John A . Young
Denver Research Institute University of Denver Denver, Colorado 80210
Fluorine Compounds as Teaching Aids in Organic Theory
Although the stigma of rote memorization traditionally attached to elementary organic chemistry has been considerably reduced by the development of systematic organic theory, it is still necessary to test beginning students at frequent intervals to determine whether their accumulating knowledge forms a coherent pattern or is only a piecemeal collection of facts. Many a student still falls victim to what might be called the aldol syndrome; he can write with great facility the equation for the condensation of two molecules of CHaCHO to give CH&HOHCHzCHO but is under the impression that the product from CHaCHr CHO should be CHaCH2CHOHCH2CH,CH0. Such a student perceives no common ground between this and other base-catalyzed carbonyl condensations, and regards the aldol, Perkiu, Claisen, Michael, Dieckmann, and Mannich reactions as completely unrelated phenomena. The problem of designing examination questions which differentiate between comprehension of principles and mere playback of recorded data continually confronts the instructor. Organic fluorine chemistry provides a wealth of untapped pedagogic resources useful for this purpose and rather more subtle than the customary device of introducing on the examination a homolog of the compound discussed in class. In a few of the more advanced textbooks (that of Kosower ( I ) is an excellent example), some illuminative results of fluorine chemistry are beginning to make their appearance, but such results have as yet scarcely breached the pages of introductory texts, although modern fluorine chemistry has progressed to the point where fluorocarbon analogs of organic compounds (e.g., C3F7COOHfor CaH7COOH) exist for most of the functional classes and structures discussed in an elementary organic course. By and large, an instructor can now substitute a perAuoro analog for a conventional organic compound with the assurance that he is talking about a real compound rather than a hypothetical one. The instructional value of employing fluorine compounds stems from the fluorine atom's unrivalled strength of inductive electron withdrawal, which on the basis of Pauling electronegativities exceeds that of chlorine by an amount equal to the diierence between chlorine and iodine. Because of this intense induction, reactions of highly fluorinated compounds often proceed with reversed polarity, relative to those of conventional organic compounds. Furthermore, whereas much of organic chemistry is built around the proton and positively charged species-many additions to carbon-carbon unsaturation, condensations dependent on addition or abstraction of a proton, proton shifts, acid-catalyzed reactions-fluorine chemistry is very often concerned with fluoride ion and nega-
tively charged species. As W. T. Miller of Cornell observed some years ago, "For unsaturated fluorocarbons, fluoride ion occupies a position as a nucleophile which is analogous to that of a proton as an electrophile for unsaturated hydrocarbons" (2). Fluorine compounds do obey the fundamental tenets of organic theory, but their frequent reversal of polarity, relative to hydrocarbon analogs, and the change in emphasis from a positive hydrogen ion to a negative fluoride ion allow the instructor to frame questions which demand reasoning rather than reiteration on the part of the student. Following are some areas of fluorine chemistry which are most fertile in this respect. Ammatic Substitution
The area par excellence is aromatic substitution. Almost all such reactions covered in an introductory text are electrophilic substitutions at a ring carbon, and students usually have little difficulty in learning the resonance structures which explain the m-directing and deactivating effect of the -NO2 group, the o,pdirecting and activating effect of -0hle or -NbIe?, and the o,p-directing but deactivating effect of halogen; however, they may fail to see why an ordinarily inert aromatic halogen atom can easily be displaced by other anions if it is situated ortho or para to nitro groups. In the looking-glass world of perfluoro aromatics, the relative importance of nucleophilic and electrophilic attack is opposite to that encountered in conventional aromatics. Substitutions proceed by nucleophilic attack, and both the directing and activating-deactivating properties of substituent groups are reversed, even though canonical structures show the same electron distribution and flow. The nitro group becomes strongly activating and p-directing, while -NhIet becomes strongly deactivating and m-directing. Direct nitration via nitronium ion is almost impossible, while aminntion nnd alkosylation prorwd so rrndily that disubstitution is wmetitnrs difficult ro avoid. \\'l~erens an amine group is normally introduced on a benzene ring by nitration followed by reduction, the sequence in hexafluorobenzene is the opposite; C6F5NHzis easily prepared but CeF5N02 is not directly accessible and must be made by subsequent oxidation of pentafluoroaniline. ~~
~~
~~
NO,
F
OMe
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- FO
NO,
F
F
NO,
F
F
F
F
+
NHs
NO,
F ~ N H B F F NH,
If one or two hydrogen atoms remain on the ring, both sets of reactionsnucleophilic and electrophilicare possible, and the optimistic syntheses which a heginning student might write are reflected to a rather surprising degree in practical utility. For instance, C6F6N02is best made by nitration of CsFsH rather than from C6Fsitself, but the fluorine atom para to the lone hydrogen is still amenable to displacement by nucleophiles. he-
F
~
F OMe
Table l .
