J O U R N A L OF THE AMERICAN CHEMICAL SOCIETY (Registered in U. S. Patent Office) (Copyright, 1952, by the American Chemical Society)
APRIL 22, 1952
VOLUME74
[CONTRIBUTION F R O M
THE
NUMBER 8
DEPARTMENT O F PHYSIOLOGICAL CHEMISTRY, SCHOOL O F MEDICINE,THEJOHNS HOPKINS UNIVERSITY]
Reaction Kinetics of Aliphatic Tertiary P-Chloroethylamines in Dilute Aqueous Solution. 11. Hydrolysis of the Ethylenimonium Ion1 BY BARNETTCOHEN,ERVINR. VAN ~ T S D A L E N AND JOSEPH
HARRIS
Study was made a t fixed pH of the kinetics of hydrolysis of the ethylenimonium ions resulting from the fist order cyclization of a series of seven aliphatic tertiary P-chloroethylamines in 0.001 to 0.0025 M aqueous solutions at 37” and 47”. This hydrolysis appeared to be uncomplicated in the case of the (0-cbloroethy1)-ethylenirnoniumions; but definite complications were observed in the case of (P-hydroxyethy1)-ethylenimoniumion, caused in large part by reaction with the end-product. It is shown that the rate of hydrolysis of these ethylenimonium ions increases with increasing pKa of the parent amine and hmce is closely related to the electron density a t the atom under attack by the water molecule. A mechanism of hydrolysis is proposed.
Process (2) is subject to the following three possible complications : (a) Reversal of reaction (1) to regenerate the parent P-chloroethylamine; this is negligible in dilute aqueous solution12 (b) kl +n interaction of E1 with hydroxyl ion to produce I, RR’NCHzCHzCl RR’NCHeCHz C1- (1) a reaction which was not observed within the range k-1 E1 center mainly around the reactivity of the cyclic pH 3.6 to 8.5 in the case of the type compound, Nethylenimonium ion, EI, toward electron-donating methyl-( o-chloroethy1)-ethylenimonium ion or any c o m p o ~ n d s . ~Experimental proof that E1 is a of its homologs; (c) combination of E1 with its singly charged cation will be presented in Paper ethanolamine. The last can be eliminated in soluI11 of this series. The reaction of E1 and water tions sufficiently acid to block the nitrogen of the resulting in ring rupture and evolution of a proton amino alcohol by forming the corresponding subis characteristic of the general reaction with un- stituted ammonium ion. Also, the amino alcohols charged electron donors of the type HX and may resulting from each of the cyclic imonium ions that contain one or more Pchloroethyl groups (see Table be represented schematically as I) are quickly withdrawn by rapid conversion to the kh corresponding second cyclic ions, the hydrolysis E1 HOH + RR’NCHzCHzOH H + ( 2 ) products of which appear in appreciable concentraI tion only after reaction (2) has run 40% or more of The resulting amino alcohol, I, if it contains one or its course. Thus, by suitable choice of conditions, two N-P-chloroethyl groups, can cyclize a t proper hydrolytic process (2) can be isolated sufficiently for pH, and each successive ethylenimonium ion can direct kinetic study. The results constitute the be similarly hydrolyzed as it is generated. Unless second link in the description of the series of reotherwise specified, this report deals with the hy- actions which the aliphatic tertiary P-chloroethyldrolysis of the first E1 resulting from reaction (l), amines can undergo a t controlled fiH in dilute in which R and R’ in the cyclic ion represent an aqueous solution. Analysis of the kinetic and alkyl and a P-chloroethyl group. qualitative data provides an insight into the possible (1) The work described in this report was performed in part un3er mechanism of the hydrolysis with accompanying a contract recommended by the National Defense Research Comopening of the ethylenimonium ring. mittee, between the O5ce of Scientific Research and Development and The hydrolysis of the N-alkyl-( P-chloroethy1)the Johns Hopkins University. ( 2 ) B. Cohen, E. R. Van Artsdalen and J. Harris, THIS J O U R N A L , ethylenimonium compounds under consideration 70, 281 (1948). is the rate-determining step for the subsequent (3) (a) C. GoIumbic, J. S. Fruton and M. Bergrnann, J. Org. Chcm., rapid cyclization, therefore the course of process 11, 518 (19461,and subsequent papers; (b) P. D. Bartlett, S. D. Rose and C. G. Swain, THISJOURNAL, 69,2971 (1947). ( 2 ) can be followed conveniently and accurately 1875 The chemical transformations of the aliphatic tertiary P-chloroethylamines subsequent to the initial, reversible, monomolecular cyclization2
