J o s e p h R. Robinson and Kenneth A. Connors School of Pharmacy University of Wisconsin Madison, 53706
Precise Kinetic Measurements for Identifying Organic Compounds
classical methods for the identification of organic compounds are described in detail in several well-known texts (1-4). During the past decade comes based upon this approach have begun to disappear from university bulletins, and have been replaced by courses that utilize, almost solely, spectral measurements for the identification of compounds. The spectroscopic techniques widely applied for this purpose are ultraviolet and infrared absorption, nuclear magnetic resonance (primarily proton resonance), and mass spectrometry. Such courses provide excellent training and preparation for modern organio chemical research and they are obviously indispensable. We regret, however, the loss from these courses of much of the traditional material, for it is in handling his own sample-especially its purification and derivatization-that the student develops much of his laboratory technique. Obviously, there will not be a return to the classical course design. We have lately felt, however, that some combination of spectral techniques with "wet chemistry" may prove to he a powerful teaching approach (and in fact this is just how many research problems are attacked). In particular, the wet chemical aspects should become more quantitative, both because they then yield more information, and because they provide more pertinent instruction. (Measurement of acid dissociation constants and determination of equivalent weights by a functional group method are examples.) In this context we have systematically introduced the rate constants of characteristic reactions as a property to aid in establishing the identity of organic compounds. This paper describes the principles upon which kinetic methods of identification are based.' Principles
Two approaches may be taken to the measurement of rate constants as criteria of identity The sample compound may itself be subjected to a reaction whose rate is studied. An example might be the study of phenols by measuring their rates of bramination. A derivative of the sample compound may be studied. For example, one might characterize amines by the rate of hydrolysis of their scetylamides.
Not all reactions undergone by a functional group can serve as bases for identification via rate studies.
Some general requirements can be written down 1 ) The reaction should be clean; that is, there should be no appreciable side reactions or subsequent reactions. There are two reasons for this requirement: first, if side reactions or secondary reactions can occur, they might vary in importance among the members of a series of compounds; second, the resulting rate constants would have little theoretical validitv. 2) The reaction must follow first-order br pseudo-first-order kinetics. This is because only a first-order rate constant can be evaluated without knowledge of reactant concentration, (The dimension of a first-order rate constant is time-'.) Since (presumably) the reactant identify will be unknown, its molecular weight and henceits concentration will be unknown. 3) Reaction conditions (solvent, temperature, ionic strength) should be common for the study of all members of the series. On the other hand, some adjustment can he made in experimental vsriahles (reactant concentration, method of analysis) to suit the particular sample, as long as these alterations have no influence on the rate constant. 4) A large number of compounds must be studied within each class, in order to provide a. substantial body of rate constants under common conditions. 5 ) The rate constants for a. series of compounds under common conditions must exhibit wide dispersion in magnitude, in order for the method to be discriminating.
One way to locate reactions for possible use is to survey known methods for quantitative functional group analysis. Although these may not be kinetically simple, their demonstrated success as analytical reactions at least assures that they are stoichiometrically satisfactory. Five classes of compounds have been studied thus far. Both approaches have been utilized, and all of the requirements listed are satisfied. Table 1describes these studies briefly and Table 2 shows some typical rate constants obtained. Several further systems were investigated and were abandoned when it was found that they did not meet some of the requirements; these reactions were the permanganate oxidation of side-chain aromatic hydrocarbons, diazotization and coupling reactions of aromatic amines, and hydroxamic acid formation by reaction of amides with hydroxylamine. Table 1.
No.
Class of oompound Alcohols Sugars
Several other examples of characterization by means of rate processes have been described, but these were either qualitative tests (as in the rate of osazone formation test for sugars) or not sufficiently systematic to be of practical value (6-7). Braude and Jackman (8)have reviewed kinetic methods for structure determination, in contrast with the present concern, which is with the identification of known compounds.
470 / Journal o f Chemical Educafion
Rate Studies for Compound Identification
Aliphptic amlnes Aliphatic esters Beneoate esters
Reaction Alkalinehydrolysisof their 3,5-dinitrobenzoate esters Oxime formation with hydraxylamine Acylation with cinn* mic anhydride Alkaline hydrolysis Alkaline hydrolysis
of sys- Disperterns sion.
Ref.
27
3,160
(9)
15
107
(10)
26
10,600
(11)
27
2,640
(IS)
36
1,640
(13)
Ratio of largest tosmallest rate constmt in the series.
Table 2. Second-Order Rate Constants for the Alkaline Hydrolysis of Some 3,5-Dinitrobenzoate Esters at 25.0% (9) Parent alcohol
Ester m.p. ('C)
10' k (M-I sec-I)
Mean
Av. dev.
