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Physical Organic Chemistry Approach from the physical chemistry side is now explaining some of the art of organic chemistry DR. JACK HINE, Georgia Institute of Technology, Atlanta, Ga. The past 20 years have witnessed a quiet revolution in the manner in which the typical organic chemist views his field. Organic chemistry in the 1930's was taught largely in terms of functional groups, with chapters of typical texts bearing such titles as Alcohols, Alkyl Halides, Carboxylic Acids. Today the trend is toward classification based on types of reaction mechanisms, with many newer texts, even at the elementary level, having such chapter titles as Electrophilic Aromatic Substitution, and Free Radical Reactions. Studies of organic reaction mechanisms by industrial organic chemists, almost unheard of a generation ago, are becoming common. Among academic investigators, the handful of pioneers in physical organic chemistry has been joined by as many new workers as in any other area of organic chemistry. The growing interest in the field has been reflected in the Journal of the Chemical Society's establishment of a separate section for physical organic chemistry (which is usually as large as the combined general, physical, and inorganic sections ). The creation of a similar section in JACS announced a few years ago was canceled because of difficulties in classifying papers, not because of lack of material. Physical organic chemistry is considered by most chemists working in the field to deal mainly with the mechanisms of organic reactions and the effect of structure on reactivity. Since the effect of structure on reactivity is discussed meaningfully only in terms of the reaction mechanism, and since reactivity data are often the best evidence for a given reaction mechanism, the two phases of physical organic chemistry have developed hand in hand. The reasons for the varying effects of substituent groups on reactivity in such cases as aromatic substitution re-
actions have been a matter for consideration and contention by organic chemists for almost a century. While elements of current theory may be found in many of the early proposals, it wasn't until the 1920's that physical organic chemistry was put firmly on the path that it has continued to follow to the present day. In that decade the development of a new electronic theory of molecular structure permitted Dr. C. K. Ingold, Sir Robert Robinson, and others to devise a theory of substituent-group effects that at first seemed designed largely to explain the available data on electrophilic aromatic substitutions (such as nitration, bromination, and Friedel-Crafts reactions), but that proved capable of correlating an ever-widening fraction of the facts of organic chemistry. The Ingold-Robinson theory of substituent effects involved assigning to any given substituent certain inductive, mesomeric, electromeric, inductomeric, and field effects that are measures of the tendency of the substituent group
Β
DR. JACK
HINE
is Regents' Professor of Chemistry at Georgia Institute of Technology. Receiving his Ph.D. in organic chemistry from the University of Illinois in 1947, Dr. Hine went to MIT as a research associate, then to Harvard in 1948 as a Du Pont postdoctoral fellow. lie went to Georgia Tech in 1949 as assistant professor of chemistry, was made associate professor in 1951, professor in 1954. Dr. Hine's main research is on organic reaction mechanisms and effects of structure on reactivity.
to donate and withdraw electrons. The application to organic chemistry of the theory of resonance and the molecular orbital theory made possible an alternate and perhaps more fundamental expression of substituent-group effects. The inductive, mesomeric, inductomeric, and electromeric effects are the influences that substituent groups have on the electron densities at other parts of the molecule due to the propagation through the molecule of the electron-attracting or -withdrawing properties of the group. The inductive effect and inductomeric (or polarizability) effect act through the molecule's single bonds, "inductive" referring to the influence in a molecule and "inductomeric" referring to the change in the inductive effect that takes place during a reaction. The mesomeric effect and the electromeric effect (the change in the mesomeric effect that occurs during reaction) act through multiple bonds, unshared electron pairs, and unfilled outer electron shells. The field effect acts through space. The study of organic reaction mechanisms also had a gradual and uncertain beginning. Its growth was stimulated by the introduction of several important concepts. One is the generalization that complicated reactions usually proceed by a number of simple steps, so that many reactions proceed via unisolable reactive intermediate species. Another is the subdivision of organic reaction mechanisms into two major classes (and often one or two minor classes). Thus, most organic reactions proceed either by a polar mechanism or a free radical mechanism. In polar reactions, adducts of electrophilic reagents (those seeking to coordinate with unshared electron pairs—acids) and nucleophilic reagents (those having unshared electron pairs that may be coordinated with some nucleus—bases ) are formed MAY
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theoretical progress in physical organic chemistry has been New Synthetic Procedures Resulting from Theoretical Advances. From the effect of dissolved 2,4,6-trimethylbenzoic acid on the melting point of sulfuric acid, Dr. H. P. Treffers and Dr. Louis P. Hammett concluded that four particles were formed for every molecule of organic acid that dissolved. This could be rationalized on the basis of the reaction:
PH V 0 CH3-O-Cv+2H2S0r CH3 OH /CH 2 C H 3 - < 3 - C = 0 + H 3 0 + + 2HS04~
Working from this evidence for the "oxo carbonium ion," Dr. Treffers and Dr. Hammett discovered that the usually unreactive methyl ester could be hydrolyzed easily by being dissolved in sulfuric acid and poured into water. Subsequently Dr. M. S. Newman showed that solution of the trimethylbenzoic acid in sulfuric acid, followed by pouring into cold methanol, yielded the methyl ester, which had been made previously only by more cumbersome methods.
