July 5 , 1952
L~ROBI.4TICSUBSTITITTION AND [CONTRIBUTION FROM THE UNIVERSITY OF
3357
ADDITIOK
NOTREDAME]
A Molecular Orbital Theory of Organic Chemistry. V1.l Aromatic Substitution and Addition BY M. J. S. DEWAR^ RECEIVED SEPTEMBER 13, 1951 The results of Parts I-V are illustrated by their application to various reactions of aromatic compounds. It is shown that the predicted effects of annular heteroatoms and of substituents of all types on the rates of reaction and the orientation of the products agree qualitatively with the predictions of resonance theory. The present treatment leads also to semi-quantitative estimates of these effects, and of the relative rates of substitution a t various positions in even AHs. (The validity of such calculations has been discussed in previous papers of this series.) The reactivities of even AHs in Diels-Alder reactions, and in reactions with osmium tetroxide, can also be estimated, the results agreeing reasonably with previous calculations,6.Band their significance in connection with carcinogenic activity is discussed. The problem of o:p ratios, etc., in substitution reactions is considered.
In Parts I-V' of this series, a general discussion of organic chemistry was given in terms of MO theory. Here the results will be illustrated by their application to some specific chemical problems, namely, the substitution and addition reactions of aromatic systems. It will be assumed that the transition state (TS) in a substitution reaction has the configuration postulated by Whelax~d,~in which the carbon atom undergoing attack has undergone a change in hybridization to sp3and is consequently removed from conjugation : e.g. X
X Y
reagent. This effect is known experimentally; thus naphthalene substitutes mainly CY with electrophilic, radical and nucleophilic reagents. In the case of an even AH, AE, can be calculate I a t once from theorem 2 of Part 11' AEa = 28(aor
AE may
AE = C
4- A E ,
~ o a )
(2,
Y
a -2a a = (11)-'/~
OS)
The activation energy the form
+
where ao-, aos are the NBMO coefficients of the T S a t the points of attachment to the center of attack. Thus for a-substitution in naphthalene the NBMO coefficients are as indicated in (I)
then be written in (1)
where C is a coristant characteristic of the reagent and the replaced group and AE, is the difference in r-electron binding energy between the initial and transition states. For a given type of substitution (X, Y constant), the activation energy A E , and so the rate of reaction, will be determined only by differences in AE,. The transition state contains a mesomeric system similar to that in the initial state but lacking one carbon atom; in the case of electrophilic substitution i t carries a formal positive charge relative t o the initial state, in nucleophilic substitution a formal negative charge; in radical substitution there is no first order charge displacement. (a) Substitution in Alternant Hydrocarbons.-In substitution of an even AH, the TS is an odd AH; for substitution by the three types of reagent the TS will be an odd AH cation, anion or radical. Since these differ only in the numbers of electrons present in the NBMO of the TS, which MO has zero energy, the term AE, in (1) will be the same for substitution a t a given position in a given even AH by reagents of all three types. The orientation of substitution, and the relative reactivity of different even AHs, should then be similar for all three types of (1) For Parts I-V see TRISJOURNAL, 74, 3341 E. (1952). (2) Rally Lecturer March-April, 1951. Present address: University of London, Queen Mary College, Mile End Road, London E.I., England. (3) G. W. Wheland, TXISJOURNAL, 64, 900 (1942).
