Relationship between Rate of Addition O f bromine to Unsaturated Compounds and Dielectric Constant of Solvent J. GORDON HANNA and SIDNEY SlGGlA Olin Research Center, O h Mathieson Chemical Corp., New Haven 4, Conn.
b Quantitative correlations between the rates of bromination of unsaturated compounds and the dielectric constants of the solvent media are demonstrated. Also, based on the substituent constants of the Hammett relationship, it is shown how the particular solvent can be selected for the most efficient bromination of variously substituted compounds.
W
the differential reaction rate technique was used to analyze mixtures of unsaturated compounds by bromination, the primary means used to control the speed of the reaction a t a practical rate was the judicious selection of solvent system (18). In that study the relative rates of reaction in different solvents were water>methanol>acetic acid>carbon tetrachloride. This conformed to previous observations that addition of halogens to unsaturated linkages is enhanced by polar media (9, 11). Data showing the relative rates of bromination of unsaturated compounds have been presented (2, S ) , but quantitative correlations of addition rates with the polarity of the solvent system are not available. Such correlations are useful for the proper choice of solvent for specific applications in analytical work. The study described here was made to find correlations among the rates of reaction, the polarity of solvents, and the structures of unsaturated compounds. HERE
Table I.
EXPERIMENTAL
The procedure used has been described previously in detail (18). .I constant temperature of 25' C. was maintained in all cases. Rate constants were obtained from the slopes of the standard second-order rate plots. In the case of butynediol, the rate constants were calculated based on the initial slopes. The first slope, beside representing the rate for t'he addition of the first mole of bromine to the triple bond, also contains the contribution from the rate of addition of the second mole of bromine. However, because the addition of the second mole is slow compared with the addition of the first mole, the initial slopes are substantially straight lines and the rate constants calculated in this manner are satisfactory for the present purpose of comparison. RESULTS A N D DISCUSSION
The mechanism for the addition of bromine to unsaturated linkages is normally depicted in two steps.
/
\ /
6+
\
\ +/ C-C + Br/ I\
Solvent Water Formic acid lfethanol Acetic anhydride Acetic acid Carbon tetrachloride
690
solvent 78 57 33
(slow)
(1)
Br
Br
\+/ C-C
/
I\
+ Br-+
Br
\I / C-C / I\
Br (fast) (2)
Bromination Rate Constants Compared with Dielectric Constants of Pure Solvents
Dielectric constant of
6-
+ B r . . . . Br*
C=C
The first step involves an initiation of the reaction by the electrophilic attack by partially polarized halogen to form a carbonium ion as an intermediate and is the rate determining step. The carbonium ion then combines with the bromide ion to form the dibromide. Other anions present in the system such as hydroxide from water, methoside from methanol, and acetate from acetic acid may compete with the bromide in the second step, but the stoichiometry of consumption of bromine is the same in each case. Brominations are, in general, secondorder reactions. However, in acetic acid in the concentration region, 0.025J1, the reaction proceeds according to the third-order law (17, 1 9 ) ; in greater dilution, about 0.001.11, the region in which the present study was made, the second-order reaction becomes established (19). Stabilization of the transition state intermediate is achieved by interaction with solvent dipoles; therefore, the more polar the solvent, the faster the reaction is expected to be. This is shown by the data in Tables I and 11, where the reaction rate constants are compared with the dielectric constants of the solvents used. The dielectric constants used for the methanol-water mixtures (Table 11) were obtained from the data of lllbright and Gosting (1). Comparison of the data for butynediol and allyl propionate in the two tables shows that, although the rate constants increase as the dielectric constants of
Vinyl acetate
Allyl propionate
Isopropenyl acetate
Rate constants, liter mole-' min.-' Diethyl fumarate 1-Octene Hexadecene
Tetrachloroethylene
Too slow >2000
230 43
>2000
20 6
>2000 73
27 3
>2000
2
0.002
ANALYTICAL CHEMISTRY
Too slow
Too blow
3-Butyne1,4-diol 22
>2000
>2000
Too slou
>2000
>2000
Too slow
0 4
P
complex is more polar than the reactants, the reaction rate incremes with the dielectric constants. Plots of log k against ( D - 1):’(2D 1) for bromination reactions (Figure 1) show reasonably straight lines and the slopes indicate that there is a considerable increase in polarity in the transition state. These plots quantitatively verify the influence of the dielectric constant’ of the medium on the rates. Equation 3 is. in geneid, not valid for comparison of reaction rates in various solvents having different dielectric constants. I t is recognized qualitatively that electron-donating substituents in an olefin accelerate the combination with positive bromine. and electron-withdrawing substituents decrease the rate of addition. However, a method to predict quantitatively the bromination rate of a compound from its structure would be useful for choosing a medium to give the most practical rate. The most useful relationshi!) in this respect is that of Hammett (7, 8) for aromatic substituents.