e
+
+
+
BARNETTCOHEN,ERVINR. VANARTSDALENAND JOSEPH HARRIS
1876
VOl. 74
TABLE I
+n KINETICCONSTANTS OF HYDROLYSIS OF FIRST CYCLICETHYLENIMONIUM IONS,RR'NCHzCH2, IN WATERAT 37" AND 47" k h x 10" e AF R
R'
PK'EO 37
*,
-AS*
kcal.9 per mole
kca1.f per mole
liter/mole min. 370 470
e.u.h
(CHdzCH ClCHnCHi 6.5 1.36 2.67 13.4 26.2 43 6.3 0.960 2.49 18.8 26.4 27 CHdCHz)a ClCHzCHs 19 CHI( CHdr ClCHaCHp 6.15' .724 2.14 21.4 26.6 CzHr ClCHzCHa 6.10 ,672 1.59 17.0 26.6 33 CHa ClCHnCHz 5.97 .906 2.38 19.8' 26.4 23 CHI HOCHICHZ 7.02 .168' 0.44' 19.1 27.5 29 ClCHzCHz ClCHiCHs 4.0b 17. 6d ... .. e Values refer to the parent t-amines. Extrapolated from 0' and 15" data, r/2 = 0.0025. r / 2 = 0.0010-0.0015. * At pH 4.0 and 5.0:,see text. Extrapolated, assuming E = 15 kcal., from 25" where k h = 6.60 X lo-'. e At PH 7.4. f l kcal. g At 37 ; f 2 kcal. .F f 4 e.u; Calcd. for 37" assuming transmission coef. = 1 (ref. 8). Includes data a t 25".
...
by measuring the rate of evolution of chloride ion by this subsequent cyclization. Likewise, the uptake of thiosulfate can usually be used to follow the change in concentration of EI. The rate of acid production during the early stages of the hydrolysis can be employed also, but less accurately.
Experimental Materials.-The ethylenimonium compounds (see Table I ) were produced in solution by cyclization of the corresponding pure tertiary p-chloroethylamines as described in Paper I of this series.8 Most of the chlorohydrin of methyl-bis(p-chloroethyl)-amine was prepared from the picryl sulfonate' and found to behave kinetically as did that from the chloride. Rate Measurements.-The general experimental procedures were substantially the same as those described in ref. 2, except as follows. In order to obtain maximum speed of production of EI, the 2-ml. sample of stock 0.25 M amine hydrochloride was added to 198 ml. of alkalinized test solution and held at PH 9.0 for 2 to 20 min., depending on the temperature and specific rate of cyclization. The acidity was then allowed to rise (or 0.05 M HNOr was added) to the predetermined PH. In sufficiently acid solution, e.g., pH 3.6, for the methyl compound, the hydrolysis products neutralized each other and the PH remained constant throughout the hydrolysis. At a pH within significant range of the PIC', of the aminoethanol formed, the acid produced was neutralized under colorimetric control by frequent successive small additions of 0.05 N NaOH. A check determination under glass electrode control showed that 0.000240004% sulfonphthalein indicator, e.g., phenol red, did not affect the hydrolysis of EI. The periodic additions of NaOH served also to measure the H + production, the rate of which was substantially the same as that of the C1evolution through at least the first 30% of the hydrolysis. Errors.-For most of the compounds studied, the probable over-all error was within 10%; for the last two compounds of Table I, it was within 15%. Duplicate experiments generally agreed to about 3% or better.
Results and Discussion The hydrolysis of each of the seven compounds specified in Table I followed a first order course. In the case of the last two compounds listed, the reaction involves some complications which will be discussed presently. The results of a representative determination are shown in Table I1 for the simplest compound, N-methyl- ( P-chloroethyl) ethylenimonium ion. The rate observed a t 37' was the same, within experimental error, at PH 3.6, 7.4 and 8.5 when determined by measurements of residual EI, of chloride evolution, or of acid production. This is shown in Table 111, which gives the apparent first order rate constants as evaluated from the best slopes through the experimental data. A com-
..