+
1
hence AE, = 2p(a 2a) = l.Slp. ,These energy differences AET may be called localization energies since they represent the energy required to localize reactive electronic groupings a t specific atoms in even AHs. Values for substitution in different positions in a number of aromatic hydrocarbons are given in Table I, in units of p. The smaller the localization energy, the more readily should substitution occur. The relative rates of substitution in different AH'S have not been measured, but predictions made from Table I agree qualitatively with the information available. Thus reactivity rises in the series benzene < naphthalene < phenanthrene < anthracene < naphthacene < pentacene. The orientations predicted from Table I again agree in almost every case with those observed; e.g., naphthalene (CY),phenanthrene (9), anthracene (9))naphthacene (5), pyrene (3), chrysene (6), 1,2-benzanthracene (7)) 3,4-benzpyrene (6).4 Triphenylene is an exception, substituting 2 rather than 1; however, the predicted difference in reactivity between the two positions is small and the 1-position is sterically hindered. A second exception is the FriedelCrafts acylation of 3,4-benzpyrene in the l-position,fiother substitution reactions giving 6-derivatives; it seems likely that in this case coordination with the electrophilic catalyst blocks the most reactive (6) position, leaving the next most reactive (1) position open to attack. Other cases are (4) For references see N. P . Buu-Hoi, P. and R . Daudel and C. Vroelant, Bull. roc. chirn., 16, 211 (1949).
5 55\~i 41v1
TABLE 1 LOCALIZATION ENERGIES IN UNITSOF 6
1.55,
1.26 1.p:
1.,81
2 25
1 1 73\
154
1J5\
68
163\J!yl
1
/2 08
I 1
l
/1.81
1 5 d
\/v
l l
1I
\ /
TI
\1.81
i
198
(!J,k,h i l /
/1.73
2 27
38
known where Friedel-Crafts reactions give unexpected products (e.g., acenaphthene), probably for similar reasons. Further work is desirable to check the predicted orientations in other ring systems, but i t seems already likely that they will in general prove correct. Such calculations would then be of some practical value since the study of polynuclear hydrocarbons has been hampered by the difficulty of ascertaining the orientations of their derivatives. (b) The Diels-Alder Reaction.-It is well known that many polynuclear aromatic hydrocarbons will undergo Diels-Alder reactions with active dienophiles such as quinone or maleic anhydride, and the evidence suggests that such reactions proceed by one-step processes through cyclic transition states ;
Brown5 pointed out that the energy difference between the initial and transition states should then TABLE I1 PARALOCALIZATION EXERGIES IN UNITSOF p, FOR THE MOST REACTIVE PARA P O S I T I O s S IN SOME ALTERNANTHYDRO-
Compound Benzene Phenanthrene Naphthalene
1.33 2.
2.08
1:4 1:4 1:4
1,2-5,6-Dibenzanthracene 5 : l O 1,2-7,8-Dibtnzanthracene 5:lO 1,2-3,I-Dibenzanthracene 5:lO Pentaphene 5:14 1.2-Benzanthracene 5:lO Anthracene 9:lO 1,2-Benznaphthacene /5:12 Naphthacene Pentacenc
(6:11 5:12
6:13
4.00 3.77 3.68 3.51 3.51 3.48 3.45 3.41 3.31 3.36 3.28 3.25 3.18
1:4 1:4 1:4 5:lO 5:lO 5:lO 5:14
5:lO 9:lO 5:12 6:11 5:12 8:13
Experimenta Points of
4.62 .... 3.82 . . 3.62 1:4 (?) 3.04 5 : 10 3.02 5:lO 3.00 5: 10 2 83 5:14 +8:13* 2.79 5.10 2.52 9:lO 2.33 6:ll 2.21 2.25 5:12 1.60 6:13
The compounds are arranged in order of increasing reactivity to maleic anhydride, insofar as this is knowzi. * As BrownChas pointed out, the monoadduct is a simple arithracene derivative, and should react more readily than pentaphene itself with maleic anhydride. In fact, only the double adduct can be isolated from the reaction, a
0-3
CARBONS Predictions This by Brown4 paper Points Points of of attack E / @ attack ElB
AROMATICSUBSTITUTION AND ADDITION
July 5, 1952