Bond Eneraies lkcal /mole) I51
NO,
H
H
energy of reaction; consequently it often proceeds with explosive rapidity and very little selectivity. The calculations show that fluorination reactions may be self-starting, as the molecular initiation processes are almost thermoneutral, in contrast to those of other halogens; indeed, the presence of free fluorine in a gas stream can be detected by self-ignition of an unlit Bunsen burner. According to Tables 1 and 2, forma-
F
Table 2.
F F F
F
- ~F F
F
A simple but defensible analogy may be drawn concerning alkylation. Although FriedelLCrafts alkylation is obviously proscribed in C6F6, an analogous reaction in terms of an attacking anion rather than cation does succeed. Thus, as an isopropyl carbonium ion alkylates benzene by replacing a proton, a perfluoroisopropyl carbanion alkylates C6F5NO2(the activating group is necessary for reaction at moderate temperature) by replacing a fluoride ion. c
CF(CF,h
Hyperconjugation
-
Heats of Reaction (kcal /mole) (6)
X'+RH-HX+R'
XZ+ R'
RX
+ X'
AH=-3(X=Cl),-34(X=F) AH = -23 (X = Cl), -68 ( X = F )
tion of a carbon-fluorine hond is accompanied by release of enough energy to break a carbon-carbon bond, and fragmentation is therefore to be expected. Ionic Intermediates
Organic ionic intermediates-carhanions and carhonium ions-can be formed either by additive or eliminative processes, most often by addition or abstraction of a proton. In fluorine chemistry carbouium ions are
The concept of hyperconjugation, or "no honddouble bond" resonance, although having come under attack on theoretical grounds, remains a useful rationalization in explaining, for example, the ease of formation of the t-butyl carbonium ion. The same concept, with suitable change of polarity, can he used in the same way to explain the ease of formation of the perfluoro-t-hutyl carbanion from perfluoroisobutylene and fluoride ion, or the acidity of (CF,),CH. (For arguments against "negative hyperconjugation,"see references (3) and(4.)
Fluorination
Thermochemical data are often adduced to explain the greater selectivity and solvent sensitivity of bromination over chlorination. The differences are even more striking when fluorine, rather than chlorine, is used for comparison. The data for C-X and X-X bond energies, along with heats of reaction for the various processes involved, clearly show why elemental fluorination is much less discriminating than bromination, why carhon-carbon bond cleavage occurs with the former hut not with the latter, and why a molecular initiatiou process is likely with fluorine but highly unlikely with bromine. The reaction of elemental fluorine with an alkane has a lower energy of initiatiou than that of any other halogen, yet produces far more 734
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Journol of Chemical Education
CF,=CF,
COP, P-
CF,CF,COF
relatively unimportant since the strong inductive effect of fluorine causes destabilization, but perfluorocarbanions are obtainable by addition of fluoride ion to fluoroolefins, in a reaction analogous to the formation of conventional carbonium ions by addition of a proton to a hydrocarbon olefin. Fluoride ion also adds very easily to fluorinated carhonyl compounds to give stable, ionic alkoxides not accessible by other means. Within limits, such carbanions and heteroanions undergo
customary nucleophiiic reactions such as displacing halide ion from alkyl and acyl halides or adding to carbony1 groups. The last of these processes, whereby a perfluoroolefin can be converted successively to an acid fluoride, a ketone, and a tertiary alcohol, is somewhat equivalent to the traditional Grignard sequence of alkyl halide, carhonyl compound, and alcohol. The most ubiquitous reaction of fluoroolelins is cycloaddition; a great variety of cyclobutanes, oxetanes, and other fourmembered rings is accessible by this means. The tendency to undergo the symmetryforbidden 2+2 addition is so strong that fluorinated dienes do not act as dienes in the symmetry-favored 2+4 Diels-Alder reaction, althoughhhey do make good dienophiis. The introduction of fluorinated compounds in discussions of correlation diagrams and the Woodward-Hoffman rules for cycloadditions is