alkylation (40 mM. of methyl iodide), and after Experimental' one day by vacuum distillation, digestion with 5 cc. of 1. Alkyl Halide Derivatives of Methionine. (a) ethanol, and precipitation with acetone. Methioninemethylsulfonium Iodide.-A mixture of 40 Anal. Calcd. for C7H1408NSI: eq. wt., 319. Found: mM. of methionine, 65 cc. of 89% formic acid, 20 cc. of eq. wt., 321, 326, 326 (acidity, phenolphth.), 322, 322, 324 acetic acid and 10 cc. (160 mM.) of methyl iodide is kept (I-, erythrosin). in a dark place a t about 25' for three days. The progress (b) N-Formylmethioninemethylsulfonium bromide is of the reaction may be followed by titration of the iodide with 0.05 N silver nitrate using erythrosin as an adsorption analogously prepared from the methylsulfonium bromide indicator (2 drops of an o.5y0 alcoholic solution added to (20 mM., 15 cc. formic acid, 13.5 cc. acetic anhydride). 1 cc. of the reaction mixture' and 1 cc.of acetic acid). The The evaporation sirup is dissolved in 15 cc. of hot ethanol. solution is distilled in vacuo to a sirup weighing 30 to 40% Crystallization is best induced by inoculation with a sepamore than the theoretical amount of the sulfonium iodide. rately prepared test-tube sample, and brought to compleDigestion with 40 cc. of methanol produces a granular tion by careful addition of acetone (180 cc.); yield 80%. Anal. Calcd. for C7H1408NSBr:eq. wt., 272. Found: precipitate. After filtering and washing with methanol and acetone it is dissolved in 30 cc. of warm 50% ethanol eq. wt., 282 (acidity), 273 (bromide). and recrystallized by the addition of 100 cc. df"efhano1; (c) N-Formylmethionineallylsulfonium Bromide.-A yield 75y0; dec. pt. about 150'. solution of 25 mM. of N-formylmethionine,' 34 cc. of 89% Anal. Calcd. for CsHrr09NSI: C. 24.7: H. 4.8: N. formic acid, 8.5 cc. of aceti.c acid and 50 mM. of allyl 4.8; S, 11.0; eq. wt.,-29i.2. Found: - C , 25.0.; .H,'4.?; bromide gave on vacuum distillation after one day, and N, 4.6; S, 10.8; eq. wt..290.3,292.0 (I-, erythrosm). drying in vacuo over sodium hydroxide, an amber-colored (b) Methioninemethylsulfoniumbromide is similarly sirup, the weight of which was 111% of the theoretical. A obtlned from 40 mM. af methionine, 50 cc. of formic acid, series of digestions with ether, continued until methylate titration' of the washings showed absence of acid, reduced 50 cc. of acetic acid and 160 mM. of methyl bromide. One cc. of the reaction mixture, 10 cc. of water, and 3 the weight to 97% of the theorktical, and the total acidity drops of an 0.5% aqueous eosin yelkiw solution are used of the washings, calculated as formic acid, accounted substantially for the loss. The compound could not be for titration of bromide: vield 72%: dec. Dt. about 140'. Anal. Calcd. for 'C&;,OlNSBc' C, 29.5; H, 5.8; N, crystallized. A&. Calcd. for QH160zNSBr: neut. eq., 298. 5.7; S, 13.1; eq. wt., 244.2. Found: C, 28.8; H, 5.7; Found: neut. eq., 299. N. 5.6: S. 12.9: ea. wt.. 244.3 (Br-, eosin). The.pr&eding two s i t s are soluble in water and formic (d) N-AcetylmethionineallylsulfoniumBromide.