the friedel-crafts acylation reaction iv. multiple substituent effect in the friedel-crafts...

Bull. SOC. Chim. Belges, 77 (1968) 273-285

T H E FRIEDEL-CRAFTS ACYLATION REACTION

IV. MULTIPLE SUBSTITUENT EFFECT IN THE FRIEDEL-CRAFTS ACYLATION OF TOLUENE WITH DISUBSTITUTED BENZOYL CHLORIDES

P.J. SLOOTMAEKERS and R. VERBEERST

Nous avons ttudib I’effet de substituants dans la reaction d’acylation de Friedel- Crafts dans le cas du toluene en solution dans I’ortho-dichlorobenzhe. Nous avons utilist des chlorures de benzoyle substitubs en position 3,4 et 3,s ainsi que le chlorure d’aluminium comme catalyseur. La relation de correlation de Hammett n’est pas verifike mBme pour des termes de la strie rtactionnelle portant des substituants en position 3 3 . De plus, dans cette strie de rtactions, I’effet des substituants est caracttrist par une dispersion pronon- cte mtta-para. Lors de I’btude d’une relation lintaire fonction de I’tnergie libre, on observe des tcarts importants au principe d’additivitk des effets de substituants compart a I’effet de substituant du chlorure de benzoyle. L’analyse des r6sultats rkvkle que aussi bien 1’Ccart par rapport a la relation de Hammett que 1’Cart par rapport au principe d’additivitt sont plus importants pour les termes de la dr ie de rtaction oh le groupe fonctionnel est le plus deficient en tlectrons. Ces termes semblent rtpondre en premiere approximation a une reaction de second ordre. Tous ces faits peuvent &tre interpret& en admettant I’existence de plusieurs agents d’acylation effectifs, dont I’un est de structure ionique, par exemple une paire d’ions, et dont I’importance relative dans la reaction globale d’acylation est dtterminte par les substituants prksents dans le chlorure de benzoyle.

INTRODUCTION

In a previous paper of this series [I], the substituent effect in the aluminum chloride catalyzed reaction of monosubstituted benzoyl chlorides with toluene in chlorobenzene solution has been studied.

Correlation of the relative reactivities by the Hammett relationship, including all members of the reaction series was not possible. A plausible explanation for the deviation of para-substituted compounds, in terms of ground state resonance stabilization, was given. Its validity however depends on the fact that meta-substituted compounds are very well correlated by the Hammett relationship. Due to the electron deficient nature of the catalyst of the reaction, all -M- or +M- substituents which might extend the reactivity domain have to be excluded, in order to obtain clean reaction kinetics. This fact severely limits the Hammett sigma-scale. A simple possibility to extend the Hammett sigma-scale, without changing the apolar nature of the substituents, is offered by the use of multiple substituted benzoyl chlorides. In this way the Hammett sigma-scale is extended from -0.25 to +0.8 sigma units. At the same time the additivity of thesubstituent effects in this reaction can be studied.

274 P. J. Slootmaekers and R. Verbeerst

RESULTS AND DlSCUSSJONS

Kinetic Results

On the basis of the equation RCOCI.AIC1, + ArH + Ar- (R)CO.AICl, + HCI, the reaction can be followed by determination of the amount of hydrochloric acid formed in the course of the reaction. Therefore, the hydrochloric acid was removed from the reaction mixture by a fast stream of dry nitrogen, absorbed in water in an especially designed titration vessel and titrated with a standardized caustic solution.

From these concentration-time data, second order rate constants have been determined for the reaction of fourteen 3.4- and 3.5-disubstituted benzoyl chloride- aluminum chloride addition compounds with toluene in ortho-dichlorobenzene solution. These results, together with the initial concentrations of the reactants, are summarized in table I.

TABLE I

with disubstituted benzoyl chlorides in ortho-dichlorobenzene (*) Second order rate constants of the aluminum chloride catalyzed acylation of toluene

Substituents

3,5-diMe 3 Me-5 CI 3.4 diMe 3 Me-4 CI 3 Me-4 Br 3,5 di t.Bu 3,5 diCl

3 CI-4 Me 3,4 diCl 3 C1-4 Br 3 Br-4 Me 3 Br-4 CI 3,4 diBr

3 C1-5 Br

1.25

0.506 3.28 3.74 1-04

11.0

28.3 28.1

15.5 14.9

14.8 15.0

4.53

4.59

0.374 3.294 0.151 0.983 1.12 0.312 8.47 8.41 1.36 4.64 4.461 1.37 4.43 4.50

(*) Experimental conditions: Benzoyl chloride-aluminum chloride 0.094 mole.1-l - toluene 0.706 mole. 1 -l, temperature 20 “C.