TABLE I1
+n
HYDROLYSIS OF CH:NCH&!Hz
AT
I
37.0'
CHtCH&l Initially, [amine,HCl] = [NaOH] = 0.002457 mole/ liter; neutralized phenol red, 0.0002%; adjusted to PH 7.4 14 min. before first sample. Reaction time,
c1produced
min.
k X
%"
min.
20 50 80 120 160 251
6.3 19.5 5.07 31 .O 5.14 42.8 4.66 53.6 5.22 70.2 4.91 Slope 5.00 Duplicate 4.93 * 100% = 1 equivalent of C1- per mole of EI.
putation based on two successive first order processes a t fiH 7.4 shows that the maximum concentration of E1 (94.3% of stoichiometric) was reached in 10.5 min. At this time, less than 2% of Nmethyl-bis-(P-chloroethyl)-amine remained in the mixture, and there was practically none a t the time of removal of the first sample. TABLE I11 APPARENT FIRSTORDERRATESAT 37' (DETERMINED FROM SLOPES) 0.00503/55.5 = k h = 9.06 X 10-6 liter/mole min.
3.6 7.4 8.5 8.5
Anal. method
Reaction,
SnOs" uptake C1- production Cl- production H production
63 72 86 30
+
%
Av .
k X
min.
tp,'
5.02 4.96 5.18 (5.0) 5.03
Hydrolysis of bis-( P-chloroethy1)-ethylenimonium ion (Table I, last compound) occurred too rapidly for confident measurement a t 37". At 25O, the production of chloride proceeded in two readily distinguished first order steps, the first representing the above compound and the second that of the succeeding hydroxyethyl-( P-chloroethy1)ethylenimonium ion (see Table IV). The uncorrected acid production ran generally parallel with that of chloride ion in the first case but diverged in the second, evidently as the result of fixation of H + by accumulating triethanolamine (pK', 7.75), the final product.
April 20, 1952
HYDROLYSIS OF
THE
ETHYLENIMONIUM ION
1877
,9-hydroxyethylamine and the final methyldiethanolamine. The computed data were in rather good agreement with the observed values for C1- and H + produced and for S207 consumed at different Reaction c1time, produced, k X 10' times from the start of the reaction to the end of the min. %" min. -1 third step. However there were serious deviations 10.0 7.7 from the assumed uncomplicated terminal step to 13.0 18.0 3.95 methyldiethanolamine.6 This brings us to a con16.0 26.1 3.45 sideration of this terminal hydrolysis. 20.0 37.0 3.99 Hydrolysis of the Imonium Ion of N-Methyl24.0 45.7 3.73 0-chloroethyl-p-hydoxyethy1amine.-The amine 29.0 59.0 (5.6) cyclizes rather quickly (half-life = 2.2 min. at From av. slopes, 3 replicates 3.66 37", pH 9.2) to the imonium ion. If the @H is changed after 10 min. to 4.0 or 5.0, the subsequent B. SECOND CHLORIDE;HYDROLYSIS OF hydrolysis rate of the imonium ion runs a simple +n first order course, k4 = 0.0093 min.-' (ie., k h = C~CH~CH~NCH~CHZ I 0.168 X min.-l). As the PH is increased, the CH2CHiOH rate constant increases to 0.00112 min.-' at PH 81 17.2 7.4, but remains first order for a t least 80% of the 100 27.2 0.68 reaction. However, at pH 9.2 the constant not 121 39.1 .85 only increases but does so a t an accelerating speed 150 49.2 .63 with time. Obviously, the last effect is due in large 180 59.4 .74 part to interaction of the imonium ion with the end 222 69.9 .72 product methyldiethanolamine, PK'a 8.32, because 330 83.5 (0.6) this effect can be reproduced a t PH 9.2 by the addition of extraneous methyldiethanolamine. From av. slope, 3 replicates 0.68 However, prolonged experiments and calculations 100% 1 equivalent of C1- per mole of EL have not permitted us to account for the pH effect Compared with the other compounds studied, as due simply to the end-product. In fact, it these cyclic transformation products of tris- P- seems that hydroxyl ion concentration introduces chloroethylamine have notably high hydrolysis an