J. E. EARLEY, C. E. O'ROURKE, L. B. CLAPP,J. 0. EDWARDS AND B. C. LAWES
3458
[CONTRIBUTION FROM
Reactions of Ethylenimines.
THE
VOl. 80
METCALF CHEMICAL LABORATORIES O F BROWN UNIVERSITY ]
IX. The Mechanisms of Ring Openings of Ethylenimines in Acidic Aqueous Solutions1
BY JOSEPH E. EARLEY, CHARLES E. O'ROURKE,LEALLYN B. CL.IPP,JOHN 0. EDWARDS AND BERNARD C. LAWES RECEIVED JASUARY 11, 1958 Kinetic measurements and product identifications have been carried out in order to elucidate the mechanisms of aevernl more imine ring openings. Xziridines studied were 2,2-dimetliylet~iyIenitnine,2-ethylethylenimine, N-(n-butyl)-ethglenimine and ethylenimine; nucleophiles studied were acetate, bromide, chloride, iodide, thiocyanate a n d thiosulfate ions, thiourea and water. Hydrolysis rates were studied over a range of temperature and pressure so as to obtain activation parameters. All of the reactions studied have been found t o correlate with known mechanistic patterns. The use of linear free energy equations for the evaluation of relative contributions of Ss l and Sx2 behavior in solvolysis reactions is pointed out. where R: is the amount of itnmoniurii ion which has been atIntroduction tacked by chloride ion b y time t , a t h e initial concentration In a previous paper,' it was reported that two of chloride ion and b the initial concentration of inimonium separate ring-opening reactions occur in solutions ion. The quantityf is the ratio of tlie total amourit of irnof 2,2-dimethylethyleniminein aqueous hydro- tnonium ion which has undergone ring-opening (including h a t which has undergone hydrolysis) to t h e amount of imchloric acid. One of these reactions, the attack of tinotiium ion which has been attacked by chloride ion. T h e the chloride ion on the irnmonium ion to yield 1- ratio, j",was evaluated by dividing t h e initial conceiitratioti chloro-2-amino-2-methylpropane was shown to be of imrnoniuni ion by the amount of iinmonium ion whicli ) The other reaction, was shown t o have reacted with chloride ion by titratioii of a second order ( S N ~process. reaction mixture after tlie reaction had becn allowed hydrolysis of the irnmonium ion t o yield l-amino- tthe o go t o completion. 2-methyl-Zpropanol was interpreted as being a Because t h e hydrolysis of an iniinoniu~nion dw.; not reunimolecular (2x1) process. sult in LL decrease of hydrogen ion concentration of the soluThe present study, on eight nucleophiles and four tion, a n alternative analytical method was needed. T h e reaction between the thiosulfate and immoriium ions ethylenimines (aziridines), was undertaken to find rapid has been suggested4 as a method for the determination of out more about the mechanisms of opening of these ethylenirnines. In order t o use this rapid reaction t o folthree-membered ring compounds. The imines low liy-drolyses of inimotiium ions, the following procedure studied and a generalized reaction scheme are pre- was employed. Solutions approximately 1 F in perchloric acid and 0.3 F i n imine were prepared. At appropriate times, sented in the equation ten milliliter aliquots of these solutions were added to an
RI
RI
\ /
,
S
+ H + z
\\
,S, -+ RJt,CCIIlY
/
R?RzC---CH* I , K1 11, R1 111, Ri IV, Rt
H
'\a/
T-
\
RZRzC--CHe = R, =r R3 = H = n-C;Hg, R Z = R, = H = R2 = H, R, = CaHa = H , R2 = R3 = CHS
I
SHK]
where U- is the nucleophile. Another goal has been the working out of a method for estimation of the relative amounts of S N 1 and S Ncharacter ~ in solvolytic reactions. Experimental R a t e constants for reactions between t h e imines and four nucleophiles ( I - , SCX-, Br- and thiourea) were measured by a method similar t o t h a t described earlier.2 Perchloric acid customarily was used as the snurce of protons, although in some cases t h e conjugate acid of t h e nucleophile was CIIIployed. X three-to-one ratio of acid t o imine was ernployed so t h a t essentially all of the imine would exist in the form of t h e iminonium ion.3 R a t e constants for the reactions between the chloride iim and t h e imines were measured in a similar manner. Hydrochloric acid was used t o provide both tlie nucleophilic ion and protons. -1st h e hydrolysis reaction competes with the relatively slow attack of chloride ion, the second-order constants for these reactions were computed from the formula
(1) Taken from parts of the Ph.D. These5 of J E . Earley a n d R. C . I.awes and the Sc.M. Thesis of C . E. O'Rourke. Presented in part a t the Symposium o n the Chemistry of Threr-1\Iembered Rings, 131st Meeting of the American Chemical Suciety. l l i a m i , Florida. April 1 I , 19.57' (2) V B. Schatz a n d L . B CIapi>,Tms JWRKAI., 77, 3113 (1933). (3) C. E . O'Rourke, L . B. Clapp and J. 0 Edwards, i b i d . , 78, 2139 (195G).