Discussion
From the data presented in references (9-13) it is apparent that reaction rate constants can be useful in the identification of organic compounds. However, this is not the only benefit from such studies, since the approach also represents a valuable teaching mechanism. These studies provide a teaching tool for instruction in isolation, purification, and identification (wet chemistry), because each reactant must be subjected to some treatment prior to reaction. In addition, kinetic data treatment and some instrumental analysis are required. Equally important educationally is the chemistry that can be designed into the study. For example, an experiment in the series can be planned to elucidate a reaction mechanism, or to demonstrate structure-reactivity relationships. Both of these approaches have been utilized in the systems described here. Such studies can be designed as short-term research projects. From the point of view of a practical means for identification, reaction rates are attractive because compounds in a class, such as a homologous series or a set of compounds containing the same functional group, may have very similar physical or spectral properties while possessing greatly different chemical properties, especially reactivities. For example, consider identification of the isomers isobutyl formate and ethyl propionate (18). The boiling points for these esters are identical, but their rates of saponification differ by a factor of 140. Recall also that for esters the traditional approach requires saponification of the ester followed by separate identification of the acyl and alcohol components, which is unnecessary when using the kinetic approach. Thus, because of its potential for distinguishing between closely related compounds and its advantages of sensitivity, simplicity, speed and economy, rate measurements should become a useful adjunct to spectroscopy and to conventional methods of qualitative analysis. Of some importance is the amount of material required to identify the compound since frequently only small quantities are available for analysis. I n all of the studies reported here only milligram quantities of chemical are required to carry out the reaction, the exact amount depending on the detecting device.
An incidental benefit from these studies is the accumulation of extensive rate data for related compounds under identical conditions. Utilization of these data for analytical design, structure-activity relationships, and mechanistic implications has, to some extent, already been attempted (IS, 16,16). There are some undesirable features associated with these studies, although they do not detract from the original premise. Some of these drawbacks have been implied in the introduction under general requirements. Relatively high purity of starting compound is frequently necessary. Another potential problem is the number of variables and sensitivity of rate to these variables, so that very careful laboratory technique must be employed. For example, the rates of some of the reactions are pH-dependent. The dependency is logarithmic, and smaU errors in pH can create large errors in the resulting rate constant. Admittedly precise work is always advantageous in scientific investigations, but in these studies it is essential. Whenever possible, the experimentalist should re-determine the rate constant of an authentic specimen under the same conditions used for studying the unknown sample. Our experience with this approach in a formal classroom laboratory setting is minimal. Two students have employed the rate of oxime formation as an identifying test fur unkno1r.11sugars in graduate counc work, and another student 111m~~mployed thc r~iteof snponification as a confirmatory test for an unknown ester. In conclusion, rate measurements applied to the identification of organic compounds can be a sensitive and discriminating method used alone or in combination with other techniques. It is a powerful teaching mechanism, and possesses the further benefit of developing collections of data that have fundamental value in studying reaction mechanisms and developing analytical methods. Literature Cited (1) McErnnIN, S. M.. "The Charaatsriaation of Organic Compoundd' (2nd ed.).MaeMillan Co.,Nsw York. 1953. (2) WILD, F.. "Characterisation of Organic Compounds" (2nd ed.),Csmbridge University Preas. Cambridge. 1960. R. L.. FVBON. R. C.. A N D CURTIN.D. Y., "The Systematic (3) SHRINE=. Identification of Organic Compounds" (5th ed.),John Wilsy & Sons Ino.. New Yark. 1964. (4) VooeL. A. I., "A Textbook of Practical Organic Chemistry" (3rd ad.). John Wilev BSonsIna.. New York. 1956. (5) G m m * a ~ .G. A,. K n ~ u r n ,D. N.. AND HACKLEY. E., Anol. Chern.. 38, 1897 (1966). (6) Anwe. T.. H e * n ~ .E. A,, AND M m m , R. K.,ChcrnistAnolysl, 49,
."
7 2 nos", LA""",.
(7) DRAY, F., nlio Wmrar, I., And. Bioehcm., 34,387 (1970). (8) BnAnn., E. AND JIC=MAN. L. M., Chap. 15 i n "Determination of Organio Structures by Physiod Msthoda" (Editor*: R ~ ~ n n E. n , A. A N D NACHOD. F. A~sdemicPress.New York. 1955.
A.,
C.),
(9) Rosrmon, J . R . , Anol. Chcm., 39, 1178 (1967). (10) MIIKEMON.T. J.; A N D ROBINBOW, J. R.. J. Pha1111. SCI.., 57, 1180
\.""",. ,,.an*>
(11) H o ~ oW. . H., AND CONNOBB, K.A,, J. Pharm. Sri., 57, 1789 (1968). (12) SUN.S. AND Co~wona.K. A,. J. Phorm. Sci., 58, 1150 (1969). R. J.. R B ~ R A K 6.. ~AND , ROBINBOW, J. R.. J. Phwm. (13) WABHXOXN. Sci., 59,0000 (1970). (14) G o a a ~ ~ a E. m A., ~ , Phil. Mag., 2,538 (1926). (15) H o ~ oW. , H., AND CONNORB. K. A,. A n d . Chcm., 40,1273 (1868). (16) Roarssoa, J. R., a m Mmamor*,L. M., J. Om. Cham., 34,3630 (1968).
Volume 48, Number 7, July 1971
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