-The acid, insoluble in other organic media. crystalline material obtained from 126 mM. of acetyl(c) . Methioninemethylsulfonium chloride could not be methionine,' 200 cc. of acetic acid and 250 mM. of allyl obtained crystalline. Preparation of an aqueous solution, bromide by distillation after two days standing and ethyl from the iodide, has been described elsewhere.' acetate digestion of the residue is impure. The pure compound was obtained by the following device: 25 g. of the (1) Aided by a grant in memory of Emma M. S. Althouse. For crude product suspended in 71 cc. of propionic acid was the preceding paper of this series cf. Toenbies and Kolb, J . B i d . brought into solution by the addition 'of 631 mM. of water. Chlm., 140, 131 (1941). OriginaL manuscript teceived June 14, After filtration, and washing with 4 cc. of propionic acid, a 1944. total of 72 cc. of propionic anhydrid6 (110% of the amount (2) Toennies, J . B i d . chm.;iaa, 455 (1940); la& CII (1940). equivalent to the water) was added in portions daily dur(a) Only the dl-form of methionine has been used in this work. ing nine days. Slow separation of the sulfonium salt ia C, H, N and most of the S determinations have been d e by Mr. caused by the disappearance of water resulting from the William Saschek, College of Physicians and Surgeons, Columbia acid-catalyzede hydration of the anhydride. Oily separaUniversity, New York, N. Y., whose aid is grntefulfy acknowledged. tions become readily crystallime on seeding (the same (4) The sulfonium, rather than ammonium, nature of the resction process on a centigram scale yields crystals on standing product is indicated by absence of an analogous reaction between when the corresponding amount of the anhydride is added The amino acid methionine and its derivatives can react as sulfides with organic halides to form sulfonium salts.2 In the present paper compounds of this type and some of the factors governing their formatio are described. The reactions invo ved are
e
+
+ 4 + +
+
+
+
methyl iodide and alanine: and also by the failure of the reaction product to react as a sul6de with hydrogen peroxide (Kolb and Toennies, I n d . Eng. Chcm., Anal. Ed.. 18, 738 (1940)). (S) Bennett, J . B i d . Chem., ill, 571) (1941); Handler and Barnham, W . ,110,SSS (1948).
( 6 ) Lavine and Toennies, ibid., 101, 727 (1933). (7) Kolb and Toennies. ibid., 144, 191) (1942). (8) For aDnlJnL of anhydride8 by methylate titration,d. T-iu and EUiott, Tru Jomna,H,OOP (1987).
100
,
-.,-
I-
/
-
--=% - -
one portion) and rubbiiig. After a total of twelve days crystals were filtered and washed four times with 4 cc. -7inoftheacetic acid and ten tiines with 50 cc. of ether; the over-
I
all yield was 60%; dec. pt. 11&122°. Anal. Calcd. for Cl&€180&SBr: C, 38.4; H, 5.8; N, 4.3; S, 10.3; allyl, 13.2; eq. wt.,312.2. Found: C, 38.3: H, 5 . 7 ; S, 4.X;,S, 10.3; aliyl, 12.8 (bromination); eq. wt; (acidity), 312.2 * 1.4, (Rr-) 312.4 * 1.5 (4 determinatiuns each). ( e ) N-AcetylmethioninecinnamylsulfoniumChloride.Ail acrtic acid solution 0.50 M in N-acetylmethionine and 0.8%.\,I in ciiinaniyl cliloride showed after five days the expected ciiloride valiie. Acetic acid was removed by i vaciiiii~idistillatioil, and cirinamyl chloride by ether estractiuii. T h e sulfonium chloride could only be obtained iii the forni of a glassy residue; nor could the bromide or iodide he crystallized. However, an aqueous solution iI.lJ-lq536 in the sulfoiiiu~nbromide and 0.07 Min ammonium I_ , . & . , rririeckatc yielded (50%) crystalliiie N-acetylmethionine20 40 60 80 100 120 ciiinainylsulfoiiiuin reineckate. Hours Anat. Calcd. for CL6H9103NS+Cr(SCN)((NH1)2-+ H20: Fig 1.