+
2
Y
v -0 1
I
0
0 0.475
0.460
I
0.490
Figure 1. Relationship between rate constant and dielectric constant 0 C’ A
Methyl crotonic acid Butenenitrile Crotonic ocid Butynediol
the solvent mistures of methanol and water increase, the constants show more rapid reaction than is espected from the rates in the pure solvents. ‘The dielectric constants of the solvent mixtures are a measure of the overall or average dielectric properties of the i n d i u m ; locally, however, one of the comiionents niay esert more ionizing influence than the other. In the case of the carlwniuni ion. it appears that the water rnoleculcs esert the dominant stabilizing effect resulting in the more raiiid reaction indicated. AUso,by the same reasoning, the water molecules can enhance the seliaration of charges in the bromine molecules by solvation and theretiy increase the reaction rate relativr to the overall dielectric constant of the solvent mixture. 1,aidler and Eyring (14) pointed out that a plot of log k against ( D - I ) / 1211 1) for reactions in mistures of t\vo ;olvents, the dielectric constants of which can tie varied by altering the comliosition of mistures, produces a *traigh line for many ionization reactions. This evolve:: from the relation reacted too rapidly in solvent5 of lowest dielectric constants. For practical purposes, therefore, the total u for a compound can be calculated and, from the graph, a convenient dielectric constant and, subsequently, a solvent with this dielectric constant selected.
Bromination Rate Constants Compared with Dielectric Constants of Methanol and Water and Mixtures of Two Solvents
llielectric constant of
Solvent solvent Water 78 5 26pc AIethanoln 76 24 l C G AIethanola 68 3 i 87; lIethanolcL 62 48 gCc llethanolcZ 57 5 0 O r ; Llethanola 56 60 OwG AIethanola 52 59 8“; AIethanola 2000
22 20
>2000
. . . ...
242 42
39 1 >2000
... . . . . . . . .
130
>io00
13
>2000
.. .. .. . . ..
...
...
>2000
28 15
3.9
... ...
27 9.9 4.7
13 5.4 ...
...
2.3
1.9
..
43
0.2
Wt.-wt. basis.
VOL. 37, NO. 6 , M A Y 1965
691
Crotonic acid and methyl crotonic acid do not fall on the line of the D us. u plot (Figure 2) but require more polar solvents to obtain the reactivity predicted from the substituent constants. Hine and Bailey (10) found that crotonic acid reacts much more slowly with diphenyldiazomethane than m-ould be expect,ed from the polar substituent constant originally obtained from ionization studies. They explained this on the basis that some of the resonance due to conjugation of the carbonyl group with the olefinic grouli was lost in going to the transition state. In the present study, this explanation also applies that the effect should he more pronounced because there is a complete loss of conjugation in the bromination reaction and therefore a complete loss of such resonance. In summary, some generalizations concerning the selection of a solvent for the bromination of specific compounds, especially as applied to rate studies, can be made. For conjugated unsaturated carboxylic acids, a solvent of dielectric constant about 55, for exa,mple 50Y0 methanol, should be used, but’ for acids in which the carbonyl group is not conjugated with the unsaturated linkage, nonpolar solvents should be used. For olefinic compounds substituted with an amide or nitrile group, 707, concentration or higher in methanol up to pure methanol are appropriate. For esters,
solvents of lower polarity range, acetic acid to methanol are indicated. Because triply bonded compounds have more electrophilic character than olefinic compounds, their rates of bromination are relatively slower and, for this reason, water was a good solvent for butynediol. In contrast, olefinic compounds containing hydroxyl groups require the most nonpolar solvents and other conditions such as lowered temperatures are necessary. Compounds containing only the electrondonating alkyl substituents also require special conditions to slow the reactions sufficiently. For unsaturated compounds, mono-, di-, and tri-substituted with halogens, the corresponding solvents indicated are the least polar ones-pure methanol and about 60% methanol, respectively. The reactions of tetra-substituted halogen compounds are too slow even in the most polar solvents and these compounds require special conditions such as elevated temperatures. In each of these cases, additional suLstituents including alkyl groups in the same molecule contribute to the electronic character of the unsaturated bond and will alter the total u value. LITERATURE CITED
(1) Albright, P. S., Gosting, L. J., J . Am. Chem. SOC.68, 1061 (1946).