equal volume of a solution 0.5 F in sodium thiosulfate and 1.2 F in sodium acetate. ,After the quenclied aliquots hat1 been set aside overnight, the utireactcd thiosulfate was titrated with standard iodine solution tu t h e starch ctid-point. The decrease in concentration of ininioniuin ion in tlie perchloric acid solution was found t o follow first-order kinetics. Since the methyl orange end-point is masked iii acetate buffers, the attack of acetate ion on various irnmoniuin inns was followed by a procedure similar to t h a t used fur the Ill-tlrolysis reactions. -1large excess of acetate ion as used and ii pseudo-first-order rate constant measured. This constant was corrected by subtraction of tlie first-urdcr hydrolysis coilstant for the appropriate imine and then tlivicied b y the acetate ion concentration t o give a second-order rate constant. The rate of the reactions between the iiiiniotiium ions anti the thiosulfate ion was measured by titrating ahquots of the reaction mixture with staiidard iodine solutions. Second-order rate constants were computed in the usual manner , -111 of the 2xperiments outlined above were carried out it1 L: \vatrr-batli a t 25.00 =k 0.05'. The reaction medium was cooled to about 20' and the imine added quickly, with vigcrnus swirling, from a weight buret or a pipet. T h e protonation of t h e imine released enough heat to raise t h e temperature of the reaction mixture t o 25' and swirling in the bat11 brought about thermal equilibrium in a relatively short time. R a t e constaiits for the hydroly.;es of three imines wcre also measured a t elevated trmperatures (40.15, 44.90, G 5 . l B 0 ) in an oil-bath lield constant t o within 1 0 . 0 5 " . Rates of hydrol!-sis were also measured a t 21 f O.,?' under ROO0 p.s.i. This was done by enclosing t h e reaction mixtures i n flexible polyethylene containers immersed in h>-dr;iulic fluid i n a co~iventiotialhigh pressure bomb, fitted witli :ti1 oilIjuiinp a n t i pressure gxuge. This bomb was placed in :Lcoilstaiit trinpcrature room for a period of several necks, tluring which aliquots were takrn as usual. Identification of Reaction Products.-The products of the reactions of 2,2-dimeth~lethyleniinitiewith HCI, H B r , H I , I-ISCS ;and thiourea. have been isolated, identified b y cotiversion to tleri\-ativcs :tiid, iti the cases i i f tlic firct fimr, tlie ~~~
-~ ~~~~~
(-L) E . Allen and
Seaman, Aizul. Chciiz.. 27, 340 (19%).
