JOHN L. HASLAMAND EDWARD ill. EYRING
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Deuterium Oxide Solvent Isotope Effects on N-H.
- 0, O-H. - 'N,and
N-He - . N Intramolecular Hydrogen Bonds'
by John L. Has1am2 and Edward M. Eyring Department of Chemistry, University of Utah, Salt Lake City, Utah 84112
(Received June I d , 1967)
Equilibrium and kinetic solvent deuterium oxide isotope effects have been measured for tropaeolin 0, 2,4-dihydroxy-4'-nitroazobenzene, N,N-dimethylanthranilic acid, N-methylN-ethylanthranilic acid, N,N-diethylanthranilic acid, and 3,7-diaza-3,7-dimethyl-l,5diphenyl-9-hydroxybicyclo [3.3.l]nonane. The solvent kinetic isotope effects for the reacOH- + AHzO lie between 3.6 and -1.2 for these compounds. The tion HA rate constants measured in water by the temperature jump-relaxation technique for the various intramolecular hydrogen bond types overlap to some extent but roughly confirm an earlier generalization based on spectroscopic data that intramolecular hydrogen bonds have strengths that decrease in the following order from left to right: O-H. . . N > O-H. -0 g N-H. .N > N-Ha . -0. The kinetic data emphasize that structural variations in a molecule near its intramolecular hydrogen bond have a greater impact on the reactivity of the bond than the fact, say, that it is an O-H- .Nrather than an O-H. bond.
+
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Introduction We have previously conducted temperature jumprelaxation method3 rate studies of the reaction
+ OH- kza'_ A2- + HzO
HA-
(1)
0
acids? The results to be presented here provide tentative answers to these questions. Since N-H- * and N-H. . N hydrogen bonds play an important role in protein conformations, the data given below on elementary kinetic steps may also provide insights to enzyme reaction mechanisms. 4
0
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in water and DzO solutions of many dicarboxylic (1) This work was supported by the Directorate of Chemical Sciences, The specific rate kz3' of this reaction was Air Force Office of Scientific Research, Grant AF-AFOSR-476-66, by found to be inversely proportional to the pK. of the the National Institute of Arthritis and Metabolic Diseases, Grant AM-06231, and by the University of Utah Research Fund and was second acid proton. Small second acid dissociation presented in part at the 151st National Meeting of the American constants in these acids have been widely attributed Chemical Society, Pittsburgh, Pa., March 1966. to a strong O-H . 0 intramolecular hydrogen bond in (2) This is an essential portion of a thesis submitted to the Chemistry Department, University of Utah, in partial fulfillment of the require the monoanion of these acids.8 Our kinetic results ments of a Doctor of Philosophy Degree, 1966. raised the following questions that could best be (3) G. Czerlinski and M. Eigen. 2. Elektrochem., 63, 652 (1959). answered by analogous studies of acids containing (4) J. L. Haslam, E. M. Eyring, W. W. Epstein, G. A. Christiansen, and M. H. Miles, J. Am. Chem. SOC.,87, 1 (1965). N, and N-H N intramolecular N-H .0, O-H (5) M . H. Miles, E. M. Eyring, W. W. Epstein, and R. E. Ostlund, hydrogen bonds : How valid are generali~ations~~'~ J . Phys. Chem., 69, 467 (1965). regarding the relative strengths of various types of (6) J. L. Haslam, E. M. Eyring, W .W. Epstein, R. P. Jensen, and hydrogen bonds? Is the solvent DzO kinetic isotope C. W. Jaget, J . Am. Chem. SOC.,87,4247 (1965). effect for proton transfer between a nitrogen and an (7) M. H. Miles, E. M.Eyring, W. W. Epstein, and M. T. Anderson, J . Phys. Chem., 70, 3490 (1966). oxygen atom markedly larger than for a similar proton (8) For a bibliography see L. Eberson and I. Wadso, Acta Chem. transfer between two oxygens? Does a relationship S a n d . , 17, 1552 (1963). between pK. and kZ3texist for nitrogen acids in aqueous (9) C. A. Coulson, Research (London), 10, 149 (1957). solution similar to that observed for the dicarboxylic (10) H. H. Freedman, J . Am. Chem. Soc., 83, 2900 (1961). a
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The Journal of Phgsical Chemistry
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DEUTERIUM OXIDESOLVENT ISOTOPE EFFECTSON HYDROGEN BONDS
The compounds selected for investigat>ion were tropaeolin 0 (I), 2,4-dihydroxy-4‘-nitroazobenzene (11), E,N-dimethylanthranilic acid (111) , N-methyl-Nethylanthranilic acid (IV), N,N-diethylanthranilic acid (V), and 3,7-diaza-3,7-dimethyl-l,5-diphenyl-9-hydroxybicyclo 13.3.1Inonane (VI).
4471
k~ = 4.8 X 105 M-’ sec-’; and for 111, k , = 1.2 X lo’ M-’ sec-1.