X
CH 3
H2SO.
CH3OH
CHCI3 + OH" ^ In another instance the great reactivity of chloroform (compared to methylene chloride or carbon tetrachloride) toward strong bases (but not toward weakly basic nucleophilic reagents such as iodide ions) suggested that first the trichloromethyl carbanion and then dichloromethylene were being formed as reaction intermediates. In aqueous solutions, the dichloromethylene intermediates are hydrolyzed further, some giving carbon monoxide and some formate.
RC02CH3
RCO
RC02H
CCI3"~ + H20
cci3""-*ci-c-ci + c r OH", H20 CI —C-C !
-*
COorHC0 2 "
Several steps
C6H5S
This suggestion was supported by the observation that chloroform was quite unreactive toward the thiophenolate ion (which is not basic enough to transform it efficiently to the carbanion) alone, but that in the presence of hydroxide ion chloroform reacted quite well with thiophenolate ion to give triphenylorthothioformate.
ci-c-ci
CH(SC6H5)3 H20
Several steps, as yet undefined
t-BuOK CHX3 — X-C-X Dr. W. v. E. Doering and Dr. A. K. Hoffmann subsequently put such dihalomethylene intermediates to good use in a rather general method for synthesizing certain cyclopropane derivatives. They found that when haloforms are dehydrohalogenated by potassium tertbutoxide in the presence of an olefin, the intermediate dihalomethylene adds to the olefin. 102
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M A Y 9, 1 9 6 0
R
R Vc x _= /
R
?
+CX2^R-C~C R
C S
R
R
V
/N
x x
transformed into new methods of synthesis The recognition of the benzyne intermediate has also led to the development of new synthetic procedures. Dr. John D. Roberts and coworkers demonstrated the intermediacy of benzyne in many of the reactions of haloaromatics with strong bases by showing that: • The reaction of sodamide with chlorobenzene-l-C 14 yields an equimolar mixture of aniline-l-C 14 and aniline-2-C14.
H I H-C I H-C
VI
H I
OCI II C H
A* NaNH2 H-C I
\r
1 H \ NH3
H
• The introduction of deuterium atoms into the ortho position of chlorobenzene decreases the reaction rate. • Halides such as halomesitylenes, which have no hydrogen ortho to the aromatic halogen atom, are quite unreactive.
NH3/ H
Among the most striking of the new syntheses based on benzyne is Dr. Georg Wittig's and Dr. Renate Ludwig's one-step synthesis of
triptycene from o-bromofluorobenzene and an-
S
H
1
1
A*
H- C I H-C
C-NHP 2
VI
C IIIbenzyne
II C-H
A* H-Ç
C-H
H-C V C-NH 2 I H
H
thracene. This replaces the brilliant but difficult multistep synthesis of Dr. Paul D. BartJett
and coworkers.
^CH
^
A knowledge of reaction mechanisms was an essential tool in working out the configurational relationships between optically active compounds, including most natural products. One of the most important types of reactions used in establishing these relationships is nucleophilic substitution at saturated carbon. Such a reaction involves the replacement of one nucleophilic reagent attached to carbon by another. Most such reactions proceed by one of two mechanisms: The Sxl (substitution, nucleophilic, first order) mechanism is a two-step process. In the first step the original nucleophilic reagent simply departs with its bonding electron pair, leaving behind a carbonium ion. In the second, usually quite rapid, step, this carbonium ion combines with the new nucleophilic reagent. ^ The Sx2 mechanism is a one-step process that is usually second order kinetically. Here, the entering nucleophilic reagent attacks carbon from one side and knocks the old nucleophilic reagent attached to the other side out of the molecule.