additional complication which we have not yet rates which are obviously associated with the been able to unravel kinetically. In short the slow terminal process and the produceffects of the substituents on the central nitrogen atom. A similar trend has been observed in ace- tion of free methyldiethanolamine in alkaline solution seem to complicate the simple hydrolysis tone-water ~ o l u t i o n . ~ Under the conditions specified, Le., low concen- through the formation of a dimer (tentatively contration of E1 and moderate pH, the hydrolysis of firmed by the isolation of a small amount of a picryl all the initial (chloroethy1)-ethyleneimonium ions sulfonate, m.p. 203O, corresponding to that of the produced by cyclization of the alkyl tris- and bis- linear dimer.3a This and the apparent action of ( p-chloroethy1)-amines was apparently uncom- hydroxyl ion tend to accelerate the disappearance plicated by cyclic dimerizations. This is attribut- of this imonium ion as the PH increases. Examination of Fig. 1 shows again the general able to the rapid cyclization in the first and third steps of decomposition, thus leaving the middle, proportionality of the hydrolysis constants found hydrolytic, step unencumbered. The kinetics and among the homologous ethylenimonium ions and accompanying analyses did not disclose the pres- the free energy changes involved in the acid-base ence of any by-products, e.g., piperazinium deriva- dissociations of the corresponding parent amines. tives, in the reaction mixtures. The observation5 The interpretation we affered in ref. 2 seems to that tris- P-chloroethylamine is transformed almost apply here equally well. The linear relation found completely to triethanolamine in buffered, dilute between -log k h of four of the homologous cyclic solution indicates that the kinetics of this complex ions and the PK: of the antecedent P-chloroethylsystem in water may yield to complete analysis amines is clear. The methyl compound occupies an after the establishment of the specific rates of the aberrant position. A direct comparison should final steps not touched upon in this study. involve the dissociation exponents of the comA comparison was made between our analytical pounds hydrolyzed, namely, the ethylenimonium data for the total series of changes from methyl- ions; but the latter are extremely weak acids (in bis-( P-chloroethy1)-amine t o methyldiethanolamine the Bronsted sense). It seems logical to carry the and the computed values based on the simple as- reasoning a step further. Since -log k h of the sumption that we were dealing with four con- ethylenimonium ion is linearly related to the fiKL secutive irreversible first-order reactions. For of the parent amine, then this correlation should this purpose we employed the experimentally deter- extend to the pKL value of each of the ethylenmined four rate constants a t 37O, PH 7.4, and the imonium ions. Although these fiK: values are unPK'a values for the parent amine, the intermediate determinable the diferences, ApK:, of those that (4) P.D. Bartlett, S. D. Ross and C. G. Swain, THISJOURNAL, 71, conform to the linear relationship can be estimated. TABLE IV
+n A. HYDROLYSIS OF (C12CH2CH?)2NCH&H2 AT 25" Initially, [tris-( i3-~hloroethyl)amineHCI] = [NaOH] = 0.001 mole/liter; neutralized phenol red, 0.0002%; pH 7.4
-
1415 (1949).
(5) C. Golumblc, M. A. Stahmann and M. Bergmann, J . Org. Chcm., 11, 550 (1946).
(6) We an indebted to Dr. Lawson L. Rosenberg for much of the laboratory work and computations involved in this phase of the #tudy.
1878
nARNETT COIIEN, ERVIN
Ti. VAN ARTSDALENAND JOSEPII HARRIS
VOI.