Experimental Section Tropaeolin 0 was purchased as the 2,4-dihydroxy-
azobenzene-4’-sulfonate sodium salt from Matheson Coleman and Bell and was used without further purification. 2,4-Dihydroxy-4’-nitroazobenzene was purchased from Matheson Coleman and Bell and recrystallized I from aqueous methanol, mp 199-200” (lit.15 199-200”). N,N-Dimethylanthranilic acid was prepared by the method of Edsall and Wyman16 to give white needles, \-I 68,70”). N-Methyl-N-ethylanthramp 71.5” Il nilic acid was prepared according to the procedure of Edsall and Wyman16 for the preparation of N,N-dimethylanthranilic acid except that N-ethylanthranilic acid was used instead of anthranilic acid as the starting material. This gave the N-methyl-N-ethylanR thranilic acid methyl ester which was hydrolyzed in III, R-CH,, R’9 CH, dilute sodium hydroxide solution and neutralized to IV,R CHB, R’ * CZH, Me Me pH 7, after which the water was evaporated under V, R CZH,, R’ CzH6 VI vacuum. The acid was extracted from the acid-salt mixture with boiling ethyl ether and the extracts were In the case of compounds I and I1 the hydrogen bond treated with activated charcoal. Upon cooling in an is of the form” 0-H N, whereas in compounds 111-V acetone-Dry Ice bath, white crystals precipitated which it is assumed to be of the 0. -H-N type. The basis were filtered and melted at 68”. Anal. Calcd for for this assumption is the measured zwitterion to neuCloHla02N: C, 67.02; H, 7.31; N, 7.82. Found: C, tral molecule ratio in water of lo4to 1 reported for N,NH, 7.36; N, 7.72. 67.08; dimethylanthranilic acid by Cohn and Edsall.12 The N,N-Diethylanthranilic acid was synthesized by high solubility of 111-V in water and their lack of abfirst preparing the hydrobromide of S,N-diethylansorption bands between 2500 and 3000 cm-’ in contrast thranilic acid ethyl ester. This was done by allowing to N-ethylanthranilic and anthranilic acids also indicate equimolar amounts (0.2) of N-ethylanthranilic acid a zwitterion. ethyl ester and ethyl bromide to react in a pressure Chair forms are assumed for the two six-membered bottle which was placed in a boiling water bath for 24 rings in compound VI with consequent N+-H. .N hr. Upon cooling, about 0.5 g of the hydrobromide of and not M+-H. hydrogen bonding. This choice is %,N-diethylanthranilic acid ethyl ester precipitated. based primarily on the well-documented greater stability of the chair over the boat form in the general c a ~ e . 1 ~ The crystals from several runs were collected and hydrolyzed with a dilute sodium hydroxide solution; after We have also found experimentally that the 0-H neutralization to pH 7 the water was evaporated under stretching frequencies of the mono- and diprotonated vacuum. The acid was extracted from the salts with forms of VI in nitromethane as well as of the free base in boiling ether, and, after concentrating and cooling of CCI, are all very sharp, strong peaks occurring between 3600 and 3680 cm-’. If the hydrogen of the hydroxyl group interacted with a nitrogen in a boat conformation, (11) M. Eigen and W. Kruse, 2.Naturforsch., 18b, 857 (1963). this peak should broaden and shift to longer wave(12) E.J. Cohn and J. T. Edsall, “Proteins, Amino Acids and P e p tides as Ions and Dipolar Ions,” Reinhold Publishing Corp., New lengths. York, N. Y., 1943,pp 96-99. Rate constants for reaction 1, where HA is a dianion (13) J. Hine, “Physical Organic Chemistry,” 2nd ed, McGraw-Hill in the case of compound I, a monoanion in 11, and a Book Co., Inc., New York, N. Y., 1962,pp 37,38. neutral acid molecule in the case of 111, have been (14) M . Eigen and E. M. Eyring, J. Am. Chem. Soc., 84, 3254 measured previously for I, 11, and I11 in water11*14 (1962). (15) I. M. Heilbron, “Dictionary of Organic Chemistry,’’ Vol. 111, using the temperature jump-relaxation method. Oxford University Press, New York, N. Y., 1934,p 129. Eigen’s results, all at 12” and in 0.1 M ionic strength (16) J. T.Edsall and J. Wyman, J , Am. Chem. Soc., 57, 1964 (1935). solution, were: for I, k23I = 3.6 X 106 M-’ see-1; for 11, (17) R. Willstatter and W. Kahn, Ber., 37, 409 (1904).