( Y Ji9 f i l ^
racene
ο VCH
Benzyne
Triptycene
CH3 I CH3-C-CI 3 I CH3
ÇH 3 CH-C® + 0H~ I CH3
CH, I 3 CH,-C® + CI" 3 I CH3 CH, 3 I CH3-Ç-OH 5 I CH, MAY
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and/or decomposed. Free-radical reactions involve the pairing and impairing of electrons. Applying these concepts to the study of organic reaction mechanisms led to the conclusion that some of the most important organic reaction intermediates are those containing carbon in an unusual valence state. These include carbonium ions (species in which there is a carbon atom with a positive charge due to having only six electrons in its outer shell), carbanions (in which there is a carbon atom with a negative charge due to having one of its outer electron pairs unshared), free radicals (with an unpaired electron due to a carbon atom with seven electrons in its outer shell), and methylenes or carbenes (with a divalent carbon atom). R 1 1 c®
/\
R R Carbonium Ion
R 1
R-C:3
tributed significantly to the success of an investigation. For example, principles of free radical chain reaction mechanisms were applied liberally by Dr. Morris S. Kharasch and collaborators in working out a host of new synthetic procedures. Dr. M. J. S. Dewar's brilliant inference that colchicine, stipitatic acid, and certain other natural products contain the tropolone ring was clearly based on the quantum mechanical theory of aromaticity. The application of physical organic theory has been important in the development by Dr. Herbert C. Brown and coworkers of a variety of specific reductions of various kinds of organic compounds by the use of hydrides. To mention an example of great industrial importance, the theory of chain reactions and of polar, steric, and radical stability effects on the reactivity of free radicals have been of the greatest importance in polymer research.
1 R Carbanion
R Current and Future Trends
1
1
c. /\ R R Free Radical
R—C—R Methylene
The contribution of physical organic chemistry to the more "useful" areas of the science, such as organic synthesis and the determination of the structures of natural products, has been of major importance. There are a number of instances in which the development of new synthetic procedures quite clearly followed a theoretical advance (often the discovery of a new reaction intermediate). The major contribution of physical organic to the other areas of organic chemistry, however, has been its effect on the modes of thought of the organic chemist. The modern organic chemist thinks of a new reaction in terms of its probable mechanism rather than just in terms of a classical "lasso" removing the elements of water or some other stable molecule from appropriate parts of the reactant ( s ). The greatest natural-product organic chemists of the day deduce structures on the basis of physical organic principles. In many cases it seems probable that new discoveries could have been made just as well by thinking in terms of functional-group reactions, but in other instances it seems clear that a knowledge of reaction mechanisms has con-
The correlation of organic chemical facts in terms of physical organic theory is, of course, far from complete —a fact that makes the field so interesting to study. Among the major chasms of ignorance is the field of heterogeneous reactions. Despite the tremendous importance of heterogeneous catalysis and the considerable amount of research that has been carried out in the field, our understanding of heterogeneous reactions is at a much lower level than that of homogeneous reactions. Among the trends that seem visible in physical organic chemistry is a greater use of physical measurements than in the past. Not only are infrared and ultraviolet spectral techniques used commonly, but new methods such as nuclear magnetic resonance and electron-spin resonance are providing information of a type hitherto unavailable. New apparatus, such as that for vapor phase chromatography, yields familiar data with a new degree of precision. In reactions where earlier investigators may have been satisfied to learn what intermediate was being formed in the rate-controling step, many physical organic chemists are currently trying to learn much more: to determine the intermediates in all of the steps and the relative
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C&EN
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heights of the various energy barriers; to learn as nearly as possible the geometrical location of every atom throughout every stage of the reaction; and to learn how changes in reactant structure, solvent, and other reaction conditions affect the energy barrier heights and molecular geometries. Pioneering advances in the quantitative correlation of the numerical data on rates and equilibria in organic chemistry are represented by the Brp'nsted catalysis law, Hammett's acidity function, and the Hammett equation for meta- and para-substituted aromatic compounds. As the mountain of available data continues to grow, new efforts are being made to find quantitative relations to fit the results in cases where correlations have not been made before and to correlate broader areas of knowledge by use of a single equation. In recent years, more and more physical organic chemists have begun to study the mechanisms of reactions of biological importance. Attempts are being made to learn the mechanisms of certain enzymatic reactions, sometimes by studies on the enzymes themselves and sometimes by studies of smaller molecules that are hoped to contain or give some clue to the nature of the enzyme's "active site." Such studies may lead to an understanding of the significance of the structures of biologically active compounds in terms of the mechanisms of the reactions that are responsible for their activities. Looking to the future, one can imagine a point where quantitative correlations have been developed to such an extent that the rates and yields of most of the new reactions that are run can be predicted in advance with reasonable precision; where the same quantitative correlations are used in designing the structures of pharmacologically active compounds. As many of today's questions are answered (or shown to be meaningless), the physical organic chemist of tomorrow will be investigating new kinds of problems and perhaps nearing an understanding of that long-studied organic reaction mechanism—life. One physical organic chemist has defined his field as that of "making a science out of the art of organic chemistry." Perhaps this point of view explains the great current interest in the field, for what more thrilling time could there be to study a subject than when it is being transformed into a science.
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