July 5 , 1958
RINGOPENINGSOF ETHYLENIMINES IN ACIDSOLUTIONS
structures related t o one common derivative. From previous work t h e two chloroamines obtained from t h e reaction of I V with concentrated HCl, l-chloro-2-amino-2-methylpropane hydrochloride a n d 2-chloro-1-amino-2-methylpropane hydrochloride, were proved t o have the structures assigned b y conversion t o known benzamides.a Products from the reaction of IV and HCl, H B r and H I were related t o t h e corresponding product from H S C S . The oily reaction product from IV a n d H S C N , presumably l-thiocyano-2-amino-2-methylpropane, was converted t o 2imino-4,4-dimethylthiazolidine b y warming t o 110" and was identified b y conversion t o a picrate. T h e iminothiazolidine structure was not proved by a n independent sytithesis since it was considered sufficient for present purposes t o relate t h e four reaction products to the one compound. T h e reaction is one used by Gabriel5 for the preparation of another iminothiazolidine. l-Chloro-2-amino-2-methylpropane hydrochloride and the corresponding bromo and iodo compounds were each separately treated with potassium thiocyanate and then with a n alcohol solution of picric acid t o give the same 2-imino-4,4-dimethylthiazolidine picrate. With t h e same experimental conditions the isomeric 2chloro-1-amino-2methylpropane hydrochloride rearranges with loss of hydrogen chloride t o P-methylallylamine, identified as t h e picrate.6 1-Bromo-2-amino-2-methylpropane Hydrobromide.-To a n ice-cold solution of 27 ml. (0.23 mole) of 48% hydrobromic acid in 100 ml. of water, 5.56 g. (0.078 mole) of IV was added dropwise while t h e mixture was stirred vigorously. Stirring was continued for six hours at ice-bath temperature and then t h e mixture was allowed t o come t o room temperature. T h e solution was evaporated at room temperature in a stream of dry air until crystals started t o appear. Removal of t h e crystals and repeated evaporations gave 14.8 g. (86%) of crude product, m.p. 182-183'. ThLee recrystallizations from acetone and sublimation gave an analytical sample, m.p. 184-186".7 Anal. Calcd. for CaHllNBr2: C , 20.60; H, 4.80; N, 6.00. Found: C,20.67; H , 4.83; N , 6 . 3 2 . The bromo compound was converted into the picrate of l-bromo-2-amino-2-methylpropaneb y treatment with aqueous sodium picrate solution. T h e picrate was recrystallized from water, m.p. 167-168'. Anal. Calcd. for CI~HI3N4O7Br:C , 31.50; H, 3.41; N, 14.71. Found: C , 31.80; H, 3.66; N, 14.80. l-Iodo-2-amino-2-methylpropaneHydroiodide .-The iodo compound was prepared in a manner similar t o the bromo compound just described with a reaction time of 3 hours in 9 0 7 , yield. Recrystallizations from an ethanol-ether mixt u r e gave an analytical sample, m . p . 145-147'. Anal. Calcd. for CaH11NI2: C , 14.71; H , 3.39; N , 4.29. Found: C , 14.91; H, 3.62; N, 4.16. -4 picrate was obtained b y an analogous procedure, m.p. 168' dec. Anal. Calcd. for CloHl&aO7I: C, 28.12; H , 3.07; N, 13.10. Found: C , 27.93; H , 3.29; N, 13.39. 2-Imino-4,4-dimethylthiazolidinePicrate.-To a solution of 6.84 g. (0.07 mole) of potassium thiocyanate a n d 5.0 g. (0.07 mole) of IV in 30 ml. of water, 9.85 g. (0.07 mole) of 72,y0perchloric acid diluted t o 100 ml. was added over a 10minute period with enough cooling t o keep t h e solution at 40". After standing one hour a t 40",the potassium perchlorate was removed by filtration and t h e solution was evaporated at 25" in a stream of dry air. The last traces of water were removed at reduced pressure and t h e product was heated t o 110' for one hour. -4 quantitative yield, 9.8 g., of crude product was obtained b u t i t could not be induced t o crystallize. -4 sample of this was converted t o the picrate in 9570 ethanol and recrystallized twice from t h e same solvent, m.p. 200-203'. Two grams (0.014 mole) of l-chloro-2-amino-2-methylpropane hydrochloride was dissolved in 5 ml. of water and a n equivalent amount of potassium thiocyanate (1.35 9 . ) was added. T h e solution was heated t o 110" in a n oil-bath and 3 ml. of water was added twice and evaporated over a 6-hour period. The product was treated with 3.48 g. (0.014 mole) of sodium picrate in 40 ml. of water. T h e picrate ( 5 ) S. Gabriel and J. Colman, B e y . , 47, 1866 (1914). (6) R. Adams and T . L. Cairns, THIS J O U R N A L61, , 2461 (1939). (7) Melting points are corrected; analyses by S . M. Nagy, Microchemical Laboratory, M.I.T., Cambridge, Mass.