be related to the difference in 7r-electron energy between the parent AH and the AH, or pair of AH’S, obtained by removing the two carbon atoms a t which addition takes place. Brown estimated these puralocalimtion energies by an ingenious semiempirical method for a number of hydrocarbons and showed that in fact Diels-Alder reactions are observed only when the corresponding paralocalization energy is small. These paralocalization energies can also be estimated approximately by the NBMO method, since to a first approximation the paralocalization energy should be equal to the sum of the individual localization energies a t the two carbon atoms. Values so calculated are compared with the more accurate results of Brown in Table 11, and i t will be noticed that they show an excellent correlation with the accurate values and with the experimental evidence. (c) Oxidation with Osmium Tetroxide.-The oxidation of AH’S to dihydrodiols with osmium tetroxide is probably a reaction similar t o the DielsAlder reaction in that attack takes place simultaneously a t two atoms in the hydrocarbon, but in this case the steric requirement is that the atoms should be directly linked to one another, i.e., ortho and not para. The case of reaction should then run parallel to the n-electron energy difference between the parent AH and the AH obtained by removing those two atoms-ie., the ortholocalization energy. Brown6 has shown such a parallel to exist. Here again, the ortholocalization energies can be estimated by the NBMO method, though a little more complexity is involved. Suppose the atoms removed are s and t, and let atom s be also linked to atom r, atom t to atom u in the parent AH. Let the NBMO coefficients of atoms r, t in the odd AH obtained by removing atom s be a,, at, respectively; and the coefficients of atoms s, u in the odd AH obtained by removing atom t be b,, b,, respectively. Then i t has been shown1 that, to a first approximation, the orders of the various bonds are Pr8 = a, Pst = b, (3) Pat = at
Ptu
= bu
The two values for pst will not in general agree, since they are approximate only; we may take their mean (4)
3359
TABLE I11 ORTHOLOCALIZATION ENERGIES OF SOME HYDROCARBONS Most Ortholocalization energyb reactive Calcd. This Brown8 paper Hydrocarbon bond”
Benzene Triphenylene Saphthalene 1,2-3,4-Dibenzanthracene Anthracene Chrysene 3,4-Benzphenanthrenc 1,2-Benzpyrene Phenanthrene Pyrene
1:2 1: 2
3.53 3.38
3.46 2.99 3.26 2.68 1:2 3.24 2.70 5:6 1 :2 3.20 2.16 1 :2 3.12 2.08 3.10 2.23 1:2 3.08 2.02 B:7 3.07 2.15 9: 10 1:2 3.06 2.35 1,2-5,6-Dibenzanthracene 3:4 3.05 1.94 1,2-7,8-Dibenzanthracene 3:4 3.04 1.99 1,2-Benzanthracene 3.03 1.90 3:4 3:4 3.01 1.84 1,2-Benznaphthacene 6:7 3.01 1.74 Pentaphene a Both theoretical methods predict similar orientations for attack, and these agree with experiment in all cases that have been studied. * The definition of ortholocalization energy used here differs slightly from Brown’s, the value4 here being uniformly greater by 2 p.
results. If the oxidation involves a simultaneous attack a t two carbon atoms, it should take place a t the two atoms with the minimum combined localization energy; in lj2-benzanthracene, these are the 5,6-positions, the ortholocalization energy for these being less than the 7,12-para1oca1ization energy. Since oxidation gives the 7,12-quinone, one may deduce that the first step is rather a one-center attack by some electron-deficient cation which takes place a t the point with the smallest localization energy. The secondary attack should then take place in such a way as to give the most stable possible product; that is, a t the position of opposite parity to the first with the largest combined localization energy provided the product is a KekulC AH (in the case of ortho positions, this will be the ortholocalization energy calculated from (8); in other cases it will be the sum of the simple localization energies). These considerations lead correctly to the prediction that 1,2-benzanthracene should give the 7,12-quinone. Some further examples are given in Table IV; the case of 1,2-benznaphthacene is particularly interesting since i t is not a t all easy to predict on the basis of current theory whether the 7,14- (VII) or the 8,13-quinone (VIII) should be formed
The ortholocalization energy is then given1 approximately by EO = 2L3(Prs Pst P t u ) = B(2ar
