PSU CHEM 408 - A Survey of Hammett Substituent Constants and Resonance and Field Parameters

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Chem. Rev. 1BBl. 97, 165-195 165 A Survey of Hammett Substituent Constants and Resonance and Field Parameters CORWIN HANSCH,*,+ A. LEO,+ and R. W. TAFT* Depertment of Chemistry, Pomona Coikge, Ciaremnt, Caiibia 9 171 I and Department of Chemistry, Universky of California, Idne, Imine, California 927 17 Received August 9, 1990 (Revised Menuscript Received December 17, 1990) Contents I. Introduction A. Fleld/Inductlve Parameters B. Resonance Effect Parameters C. R+ and R- Values D. Resonance Effect a, Values from NMR Chemlcal Shifts of Para-Substituted Fluorobenzenes Relatlve to Their Meta Isomers as Internal References E. Calculated 6, and up Values and Shortcomings I I. Discussion I I I. References 165 166 177 187 188 190 191 192 I. Intralucton The Hammett equation (and its extended forms) has been one of the most widely used means for the study and interpretation of organic reactions and their mechanisms. Although the Hammett methodology has been criticized by theoreticians because of its empirical foundation, it is astonishing that u constants, obtained simply from the ionization of organic acids in solution, can frequently predict successfully equilibrium and rate constants for a variety of families of reactions in solu- tion. Almost every kind of organic reaction has been treated via the Hammett equation, or its extended form. The literature is so voluminous and extensive that there is no complete review of all that has been accomplished. Hammett's success in treating the electronic effect of substituents on the rates and equilibria of organic reactions1P2 led Taft to apply the same principles to steric and inductive and resonance effects? Then, more recently, octanol/ water partition coefficients (P) have been used for rationalizing the hydrophobic effects of organic compounds interacting with biological systems? The use of log P (for whole molecules) or n (for sub- stituents), when combined with electronic and steric parameters, has opened up whole new regions of bio- chemical and pharmacological reactions to study by the techniques of physical organic chemistry.sf3 The combination of electronic, steric, hydrophobic, hydrophilic, and hydrogen-bonding7 parameters has been used to derive quantitative structure-activity re- lationships (QSAR) for a host of interactions of organic compounds with living systems or parts thereof. The binding of organic compounds to proteins,8 their in- teraction with enzymess and with cellsloJ1 and tiasues,12 their inhibition of organelles,l' and as antimalarial^'^ + Pomona College. t University of California Irvine. 0009-2665f9 110791-0 165$09.50/0 and antitumor agents,loJ4 their action as hypnoticslSJ6 and anesthetics,17 as well as their use in pesticide de- sign,'* in toxicology,1s in mutagenicitym and carcino- genicity21 studies, their fate in metaboli~m,2~!~~ in en- vironmental ~ystems,2~ and their behavior in chroma- tographic system^^^*^^ have all been treated via QSAR. The explosive growth of correlation analysis of bio- logical processes via substituent constants has some- what changed the focus in the development of u con- stants. Until the 1960's the use of substituent constants was almost entirely in the hands of physical organic chemists who generally worked with "well-behaved" substituents to analyze highly refined data from reac- tions in homogeneous solution. Their goal was to obtain very precise correlations and understanding for clearly defined but limited organic reactions. Applications of QSAR to biological systems, drugs, pesticides, toxicol- ogy, etc. brought under consideration much wider structural variations (including less well-behaved sub- stituents) and activity data (dependent variables) of much lower quality. Noise in the biological data in the range of 20 to 100% was common so that small errors in u and n, became less significant for this work. Re- searchers in these fields required parameters for a much wider variety of structure and were willing to accept a lower precision if necessary. This shift in emphasis led Hansch and Leo to compile and publish in 1979, a truly comprehensive data base of substituent constant^.^ During the following nine years many new substituent constants have been published, so that in this report we have been able to list both u, and a values for 530 different substituents (Table I). With t\e use of values derived from F NMR shifts of meta- and para-substi- tuted fluorobenzenes, the number is increased to over 660, including many substituents containing metallic atoms and highly interactive neutral and charged sub- stituents. Exner2 has also compiled an extensive list of u constants including examples where only a, or up is known, and he has attempted to evaluate their reli- ability. We have attempted to list all examples where both u, and u have been reported and where more than one set of values exist we have selected the set which in our judgement is the most reliable. In some instances of very doubtful reliability we have placed the values in parentheses. The values of u were defined by Hammett from the ionization constants of benzoic acids as follows (1) where KH is the ionization constant for benzoic acid in water at 25 "C and Kx is the corresponding constant for a meta- or para-substituted benzoic acid. Some of the benzoic acids are so insoluble in water that mixed solvents such as 50/50 water/ethanol must be used. These secondary values have been linearly related to ax = log Kx - log KH 0 1991 American Chemical Society166 Chemical Reviews. 1991. Vol. 91. No. 2 Hansch et aI. CWin Hansch in 1944 received his Ph.D. from New York Unlv- ersity in the field of synthetic organic chemistry. studying under Professor H. G. Lindwall. After a brief postdoctoral period with Professor H. R. Snyder at the University of Illinois. he joined the du Pont Co. and worked first on the Manhattan project at the University of Chicago and Richiand. WA. and then at the experi- mental station in Wilmington. LE. In 1946 he joined the Chemishy Department at Pomona College. where he has remained except for two sabbatical leaves, one in Professor Prelog's laboratory in Zurich and the other in Professor Huisgen's laboratory in Munich. His main interests in research have been the high-temperature dehydrocyclization reaction and the correlation of chemical struc- ture with biological activity. ./ .. iB / , --, Albert Leo was


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