3459
was recrystallized twice from 95% ethanol, yield 4.5 g., m.p. 204-206'. A mixed m.p. with t h e picrate described above gave a m.p. 203-206", An analytical sample was prepared b y three more recrystallizations from 95% ethanol m.p. 205.6-206.4". Anal. Calcd. for C I I H ~ & ~ O ~ C S ,: 36.77; H, 3.65; S , 19.49. Found: C,37.08; H,3.85; N, 19.63. B y a similar procedure, l-bromo-2-amino-2-methylpropane hydrobromide and t h e corresponding iodo compound were converted t o the same picrate. Hydrolysis Products. Potentiometric Analysis.-Hydrolysis of imine I11 or IV gives two different products depending on t h e site of attack b y water. Thus, d a t a on t h e relative amounts of isomeric aminoalcohols for each case were needed. Because of t h e difference in basicity of t h e two aminoalcohols from I V , a direct potentiometric titration analysis could be applied t o the reaction mixture. If t h e equations corresponding t o conservation of mass and charge are set u p for a solution in which t h e acidity due t o the presence of two weak acids has been exactly half-neutralized, one may derive the equation
where G is the fraction of t h e original weak acid concentration accounted for b y t h e acid A' and K ' , is t h e dissociation constant of this acid. The second weak acid has a dissociation constant K,". Solutions 0.15 F in 2-hydroxy-2methylpropylammonium perchlorate a n d 0.355 F in perchloric acid were prepared and titrated potentiometrically with standard base at 25.0". A small amount of formalin was added just before the second end-point t o sharpen this end-point. Titrations of identical samples containing the perchlorate of 2-amino-2-methyl-1-propanol also were carried out. T h e pH at the half equivalence point of these titrations was taken as the pK, of the aminoalcohol under t h e experimental conditions T h e apparent pK of the hydrolysate of I V was measured in an identical manner. T h e values obtained for these pK's, 9.25 rt 0.01, 9.65 rt 0.02 and 9.32 =k 0.04, respectively. when inserted in the above equation, indicate t h a t about 23% of the hydrolysate of IV is 2-amino-2-methyl-1-propanol. I n previous work on t h e hydrolysis of imine I V in hydrochloric2 or sulfuric acid* only the isomeric l-amino-2-methyl-2-propanol was obtained. Distillation Analysis.-Gas phase a n d "reversed phase" chromatography of t h e products of t h e imine hydrolysis were tried without success, b u t i t was found possible t o employ fractional distillation t o t h e problem of separating the aminoalcohols since the boiling points are approximately 10" a p a r t . T h e composition of t h e fractions obtained was checked b y comparison of the refractive indices with those of the pure compounds. From IV, the hydrolysis mixture was found to contain 857, of l-arnino-2-methyl-2-propanol and 15% of the 2amino isomer. From I11 t h e ratio of 2-amino-I-butanol (6170) to 1-amino-2-butanol (227,) was close t o three t o one. However, a significant amount (- 17%) of higher boiling material (polymer?)also was found.
Results Kinetics.-Before the study of various imines and nucleophiles was carried out, an intensive study of the reaction of four nucleophiles (I-, Br-, SCN-, thiourea) with I V was made. The rate of the attack of such nucleophiles on the imine was found to be of the second order. The firstorder dependence on nucleophile concentration was checked by variation of its initial concentration. The order in immonium ion was determined primarily by following its change in concentration with time over a considerable fraction of reaction in the presence of excess nucleophile; plots of log concentration against time were linear in such circumstances. Further, excellent straight lines were obtained when data for runs with comparable concentrations were plotted in accordance with second-order kinetic laws, and the second-order rate (8)
T.L. Cairns, THIS J O U R N A L63, , 871 (1941)
3460
c.