+ + + + b. + 2bu) at
(5)
Values so calculated are compared in Table 111with the accurate values obtained by Brown and with the results of experiment; the agreement is qualitatively excellent.’ (d) Oxidation to Quinones.-The mechanism of oxidation of hydrocarbons to quinones is not known, but i t can be deduced from the preceding (6) R. D.Brown, J . Cham. Soc., 3349 (1950). (7) The use of the NBMO method to calculate ortholocalization and garalocatization energies involves a cruder approximation than its Us6 t d hrlclihte rlmple localilution energies b o a quantitative comerpendenrr would aot bo .rpcctrd in thr fermer camsL
VI1
VI11
(e) Biochemical Oxidation of Aromatic Hydrocarbons.-An analogous argument suggests that the biochemical oxidation of hydrocarbons to dihydroo-diols is a reaction akin to the osmium tetroxide oxidation, since it involves attack a t double bonds and not a t reactive meso positions; these reactions cannot therefore involve one-center attacks by radicals as some authors have suggested, HOwever,
33m
Vol. 74
TABLE IV to undergo addition rather than substitution with PREDICTED ORIENTATION A N D RELATIVE EASEOF ATTACK the usual electrophilic reagents. Both reactions will of course proceed through similar intermediate I N CrOc OXIDATION OF AROMATICfIYDROCARBOSS TO QUINONES
Hydrocarbon
Predicted quinone
Benzene 1,4 Saphthalene 1,4 Phenanthrene 9,10 Chrysene I,? Pyrene 3,s 3,lO 1,2-nenzatithr3cent. 7,12 AIIthracene 0,lO Naphthacene s,12 1,2-~etizonaplithuc~iie 8,l:: Pentacene t!,13
+
A E / @ for primary attack
2.31 1.81 1.79 1.(j7 1.51 1.35 2.10 I . 1r: 1 .09 0.80
Quinone formed .
I
1,4 9,lO 1,3 3,s 3,10 7,E 9,lO $12 Y,13
+
6,13
the reactions cannot be strictly analogous to the osmium tetroxide oxidations since the products are invariably truns-diols.* I t seems more likely that in this case the first step is an addition of some biochemical acceptor to a double bond to form a T complex, and that the latter then reacts with some nucleophilic reagent such as HO- or HzO to give a trans-diol derivative; the reaction would then be analogous to the usual electrophilic additions to olefins, which will be discussed in more detail in a later paper of this series. (f) Carcinogenic Activity.-A. and B. Pullman noticedg that carcinogenic activity is shown only by hydrocarbons having a phenanthrene structure with a bare 9,lO-bond which they called the K region of the molecule. They found a semi-quantitative correspondence to hold between carcinogenic activity and a theoretical quantity which they termed the total charge density of the K-region, this being defined as the sum of the bond order of the Kregion bond and the indices of free valency of the terminal atoms. It can be shown that the corresponding quantity in MO theory is linearly related to the ortholocalization energy of the K-region, beirig greater the less the ortholocalization energy. Accepting the empirical correspondencelo between bond orders and free valencies determined by the MO and VB methods, this result implies that the first step in carcinogenic action is an attachment of the hydrocarbon to some acceptor grouping in the eel1 by one-step addition to the K-region bond. Undoubtedly this in itself cannot be the basis of carcinogenicity, since many hydrocarbons with low minimum ortholocalization energies are noncarcinogenic; but i t does seem to eliminate from consideration free radical mechanisms for carcinogenesis. (It is still entirely possible that the preliminary association with cell constituents involves forniation of n-complexes rather than simple adducts, the more so in view of the arguments from biochemical oxidation which were considered above.) (g) Addition vs. Substitution.-Many reactive hydrocarbons, particularly the higher acenes, tend (8) Cf.Biochemical Society Symposia No. 5 ; Biological Oxidation of Aromatic Rings, Cambridge, 1950. (9) A. Pullman a n d B. Pullman, Acta de 1'Union litter. c / l e Cancer, 6, 57 (1948); Bull. SOC. chim. Bid., 31, 343 (1!)49); J.chim. p h y s . , 46, 212 (1940).