( 2 ) Anantakrishnan, S. V.)Ingold, C. K., J . Chem. SOC.1935, pp. 984, 1396.
(3) Anantakrishnan, S. Y.j Venkataraman, R., Ibad., 1939, p. 224. (4! Charton, L l . , J . Org. Chem. 26, 735 (1961). (5) Charton, M.,Sfeislich, H., J . A m , (‘hem. SOC.80, 5940 (1958). (6) Frost, A. A., Pearson, R. G., “Kinetics and Mechanism,” p. 130, %‘]ley, Sew York, 1953. ( 7 ) Hammett, L. P., Chem. Revs. 17, 125 119351. (8) Hammett, L. P., Trans. Faraday SOC.34, 156 (1938). (9) Hine, J., “Physical Organic Chemistrv,” D. 215.- McGraw-Hill. New Yock, 1$62. (10) Hine, J., Bailey, W. C., Jr., J . Am. (‘hem. SOC.81, 2075 (1959). (11) Ingold, C. K., “Structure and Mechanism in Organic Chemistry,” p. 658, Cornel1 Cniversity Press, Ithaca, 1953. (12) JaffB, H. H., Chem. Revs. 53, 191 (1953).
(13) kirkwood, J. G., J . Chem. Phys. 2, 351 (1934). (14) Imdler, K. J., Eyring, H., Ann. ‘Y. 1’. Acnd. Sci. 39, 303 (1940). (15) LIcDaniel, 1). H., Brown, H. C., J . Org. (’hem. 23, 420 (1958). (16) Price, \$’. C., (’hem. Revs. 41, 257 (1947). (17) Robertson, P. W., de la Mare, P. B. D., Johnston, W. T. G., J . Chem. SOC. 1943, p. 276. (18) Siggia, S., Hanna, J. G., Serencha, 5 . XI.. ANAL.CHEM.35. 362 (19631. (19) Walker, I. K., Robertson, P. ’W., J . Chem. SOC.1939,p . 1515. RECEIVEDfor review April 13, 1964. Resubmitted October 28, 1964. Accepted February 18, 1965.
Single Extraction Method for the Simultaneous Fluorometric Determination of Serotonin, Dopamine, and Norepinephrine in Brain ROBERT M. FLEMING and WILLIAM G. CLARK Psychopharmacology Research 1aboratories, Veterans Administration Hospital, Sepulveda, Calif., and Department of Biological Chemistry, University of California Center for Health Sciences, 10s Angeles, Calif. ERIC D. FENSTER’ and JACK C. TOWNE Veterans Administration Hospital (Research), and Department of Biochemistry, Northwestern University Medical School, Chicago, 111.
A method has been developed for a single solvent extraction and the simultaneous determination of serotonin (5HT), dopamine (DA), and norepinephrine (NE), in less than 1 gram of brain tissue in the presence and in the absence of relatively large amounts of their precursor amino acids and some related analogs. Essentially the method involves acetone extraction of the amines from brain homogenates; removal of the acetone by evaporation in vacuo;
692
ANALYTICAL CHEMISTRY
S
extraction of the residue with butanol saturated with 0.01 N HCI; addition of heptane to return the amines to an aqueous phase; passage of the aqueous phase through an ion exchange column which retains the amines but not the amino acids; and elution and fluorometric analysis of the amines. The endogenous amine content (pg.1 gram fresh tissue f std. dev.) found in 1 1 mouse brain pairs was: 5HT, 0.55 f 0.03; DA, 0.70 5 0.06;
to the roles of t h e biogenic amines 5HT, D-4, and NE in brain have been made possible by increasingly improved and sensitive means of determination. Present methods are capable of efficient extraction of just one or two amines by agents such as butanol (6, I ? , fg), acetone (1, 2, 9. l o ) , perchloric acid ( 5 ) , or trichloroacetic acid (Wf). However,
NE, 0.48
Ill.
f
0.03.
TUDIES RELATED
1 Present address, Department of Biochemistry, rniversity of Chicago, Chicago,