J. E. EARLEY, E. O'ROURKE, L. B.CLAPP,J. 0 . E D W A R D S AND B.c. LAWES
constants from the different experiments were found to agree well. In Table I, the results for these experiments are presented. TABLE I
REACTIONS OF
Nucleophile
Br-
SCN-
I-
2 , 2 - D I M E T H Y L E T H Y L E N I M I N E WITH SEVERAL
fia
1.0
2.0 1.0 2.0 1.0 2.0
SC(P\"z)? 1.0 Ionic strength. in aqueous solution.
NUCLEOPHILES Number of runs knb
Av.
% dev.
6 2.0 x 10-3 2 4 1.79 X 0.5 3 1.6 X 10 6 1.413 X 0.6 6 1.78 X 3 3 1.78 X 6 4 . 1 X lo-' 1 Units are liter-xnole-'-sec.-',
so
placement reactions. Table I11 shows the values of the parameters which were found, by the method of least squares, to give the best fit of the rate data. For reasons discussed below, the values of K O which can be related to the rate of hydrolysis are treated as parameters a t this point. The rate results are presented in the form of linear free energy plots in Fig. 1.
Reaction, 70
83
Vol.
L'ALUES
OF
TABLE I11 PARAMETERS FROM LINEARFREE ENERGY EQUATIONS
100
93 9G
at 26"
As may be seen from the table, most of these experiments were carried out a t ionic strength one. I n the thiocyanate case some of the experiments were carried out a t ionic strength two in order to get more reproducible results as a t the lower ionic strength poor rate constants were obtained. In order to see how much difference this change in ionic strength caused, check runs a t the higher ionic strength were made with iodide and bromide ions. I n neither case was the rate seriously altered; in fact, with iodide ion the rate constant was the same a t both ionic strengths. In the fifth column of the table, the average percentage deviation of the rate constants from the mean is presented. In the final column are recorded the percentages of theoretical yields of product as calculated from the titration data. The divergences from 100% in the cases of bromide and iodide ions are felt to indicate that the primary product of the reaction is undergoing hydrolysis. Indeed, i t was found that pure samples of this 2 iodo-amine were not easy to prepare, as a result of a marked instability of the compound. Rate Constants.-In Table 11, the rate constants for the reactions of four inimonium ions
Etllylcn2-Ethylethylen2,2-L)irneth).letliyleii-
2 . 7 3 2 . 1 2 0.026 1.39 2 . 2 1 .013 3.87 2 . 0 1 ,027
1.54 0.87 0.658 .91 2.28 .83 a Calculated from the equation log k - log ko = a E , PH. Calculated from the equation log k - log ko = sn.
+
It is worthy of mentioil that thiourea acts as a stronger nucleophile than iodide ion toward IV as predicted by the electrode potentialslO; data on mustard cation displacementsll had suggested that thiourea might have an abnormally low nucleophilic power. There is firm evidence for the belief that in these reacfions ring-opening occurs simultaneously with nucleophilic attack. The product isolated from the reaction of IV with thiocyanate has the thiocyanate group attached to the primary carbon ; this situation certainly would not prevail if a carbonium ion intermediate were formed. The rings