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Volume 71,Number 13 December 1967
JOHN L. HASLAM AND EDWARD XI. EYRING
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Table I : Ionization Constants" Determined in Water and Deuterium Oxide at 2.5 i 0.1' Hz0
Dz0 Methodc
Acid
pKaM
pKsT
pKaM
pKsT
APK~
2,4-Dihydroxy-4'-nitroazobenzene 2,4-Dihydroxyazobenzene-4'sulfonate sodium salt X,N-Dimethylanthranilic I\'-Methyl-N-ethylanthranilic N,N-Diethylanthranilic 3,7-Diaza-3,7-dimethyI- 1,5diphenyl-9-hydroxybicyclo [3.3.1]nonane
11.67f0.02
11.91
12.31f0.02
12.58
0.67
S
12.01&0.03
12.41
12.61&0.02
13.06
0.65
S
8.51 f 0.02 9 39 f 0.02 10.46f0.02 6.22 f 0.02d 8.84 i.0.02'
8.59 9.47 10.54 5.98 8.76
9.12f0.02 9.94 =t 0.02 11.02~0.02 6.93 f 0.03 9.41 f 0.03
9.21 10.03 11.11 6.66 9.32
0.62 0.56 0.57 0.68 0.56
P P P P P
'Tabulated as -log K =pK. Equations 2 4 in the text show relationships between KaM= aE+[zk-] /[HA] and KaT = UH+UA-/UHA, where a ~ denotes + hydrogen ion activity, [A-] denotes the monoanion concentration, etc. The mixed constants KSMwere determined in solutions having an ionic strength adjusted to 0.1 M with KN03 a t the titration midpoint. The mean deviations are based on from seven to as many as sixteen independent determinations. a ApK 3 pKD - pKH, where D and H denote DLOand water as solvents and the con:,tants are thermodynamic, pK,T. S, spectrophotometric; P, potentiometric. pK for the dissociation of the acid H2A2+. e pK for the dissociation of HA+.
the ether solution, white crystals precipitated, mp 124(3) 125' (lit.'&120-121"). pKaT = pKaM f 5 logy* (4) I n the case of 3,7-diaza-3,7-dimethyl-l15-diphenyl-9hydroxybicyclo [3.3.l]nonane, the dipicrate was preThe values used for y* in 0.1M ionic strength solutions pared according to the procedure of Hohenlohewere 0.83 and 0.81 for water and deuterium oxide, reOehringenlg to give yellow crystals, mp 235-238" dec spectively. The thermodynamic acid dissociation con(lit. l9 234--236"dec). The diperchlorate was prepared stant KaTfor compounds I and I1 was calculated using by addition of 7Oyoperchloric acid to an ethanol solueq 4 and 3, respectively, with the minus sign since the tion of thch free base which precipitated in small white hydroxyl proton in the 4 position is more acidic than crystals on addition of enough ethyl ether to produce that of the 2 position. Equation 2 with a minus sign turbidity and with cooling. Anal. Calcd for GIH,was used for compounds 111-V using an activity coef0sNzC12: C, 48.19; H, 5.39; N, 5.35; C1, 12.55. ficient of unity for the zwitterion. Equations 3 and 2 Found: C, 48.35;H, 5.63; N, 5.31; C1, 12.83. were used with the plus sign in calcuiating the first and Heavy water (99.7%) was obtained from Columbia second pK's respectively, for VI. The ionization conOrganic Ciiemicals. stants and the equilibrium isotope effects ApK, Le., In the case of compounds 111-VI, the acid dissociapKD - pKH, are shown in Table I. tion constants of Table I were determined by potenThe temperature-jump equipment and experimental tiometric 1,itrations using a Radiometer pH apparatus. procedure have been described previ~uslg.~-~ The procedure has been described previously.*-' SpecThe three equilibria involved in basic solution are trometric titrations were carried out on compounds I shown in the reaction scheme and I1 using a procedure described by Albert and Ser3 kr3' 3' jeant.20 The solutions were made 0.1 M in total ionic HA InHzO AHIn HzO strength and 0.02 M in buffer concentration, the reka'3 mainder heing KN03. At high pH where suitable buffers were unavailable the ionic strength was the HA HIn 2 sum of 0.01 M IO-H...O~N-H...N>N:-H...O. This order is the same as that proposed by Freedmanlo on the basis of spectroscopic evidence for a different, larger set of compounds. This agreement lends support to the assumption that kat is a semiquantitative measure of intramolecular hydrogen-bond strength. However, rather than being a telling confirmation of the generalizations regarding relative hydrogen-bond strengths made by Freedman and others, our kinetic data emphasize that structural variations in a molecule near its intramolecular hydrogen bond have a greater impact on the strength (reactivity) of the hydrogen bond than the fact, say, that it is an 0-Ha . . N rather than an 0-He . .O bond.
Acknowledgment. The authors gratefully acknowledge helpful conversations with Professors L. L. MCCoy, M.M. Kreevoy, E. L. Allred, and G. G. Hammes. (30) T. C. French and G . G. Hammes, J. Am. Chem. SOC.,87, 4669 (1965). (31) E.M.Eyring and J . L. Haslam, J.Phys. Chem., 70, 293 (1966)., (32) C. A. Bunton and V. J . Shiner, Jr., J. Am. Chem. SOC.,83,3207 3214 (1961). (33) (kH/kD) I
(kH/kD)exptl/
(kH/kD) 1 1 .
Volume 71, Number 13 December 1967