-Reaction of haloacetic acids with methionine SCN, 36.0; HtO, 2.8. Found: Sc?J,P 36.0, 36.0, 36.1; H,O (78". in cncuo) 2.5. 111 89V0 formic acid, a t 36-28'. I n the iodoacetic acid In contrast to the unacylated sulfonium derivatives the reaction, 1-cc. samples were titrated directly with 0.05 N N-acylated derivatives are soluble in the lower alcohols. silver nitrate in the prcseiice of erythrosin (cf, section la). 3. Reaction Rates.-While the greater similarity beIii the bromoacetic acid reactions 1-cc. samples were added tween the solubilities of haloacetic acids and their reacto 50 cc. of water and 2 drops of eosin solution (cf. sectioii tion products with methionine or acylmethionines makes the isolation of the latter more difficult than that of the lb) atid titrated Methionine, 0 04 M ; 0, ICHzCOOH, alkyl sulfoiiium derivatives, it makes them more suitable 0 82 .If; a, BrCH2COOH, 0 86 M ; m, BrCHZCOOI-I,4 01 j ( l
.11
100
z i,
6 40 c;
ii
.2 E
8
20
100
200 300 400 Hours. Fig. 2.-The effect of water and acetic acid on the reaction of methionine and bromoacetic acid in formic acid a t room temperature (25-28'). For analytical technique ;ee note under Table 1. Symbol
.-)
Medium
CHaCOOH, M FlzO, 'If
Methionine. M BrCH&OOH,
hf
rn 0 HCOOH HCOOH HCOOH HCOOH LII
+
-
CHzCOOH 6 0 "
+
-
0 18
0 18
2 0 20
0.36
0.36
0.40
I
I
CHsCOOH 6 ti 2
0.40
0 20
I-,
i
, ?
. = < . . , . 20 40 BO 80 100 120 Hours Fig. 3.-The reactions of methionine and N-formylmethionine with allyl bromide a t room temperature (2126'). To 3-cc. samples, 10 cc. of ether was added and 25 cc. of a cold solution 0.02 M in FeNH&O& and 1 M in HNOg, and titration was carried out as noted under Table I. Removal of allyl bromide from the aqueous phase by ether eliminates its hydrolysis as a possible source of titration error. The values for the upper two curves were obtained by deductindfrom the net values those of the allyl bromide.contro1. '
3
,
Symbol -.,
HCOOH, M CHaCOOH, M HaO, M CHsCOOSa, M Allyl bromide, M hkthionine, M Formylmethionine, 111
0 13 6.5 7 0 20 0 20
-
0
13 6.5 7 0 20 0 20 0.10
-
13 6.5 7 0 20
0 20
-
0 10
(9) Carlsohp end Neumann. J . prakl. Chcm., 147. 38 (1936).
HEATSOF
May, 1945
FORM;\TION OF
AMMONIUM AdLUMINUMSULFATES
85 1
TABLEI EFFECTO F ACIDITYLEVELAND MEDIUMO N THE REACTION O F hIETHIONlNB AND BROMOACETIC ACID These reactions were run simultaneously. The temperature was 25-28“. Rroiiiide ion was determined as follows: to 1 cc. of the reaction mixture add 25 cc. of H20,3 cc. of 7.5 11f H K O P(which has been boiled to remove free nitrogen oxides) and 0.5 cc. of a 1 ilf solution of FcNH4(S0d)2in 0.1 N HSOJ. Cool and add 0.1 or 0.2 cc of 0.05 N KSCN, titrate to colorless with 0.05 N AgNOs and complcte titration with 0.05 N KSCN. The hchavior of aiialogous reaction mixtures in which alanine was substituted for methionine showed that there are no significant blaiik values under these conditions. HCIO4 + ’tf 0.44 .... .... 0.33 0.22 CHCOONa
Medium: HCOOH CHaCOOH 6 . 6 A[ Hz0 0.20 M Methionine BrCH2COOH 0.40 M
+
+
Medium: HCOOH CH,COOH 6.0 M 7 M Hz0 0.18 M Methionine BrCHlCOOH 0.36 M
+
+
I
I
4 Af
....
....
....