are opened by nucleophiles a t relative rates which correspond to values of a and s which are normal for displacements in rate-determining steps.g,'" Again such a situation would not be expected to prevail if there were a carbonium ion intermediate. Finally, all four imines react a t rates which reflect their nucleophilic character, suggesting that all proceed by a similar mechanism. I t seems rather likely that the mechanism of these reactions is one in which the nucleophile attacks the back side (to nitrogen) of the methylene carbon. Such a schematic equation is shown in the TABLE I1 introduction. RATECONSTANTS FOR RINGOPENISC:REACIIOXS Rates of hydrolyses for the four imines werc meas106 X k . 1. mole-'sec.-', a t 25'; p = 1.0 ured a t 23" using perchloric acid as the catalyst. 2,Z-Dimethyl2-EthylN-ButylThe measured first-order rate constants are listed EthylenethylenethylenethylenhTucleoimine imine imine phile En imine in Table 11. For comparison with the second-order 0.703 0.3 3 67 0.452 Hx0" rate constants for reactions involving more active H20b 0.00 0.0~7 0.0083 0.0127 o . n o ~ nucleophiles these hydrolysis constants divided by CHsCOO- 0.95 4.73 2.96 5.18 2.2 the concentration of solvent water are also shown c11.24 7.56 3.5B 5.48 1 in Table 11 and in Fig. 1. Rates of hydrolysis a t Br1.51 33 17.8 28.3 8.3 SCN1.83 24Y I13 230 110 temperatures other than 23" and a t SO00 p.s.i. are 12.0G 207 1b3 43G shown in Table IV. The activation therinodySC(NHd2 2.18 G80 nainic quantities are also shown in Table IV. SaOa" 3.57 4880 5!)20 5:1fj(l 3500 Although the reactions of active nucleophi1e.s a First-order rate constarit k, calculated 011 the hasis of t h e assumption t h a t k , = k,,,. * Secoiid-order rate constant with the ionic form of IV are undoubtedly bimokz calculated 011 the basis of the assumption t h a t kz = k,,,/ lecular, the hydrolysis of this ion has been reported [HzOI. to be unimolecular.' The tertiary carbonium ion and seven nucleophiles, other than water, are given. which would be an intermediate for this hydrolysis These rate constants can be correlated well by would be expected to be more stable than the either of the equation^^^^^ for relative rates in dis- corresponding species which would be involved in (11) A . G. Ogston, E, R. Holiday, J. St. I.. Philpot a n d 1,. A. (9) c. G. Swain and c. B. Scott, THISJ O U R N A L , 76, l i l (1953). (10) J. 0. Edwards, ibid., 76, 1540 (1951).
Stncken, Tvuirs. P a ~ d u ySuc., 44, 4.5 (1948).
RINGOPENINGS OF ETHYLENIMINES IN ACIDSOLUTIONS
July 5 , 1958
RATECONSTANTS
Imine Irthylen-
T,
"C. 21
AND
2,Z-Dimethylethylen-
FOR IMINE
AV*
k. AH*, kcal./ CC./' mole A S * , e.u./mole mole set.-' 4.61 X 10-7 23.0 f 0.6 -- 9.4 f 1.0 1.8
4.43 x 6.17 x 9.76 X 65 8.15 X 21 2.64 X 2Ia 2 . 7 9 X 25 4 58 X 45 5.83 X 65 5.33 x 21 2.10 X 21" 2.32 X 25 3.63 X 40 2.90 X 45 5.23 x 21" 25 45
2-Ethylethylen-
TABLE IV ACTIVATION QUANTITIES IIYDROLYSES
3461
10-7 10-7 10-0 10-6 lo-' 23.1
3-z
0.1 - 1 0 0 zk 0
10-7 1010103 24.3 k 0.4 -1.9 =k 1 . 0 10-0 10-O 10-6 10-5
-2.5
-4.4
8000 p.s.i.