(10) C. A. Coiilson, P. Daudel and I @-naphthylamine> a-naphthylamine implies increasing =+=E activity in the series Ph < pnaphthyl < a-naphthyl as predicted from Table V. l7 The effect of * E substituent on the ease of a reaction such as substitution can be expressed in terms of its A * . Let the NBMO coefficient of the un(17) I t is easily shown that the effect of the & E group in this connection should run parallel t o its & E activity.
substituted TS a t the point of attachment of the substituent be a,, and the energy dtfference between the unsubstituted initial and transition states be LE”. Then the corresponding energy cliff erence LEs for the substituted TS is given approximately 1) \ Ah, = M o ( l
+- u ; 4 ’ )
*
-
(121
hote that ii the substituent is attached to an inactir-e atom, ar = 0 and L E , = AEo, as stated earlier. Note also that a, will be greatest for substitution in the ring bearing the substituent, so that the effect of the latter tends to be localized (cf. the effect of heteroatoms in heterocyclic systems). (j) +E Substituents.-The effects of +E substituents can be derived from those of equivalent * I: substituents in the same way that the properties of heterocyclic compounds were derived from those of equivalent AH’S. The effect will fall into two parts; the first identical with that for the equivalent &5 substituent, the second a measure of energy changes due to changes in charge density ‘it the heteroatoms. Since these will vanish (approximately) if the substituent is attached to a neutral XH, the effect of the +I{ substituent Iection, it is easily shown that the stabilizing effect 011 the odd SH ion S is given by AL
=
-It.+
i c,tE-a,[1
where (1, = b, u r
+- a,.l
I
I
1 iI
since the first-order perturbation energy vanishes, just as the total 7r-electron energy of RS, S being a n even AH, is to this approximation the same as the sum of the 7r-electron energies of R and S. However, in forming RCHZ, the zero energy A0 of CH3 remains unchanged, while all the bonding MO’s of R are depressed; whereas in RS, some of the bonding MO’s are depressed, others raised. The net effect is therefore much greater in the former case, and it can be estimated approximately as follows. Let the 7r-electron energy of R be A&, and its * E activity be A *. Then the nelectron energy of RCH=CH2, A&, is given ap1roximately by AE1 = AEO - 26
(15)
Let the n-electron energy of RCHz be A&. The NBMO coefficient of the methylene is given by (1 A *)-’’;. Hence
+
AEI
LE2
- 26( 1 + A * ) - I / ?
(16)
Coinbinitig (15) and (16)) the stabilizing effect of I< on CH3 is given approximately by A E = AEo - AEf
=.a(]
-(l+A4*)-l~l)
(17)
which is very approximately A’P. Hence A’ should be a measure of the stabilizing effect of the substituent. It is easily seen that the same should apply for ions. Although the chemical evidence is obscured by steric effects, i t does suggest that the stabilizing effect on both ions and radicals rises in the series Ph < ,&naphthyl < a-naphthyl < 9-anthryl as Table V requires. 11) -E Substituents.-The effects of -E sub-
July 5, 1952
3363
AROMATIC SUBSTITUTION AND -4DDITION
about by the inductive (+I) effects of the latter. Here similar conclusions will be reached by a simpler and more general argument, using the results obtained in section (h) above. Consider the TS for a substitution reaction; the carbon atom r a t which attack takes place is linked by four u-bonds, and since its environment will have relatively little selective influence on these, the charge density qr a t that atom will be approximately the same for various substitution reactions with a AE. = AEo - nb.P + 28(1 - (1 + A *)-'/z) (20) given reagent. Suppose the coulomb term of the where n = 2 for electrophilic, 1 for radical, and 0 for atom to be ar, and the charge density in the initial nucleophilic substitution. For substitution a t vari- state to be q:. Then the a-electron energy differous positions in the AH, the final term in (20) will ence AEr between the initial and transition states is remain approximately constant; also when b, = 0, given to a second approximation by AE, > AE,. Hence the substituent (CHz-) should AEr = AE; a r ( ~ 4:) (231 deactivate R to nucleophilic substitution a t all positions, and to radical or electrophilic substitution a t where AE: is the first approximation obtained prepoints of like parity to the point of attachment of the viously. Evidently this second-order effect leads substituent, and i