49 hr., yo 218 hr., % 385 hr., %
48 87 92
45 86 92
47 84 91
41 84 93
42 86 95
44 88 96
% % % %
59 78 95 97
57 75 90 100
57 75 96
54 74 93 98
57 78 94 99
58 78 96 102
44 hr., 93 hr., 213 hr., 376 hr.,
for the study of kinetic factors, because no problems of vapor pressure are encountered over a wide range of solvent composition and temperature. Figure 1 shows examples of reactions between methionine and monoiodo- and monobromoacetic acid. The latter seems to be somewhat more reactive than the former. Monochloroacetic acid, on the other hand, is of extremely low reactivity. A solution of 0.08 M methionine and 0.16 M monochloroacetic acid in water (which favors sulfonium reactions, see below) containing 0.05 M perchloric acid showed a half-time of reaction of approximately fifteen hours a t 74’. The results shown in Fig. 2 indicate that among different media the sulfonium reaction is increasingly favored in the following order: acetic acid, formic acid, water, i. e., in the order of increasing dielectric coristarit.10 The accelerating effect of water is further borne out by the data of Table I. These (10) Cf. Bost and Everett, THISJOURNAL, 63, 1753 (1940).
[CONTRIBUTION FROM
THE
0.10
0.30
data also indicate that in the formeous-aceteous media both strong acids and strong bases (sodium acetate) slightly but defititely cata!yze sulfonium formation. A comparison of the reactivities, with allyl bromide, of methionine and N-formvlmethioniiie. is shown in Fie. 3. interference of the poiitive nitrogen charge (HO6CCH(NHsf)-CH?--CH~-S-CH3) with the estahlishment of the positive sulfur charge could explain the qlow-rr reaction of the free amino acid.
Summary A number of alkyl sulfonium salts derived from niethionine and N-acyl-substituted methionine have been isolated and certain factors governing their formation have been studied. PHILADELPHIA
30, P A .
RECEIVEDFEBRUARY 23, 1945
WESTERNREGION,BUREAU07 MINES, U. S. DEPARTMENT OF CALIFORNIA ]
THE
INTERIOR, BERKELEY,
Heats of Formation of NHJ.l(S04)2~12H20 and NH,Al(S04)21 BY FRANK E. YOUNG^ Several recent thermochemical investigations a t the Pacific Experiment Station of the Bureau of Mines have dealt with aluminum compounds of current metallurgical interest, Previous papers by the author described new determinations of the heats of formation of two hydrates of aluminum nitrate, a anhydrous and hexahydrated aluminum sulfate, and anhydrous and dodecahydrated potassium aluminum ~ u l f a t e . ~Other papers reported low-temperature specific heats, entropies, and high-temperature heat contents of some of these and related compounds.6 The (1) Published by permission i f the pirector, Bureau of Mines, U. S. Department of the Interior. Not copyrighted. (2) Chemist, Pacific Experiment Station, Bureau of Mines. (3) Y o u n g , TEISJOURNAL, 66, 777 (1944). (4) Young, ibid., 67, 257 (1945). (5) (a) Moore and Kelley, ibid., 64,2949 (1942); (b) Shomate and Kelley. ibid., 66, 1480 (1944); (c) Shomate.and Naylor, ibid., 67, 72 (1945); (d) Shomate, ibid., 67, 765 (1945).
present paper, a continuation of this work, prer sents new determinations of the beats of formation of nearly anhydrous (1.80% water) a d dodecahydrated ammonium aluminum sulfate and gives an estimate for the completely dehydrated compound. Materials and Method J. T. Baker analyzed ammonium sulfate containing 0.02% impurities was dried a t 62’ and stored over Dehydrite uptil used. The average of four sulfate analyses6 indicated 99.96y0 purity. Mallinckrodt “Analytical Reagent” ammonium aluminum .sulfate dodecahydrate was used without drying or other treatment. Analyses for alumina showed 99.78% purity. Correction was made in the thermal results for the 0.20% alkali sulfate found to be present. “Anhydrous” ammonium aluminum sulfate’ was pre(6) These analyses were made by E, H. Huffman, formerly metallurgist, Pacific Experiment Station, Bureau of Mines. (7) This material was prepared and analyzed by A. E. Salo, metallurgist, Pacific Experiment Station, Bureau of Mines.