mechanistically similar reactions of I11 or I. I n the event that both unimolecular and bimolecular paths were important in these hydrolyses the experimental first-order rate constant would be composed of two terms L
p
=
ki
+ h[H20I
where k1 is the first-order rate constant for S N 1 ring-opening and kz [HsO] pertains to the bimolecular, nucleophilic (SN2) attack of a water molecule on the imine ring. It is not possible to evaluate kl and 82 using only kinetic measurements on the hydrolysis reactions, since in the presence of excess solvent all these hydrolyses follow first-order kinetics. An indication that the mechanisms of the various hydrolyses are not all identical can be gained from the activation quantities listed in Table IV. The enthalpies of activation for the hydrolyses of I11 and I are almost identical, while that for the hydrolysis of IV is higher. The entropy of activation for the hydrolysis of IV is about 8 e.u. more positive than the corresponding entropies for the other hydrolyses. The influence of pressure on the hydrolysis of I V is about twice as great as on the hydrolyses of the other imines. Since the pressure effects are small, i t does not seem appropriate to draw any conclusions from them; but the enthalpies and entropies of activation indicate that there is a significant difference between the hydrolysis of IV and the corresponding reactions of the other imines. Analysis of the products of these hydrolyses supports this interpretation. Both potentiometric analysis and fractional distillation of the hydrolysate of IV show that approximately 20y0 of the product is 2-amino-2-methy1-1-propano1, the remainder The former being l-amino-2-methyl-2-propanol. alcohol would be expected to be the predominant product of an S N 2 mechanism, whereas the latter amino alcohol would be expected to predominate if an S N 1 mechanism were operative. On the other hand, fractional distillation of the hydrolysis of 111 indicates that the aminoalcohol products of this reaction are approximately 22% 1-amino-2-butanol and 61% 2-amino-1-butanol. In this case the prod~ occurs in uct corresponding to the S N reaction much greater yield than that corresponding to the S N 1 mechanism.
1
I 0
I I
I 2
En . Fig. 1.-Linear free energy plots using equation of ref. 10 for three imines and six nucleophiles. Hydrolysis constants were not used t o establish the best lines. Data for 25' were taken in aqueous solution.
Recent work has shown that the entropies of activation for SN1 and S N reactions ~ in similar systems are distinctly different, with the A S * for ~ being as much as thirty units the S N reaction ~ more positive than the A S * for S ~ 2 . lAlthough quantitative comparison is not possible in view of the competing reactions, the more positive A s * for the hydrolysis of IV is another indication of a significant SN1 contribution. The parameter ko in the equation (either one) used to correlate the rate constants of the reactions of the more active nucleophiles corresponds to the value of the hydrolysis rate constant which is consistent with the second-order rate constants used to evaluate this parameter. Therefore, the computed value of ko should be close to the measured rate constant kexp, when the concentration of solvent water is taken into account, if the hydrolysis involves the same mechanism (SN2) as do the reactions of the more active nucleophiles. In Table V are listed the negative logarithms of K O and of kexp/'[HzO] for the various hydrolyses. It will be observed that the hydrolysis of IV proceeds a t a faster rate than the rates of the reactions of the same imine with active nucleophiles would indicate. This is not surprising in view of the other evidence that there is a sizable S N 1 contribution to this reaction. As a first approximation, we may (12) (a) R . W. Taft, Jr., E. L. Purlee, P. Riesz and G.A. DeFazio,
THISJOURNAL, 7 7 , 1584 (1955); (b) F. A. Long, J. G. Pritchard and F. E. Stafford, i b i d . , 79, 2362 (1957): (c) other references cited in a and b.
3462
PURNENDU B. TALUKDAR AND DAVID A. SHIRLEY
Vol. 80
take the results of the product analyses as a measure of this contribution and compute an estimated second-order rate constant from the experimental rate constant. A similar though smaller correction may be applied to the hydrolysis of 111, using the results of the fractional distillation as a measure of the s N 1 contribution. In the case of the hydrolysis of 111 the amounts of the isomeric aminoalcohols would not be expected to be as good a measure of s N 1 contribution since the steric effect of the single ethyl group would be less effective in blocking direct nucleophilic attack on the more substituted carbon than the steric effect of the two methyl groups in IV. On the other hand there seems to be a small amount of polymer formed during the hydrolysis reaction and this concurrent polymerization would require an additional correction, which would tend to offset the above-mentioned difficulty in the interpretation of the aminoalcohol analysis. The final corrected values of the second-order hydrolysis rate constants, computed from experimental data, are listed in Table V. It will be observed that these