t should accelerate radical or elec- to a selective activation of positions adjacent to hettrophilic substitution a t other positions. These con- eroatoms or heteroatomic substituents (with +I acclusions agree in general with current theory and tivity) if those positions were electron-deficient (low experiment although detailed quantitative informa- q') in the initial state; and to a selective deactivation tion is still lacking. The effect of replacing CH2- if those positions were electron-rich. Since u-bonds by a heteroatomic - E substituent can be discussed have low polarizabilities, we may take q. = 1 in only for electrophilic substitution which is fortu- (23) as a first approximation; and the charge distributions brought about by various substituents nately the most important case; we then have have been deduced in earlier papers of this series.' AE, = AEo - 2b.P + 2p(1 - (1 + A*)-'/l) From these considerations i t follows that positions a ( 1 + A *)-I (21) adjacent to cyclic heteroatoms or +E substituents The change has the effect of deactivating the whole should be selectively activated, and positions adjaof R to substitution, since the last termin (21) will be cent to - E substituents selectively deactivated, to roughly independent of the point of attack. The substitution. These conclusions agree with those predicted orientation of substitution remains unaf- reached previously16 and with experiment ; thus fected. This conclusion again resembles that the o :29'9 ratio is less than unity for substitution of from current theory. -E-substituted benzenes, and greater than unity (m) Activities of +E and -E Substituents.-It for substitution of +E-substituted benzenes, and is less easy to find concise definitions of +E or of the effect increases with the +I activity of the sub-E activity analogous to that of &E activity. stituent.'* The best measure seems t o be the difference ( A+) in It should be emphasized that this electronic inn-electron energy between RH and RCH2- for a fluence on o:p-ratios etc., may be outweighed by +E substituent R, and the difference ( A - ) be- steric effects or hydrogen bonding; such extraneous tween S H and SCHs for a -E substituent S. In factors have been discussed elsewhere.18 I t should the notation of the previous sections also be noted that similar factors may arise in ring systems other than benzene, and may even be trans.4' = 2P(l - (1 + A * ) - ' / * ) &as(l + A * ) - l mitted to neighboring rings; thus nitration of S quinoline gives comparable amounts of 5- and 8 4 A - = 2pb. bfa, (22) troquinoline, although the analysis given previS ously would suggest that the 5-position should be the sums in each case being over the heteroatoms in selectively deactivated; however, the 8-position is the substituents, and also over any carbon atoms only two bonds removed from the nitrogen, which whose electron affinities are appreciably altered by under the conditions of the reaction will be present + inductive effects. A quantitative test of (22) must as the highly positive ion 3"; selective inducbe deferred for lack of adequate data. (n) Ortho-para Ratios, etc.-The first-order tive deactivation of the 8-position might therefore treatment given above often predicts identical re- be expected. In the case of a-nitronaphthalene, activities for positions in moIecules which in fact where the nearest heteroatom is now three bonds are known to differ chemically; the ortho and para away from the 8-position, nitration gives predomipositians in monosubstituted benzenes are good ex- nantly l&dinitronaphthalene, in spite of the fact amples. This problem has been discussed else- that formation of this isomer must involve considwhere" and i t was shown that the discrepancies erable steric hindrance. could be ascribed to the changes in electron affinity NOTREDAME,INDIANA of carbon atoms adjacent to heteroatoms, brought (19) The factor 2 is a statistical factor allowing for the fact t h a t them
all. At an inactive position such a substituent should have no first-order effect. Consider now the differences in total a-electron energy between the initial and transition states for substitution of an even AH R , and of RCHZ-. Let CH2- be attached to atom s in the TS from R, the NBMO coefficient there being b., and let the energy difference be A&, AE. for R, RCHZ-, respectively. Then from (18) and (19)
+
+
(18) M. J
S Dewar, J Chcm S o c , 463 (1949).
a r e 2 o r t h o positions, b u t only one para.