74
I
remained constant for the hydrolysis of the first ethylenitiionium ions of ilie compounds studiecl ’Therefore we have no evidence for the participatioii (Jf hydroxyl ions in these cases; although we did find this to be apparently the case for the second 2 .4! E1 ion of inethyl-bis-( P-chloroethy1)-amine. Hence, 2 4.0 we must dwmie generally a direct interaction of me I HzO through the polarized C-N linkage to produce a substituted ethanolamine and a proton. SThere the reaction is exceedingly slow, or the concentration of hydroxyl ions is appreciable, or both, then I 4.2 the effect of the latter ion is superposed. It has been pointed out that the high reactivity of the ti [I 6.2 6.4 E1 ion is the combined result of the strain of the 3PK‘.. membered ring and the polarizing effect of the Fig. 1.-Relation of pK’, of honiologous parent amines to the hydrolysis rate of their cyclic ethylenimoniuni ions a t positive charge on the C-N linkage.3b The ion is thus very reactive toward any nucleophilic agent I 37’: RR’+?;CH&Hz, R = CHsCH2C1; R’ = Me = capable of attacking the carbon of the 3-membered methyl; Et = ethyl; %-BU= n-butyl; n-Pr = 12-propyl; ring. The energy of activation of the hydrolytic proci-Pi- = isopropyl. ess lies from 13.4 to 21.4 kcal. (Table I), values From the slope shown in Fig. 1, they should be rather less than that for cyclization, which is about + i l -33 kcal.? expected for the formation of a polar, RR‘NCHzCH2 R’ = CHZCHzCl solvated intermediate, the entropies of activation R = Et n-Bu X-Pr i-Pr were all large negative values7 This accounts for APK.’ = 0.03 0.15 0.20 the relative slowness of the reaction, despite the Mechanism of Hydrolysis of the Ethylenimon- inore favorable energy of reaction. From the data presented here, one can readily ium Ion.-The E1 ion may be regarded as an intramolecularly stabilized carbonium ion and, as such, select a series of 4 compounds with increasing Pit can undergo the reactions characteristic of the chloroethyl substitution and observe that there is C+ ion. Among these are reactions with anions, a considerable increase in the hydrolysis rate e.g., C1-, OH-, ,5207, as well as with uncharged associated with a decrease in the electron density electron-donors such as RDN, etc. The polar of the ring carbon under attack. nature of the E1 ion indicates that it is undoubtedly ( 7 ) S Glasstone, K J Laidler and H Eyring, ”The Theory of Rate Processes,” lfcGran-IIi11 Rook L o , Inc , New York, N Y , 1911 highly solvated in water. A t pH levels betweerr 3.0 and 8.5, the rate values BALTI3IORE 5 , hfARYL.+Nn RECEIVFD SFPTEVBER 17, 3%1 3.8
I
I
I
I
I
-
[CONTRIBUTION FROM
THE
DEPARTMENT O F
CHEMISTRY, SCHOOL UNIVERSITY ]
PHYSIOLOGICAL
OF
MEDICINE, THEJOHNS Hoperrs
Reaction Kinetics of Aliphatic Tertiary 0-Chloroethylamines in Dilute Aqueous Solution. 111. Reactions of the Ethylenimonium Ion with Certain Anions1 B Y BARNETT COHEN,
ERVINR.
ITAN XRTSDALEN AND JOSEPH
HARRIS
The kinetics of the reactions between thiosulfate, bicarbonate, chloride, propionate and benzoate ions with the first ethylenimonium ions of several aliphatic tertiary 8-chloroethylamines was studied and the rate constants of these reactions established. Variation of ionic strength causes pronounced changes in rates which can be explained quantitatively by the Bronsted-Debye relationship only if the ethylenimonium ion is a singly charged cation. Rate of the reversal of the initial cyclization of the parent amine by reactions of the ethylenimonium ion with chloride ion was investigated, and from this i t was shown that this initial cyclization in dilute aqueous solution is over 99.5Yc complete.
The ethylenimonium ion produced in the cyclization of an aliphatic tertiary P-chloroethylamine acts like an internally stabilized carbonium ion, consequently a great variety of reactions is possible. In this, the final paper of the series, we report studies on the kinetics of the interaction with SzOrl HCOr, C1-, propionate and benzoate t o form the corresponding esters. By suitable manipulations, we were able to isolate the reactions and examine many of them in considerable detail. (I) The work described in this report was performed in part under a contract recommended by the National Defense Research Committee, between thc‘Office’of Scientific Research and Development and the Johns Hopkins University.
After the initial reversible cyclization , 2 the kl
RR%”iI,cTI.ei
2 rm‘xcrT:cIr2+ ci+
1
-
7
(1 I
k i
I
I1
(EI’I
reactions of I1 in water may be represented schematically as3 (2) B. Cohen, E. R. Van -1rtsdalen and J Harris, THIS J O U R N A L 70.. 281 (1948). . ~, (3) C. Golumbic, J. S.Fruton and M. Bergmann, J . Org. Chcm., 11, 518, 543, $50 (1916); (bl P. D. Bartlett, S. D. Rose and C. G. Swain. ’ m S J O U R N A L , 69, 2971 (1917).