values than are those from the equation of Edwards.'O Several explanations might be advanced for this behavior, perhaps the most obvious being that the nucleophilic constant (En) for water is somewhat high (;.e., water is not as strong a nucleophile as predicted). If the value of this constant were -0.14 for water, the estimated values would all agree within experimental error with the computed values of ko. This small effect might be due to the fact that the species being attacked in these reactions are cations, while uncharged substrates were used in the evaluation of the nucleophilicity constants. Although the deviation certainly seems real, it is not large enough to invalidate the correlation equations. The values of the activation thermodynamic quantities for these three hydrolyses, the product analyses and the relationship between the rates of imine hydrolysis and the rates of the faster reactions all point to the conclusion that the acid is primarily hydrolysis of 2,2-dimethylethylenimine ~ although there is a small s N 2 conan S N reaction TABLE 1. tribution. The acid hydrolysis of "ethylethylenCOMPARISON OF SECOND-ORDER HYDROLYSIS RATE C O S imine is primarily S K with ~ a possible small S N 1 STASTS contribution. The comparable reaction of ethylenOK fiki $kat Oko imine is probably exclusively S ~ 2 . l ~ Imine (Hz0) (corr.) (E) (SS)C Our results also indicate that the equations 2,2-Dimethylethylrn7.179 7.703" 7.312 7.642 which have been p r e ~ e n t e d ~ zfor ' ~ the correlation 2-Ethylethylen8.083 8.216' 7.858 8.182 of nucleophilic displacements, can be used to estiEthylen7.898 7.898 7.B60 7.812 ~ in certain mate amounts of S N 1 and S N character a Corrected using product analysis b y potentiometric solvolysis reactions. When combined with data method. Corrected using product analpsi? b y fraction See d a t a in Table 111. distillation. on activation entropies, etc.,I2 this method shows values, for all three hydrolyses, are below the cor- promise of giving satisfactory answers to solvolytic responding values of ko from either correlation mechanism problems. (13) Compare G . J. Buist and H. J. I,ucas, THIS J O U R N A L , 79, equation, computed from the rates of the faster reactions. The ko values using the equation of 0157 (19571, a paper puhlished while this one was in preparation. Swain and Scottg are closer to the experimental PROVIDENCE 12, R. I.
[CONTRIBUTION FROM
THE
DEPARTMENT O F CHEMISTRY, THEUSIVERSITY O F
TEXNESSEE]
Synthesis of 12- (Dialkylaminoalkyl)-benzo [a]phenothiazines BY
PURNENDU
B.
T A L U K D A R ' AND
DAVIDA.
SHIRLEY2
RECEIVED JANUARY 16, 1958
A series of 12-(dialkylaminoalky1)-benzo[alphenothiazines has been synthesized for pharmacological evaluation. These compounds were obtained by thionation of various i\'-phenyl-a-naphthylamines and condensation of t h e resulting benzo [a]phenothiazines with dialkylaminoalkyl chlorides using sodamide. Several N-acyl and sulfone derivatives of the benzo [a 1 phenothiazines also were prepared
The past decade has seen considerable work on phenothiazine chemistry which was initially stimulated by the observations of Halpern3 and Charpentier4 on the antihistaminic activity of 10dialkylaminoalkylphenothiazines. More recently additional stimulus has been provided by the discovery of the effects of these phenothiazine types in treatment of mental illness. In spite of the large amount of work on pheno(1) Post doctoral Fellow 1957-58 on study leave from East India Pharmaceutical Works Calcutta ( 2 ) To s h o r n inquiries regarding this paper should be sent ('3) B N Halpern, Cotn+t rend SOL b i d , 140, 36'3 (19-16) ( 4 ) P Charpentier, Conlpl T e n d , 225, 306 (1917)
thiazine derivatives5 little attention has been given to the benzophenothiazines. We have undertaken in this Laboratory a study of reactions and reaction products of the various benzophenothiazines. The present paper describes the synthesis of some new derivatives of benzo [alphenothiazine with particular emphasis on the N-dialkylaminoalkyl types. Our initial objective has been the synthesis of compounds related to the therapeutically useful phenothiazine types. Thionation of N-phenyl-a-naphthylamine in the presence of iodine catalyst leads to benzo[al(5) 5 P \Tas,ie
C h ~ n iR
~ L 5T4 , 7 9 i i l O i l )