very useful in showing how weakening of the pi bond can confer respectability on a level crossing, completely changing the observed course of reaction. Questions utiliiing these differences from conventional organic chemistry can be posed a t any desired level of difficulty. Why is (CF3)&OH more acidic than (CHa)aCOH? Predict the relative ease of hydrolysis of CFaCHzBr and CHaCH2Br. Account for the fact that perfluoroketones form stable gem-diols and gem-diamines. How could CBF5NHNH,be made from C6F6? How could tetrafluoro-o-phenylenediamine be made from C6F6? Rationalize the fact that bromine is 1600 times more selective toward tertiary hydrogen than is fluorine. (Given the bond energies of Table I), predict some side products from elemental fluorination of propane. Why does less fragmentation occur when cobalt trifluoride rather than elemental fluorine is used as a fluorinating agent? If fluorinated olefins react by nucleophilic rather than electrophilic attack, propose a mechanism for the addition of methanol to C F z 4 F e in the presence of MeONa. What product is formed when (CF&CO is first treated with fluoride ion and then with bernoyl chloride? Questions like these should be suitable for an elementary course; a t the other extreme of sophistication lie proof of structure, prediction of products, and deduction of mechanism for more elaborate reactions and molecules. Fluorine has very marked effects on infrared band frequencies (the carhonyl absorption for RFCOF appears a t 1870 om-', on nmr (both 19F chemical
shifts and coupling constants are greatly different from 'H values), and on mass spectra (because of the obvious mass difference between 'H and 19F). These effects all help in devising problems in which the instrumental data given are unfamiliar but which are susceptible to previously learned problem-solving techniques. The transposition of students into this peculiar land of fluorine chemistry, where the underlying rules are the same as usual but the conventions are entirely different, can effectively separate those who reason from those who do not. Students who memorize equations find themselves a t a complete loss, while those who understand principles sometimes enjoy the mental exercise, after an initial shock of bewilderment. The author has frequently used questions based on fluorine chemistry on examinations ranging from elementary organic to PhD comprehensives and orals. The results have usually been quite indicative of the student's depth of understanding of chemical principles. For those who may find intriguing the suggestions made here, but are unfamiliar with fluorine chemistry, there is no single complete compilation of results in the area. Sheppard's book (6),although not comprehensive, provides excellent coverage of the topics included and is very well annotated. A succinct account of the chemistry of hexafluorobenzene is given by Banks (7), hut no extensive discussion of this topic is available in one easily accessible source. The series "Fluorine Chemistry ReviewsJ' has good articles on hexa-fluoroacetone (8),fluoroalkyl ions (9),and cycloadditions of fluoroolefins (10,Il). Thermochemical data have been reviewed by Patrick (5). Kosower (I) includes a good many applications of fluorine compounds in his book on physical organic chemistry. Litemlure Cited (1) Kosowmn, E. M.,"An Intruction to Physical Organia Chemistry:' John Wilsy & Sons, Inc., New Yark,1968. , T. JR.. FRIED,J. H., AND GOLDWHITE.H..J . Amel. (2) M m ~ n W. Cum. Soo., 82, 2091 (1960). (3) S n z ~ ~ * n W n ,. A,, J . Amr. Cham. Soc., 87, 2410 (1965). D., J . Amcr. Chsnr. Soo., 89, 692 (4) STamTwresm, A. Jn., AND HOLT.TE. (1967). (5) PATRICK, C. R.,Ad.. Fluorine Chem.,2, 1 (1961). (61 SHEPPARO, W.A.. AND SXARTB. C. M., ''Organic Fluorine Chemiatry." W. A. BENJAMIN. Ino.. Nav York. 1969. (7) B m s e . R. E.,"Fluorocarbons and Their Derivativez:' Oldbourne Pram London, 1964. . J.. Fluorine Chsm. Rsu., 1. 145 (8) Kaeapm, C. G..A N D M m m e ~ o n W. (1967). (9) Y o m a , J. A,, Fluorins Chsm. Rm.,1. 369 (1967). (101 P E Z ~ Y D. , R. A,, muonm cham.RW.,I,253 (1867). W. H.,Fluorine Cham. Reu.. 2,1 (1968). (11) sx~nxm~,
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