In a previous paper [l], chlorobenzene was chosen as the solvent. But in view of the expected high reactivity of some disubstituted benzoyl chlorides, chlorobenzene had to be replaced by the more inert orthodichlorobenzene. The former would be acylated in the experimental conditions of the reaction. In order to make possible a comparison with the previously published results in chlorobenzene solution, which is in fact the aim of this study, some representative monosubstituted members of the reaction series have been remeasured in ortho-dichlorobenzene. These results are given in table II.

Hammett relationship

Before proceeding in an examination of the correlation of the relative reactivities of the meta-substituted members of the reaction series in a Hammett relationship

Friedel-Crafts acylation reaction 275

over an extended sigma-domain, it must be shown that the meta- and para-substituted members of the reaction series exhibit the same behaviour in this solvent, ortho- dichlorobenzene, as already found in chlorobenzene solution [l].

TABLE I1 Rate constants for the acylation of toluene in ortho-dichlorobenzene solution

with monosubstituted benzoyl chlorides (*)

Substituent klko kz. lo4 1 .mole-'. sec-'

H 3-Me 3 t-Bu (**) 3 CI 3 Br

4 Me 4 CI 4 Br

3.34 1.00 2.21 0.66 2.03 0.61

17.0 5.09 17.2 5.15

0.85 5.50 6.23

0.25 1.65 1.86

(*) Experimental conditions as in table I. (*I) Measured by Dr. G. Hoornaert.

A Hammett plot for the mono-substituted members of the reaction series in ortho-dichlorobenzene is shown in figure 1, which as expected, closely resembles the one obtained in chlorobenzene solution.

Moreover, when the relative reactivities in ortho-dichlorobenzene (0.093 molar initial concentration, 20 "C) are plotted against the relative reactivities in chlorobenzene (0.19 molar, 25"C), a linear correlation is obtained (fig. 2). All results con- cerning the Hammett relationship of the benzoylation of toluene as obtained from this study, may therefore safely be generalized for all apolar solvents.

Interpretation of the slope 1.136 in figure 2 is not a straightforward matter: the change of chlorobenzene to ortho-dichlorobenzene should be accompanied by a diminution of the importance of the substituent effect as the dielectric strength of the solvent has increased [2, 31. But both reaction series differ also by the initial concentration of the benzoylchloride-aluminium chloride addition compound, and it has been shown (*) that the dielectric strength of the solution of a Friedel-Crafts complex is largely determined by the concentration of this compound. Moreover, from the compilation of reaction series by Jaffe [4], it is seen that both cases, decrease and increase of reaction constant with increasing polarity of the solvent are encountered. Therefore no importance can be attached to the increase in substituent effect in the reaction series here presented.

The Hammett correlation of the reaction series composed of disubstituted benzoyl chlorides is examined in figure 3. From this drawing it is evident that the benzoylation of toluene in apolar solvents does not obey the Hammett relationship.

(*) Results to be published with L. Brandt.

276 P. J . Slootmaekers and R. Verbeerst

Fig. 1 - Substituent effect as measured by the Hammett substituent constants, in the Friedel-Crafts acylation of toluene with substituted benzoyl chlorides in ortho-dichlorobenzene.

+ 9

-a

/

-

,

- 0,5 0 + 0.5

log ( k / k o ) C B , 2 5 O C I

Fig. 2 - Correlation of the relative reactivities in the aluminum chloride catalyzed reaction of substituted benzoyl chlorides with toluene in chlorobenzene and ortho-dichlorobenzene solution.


Also the separation between meta- and para-substituted members of the reaction series has been amplified.

It has been assumed, in the construction of figure 3, that multiple substitution would result in a substituent effect made up by additive contributions of the individual substituents. The compounds which emphasize the curvature in the Hammett plot of the purely meta-substituted members are the 3.5-dichloro- and the 3-chloro-5 bromo-benzoyl chlorides.

3C1-5CL

e

t G I I 4 I 1 1 I

- a2 0 + 02 + 0.4 + 06

Fig. 3 - Hammett correlation of the relative reactivities in the aluminum chloride catalyzed reaction of 3.4- and 3.5-disubstituted benzoyl chlorides with toluene in ortho-dichlorobenzene solution.

Additive behaviour of these substituents is to be expected, since they behave additive e.g. in the ionization of benzoic acids [5], the alkaline hydrolysis of ethyl benzoates [5 , 6] and ethyl cinnamates [A, the benzoylation of anilines [5] , the reaction of diazodiphenylmethane with benzoic acids [8] and the reaction of thio-urethane formation from arylthio-carbimides [9]. Accordingly the curvature in the Hammett plot must be due, in first instance, to a non-additive behaviour of the various substituents in this reaction.

Also a change in isomer distribution, as already examined [l], cannot be invoked, as seen in table 111: although the isomer distribution is not constant, the variation is far from sufficient to explain the deviation of the individual compounds in terms of an unjustified use of the experimental rate constants.


Consequently, it may be considered definitely established that the reactivities in the Friedel-Crafts benzoylation of toluene in apolar solvents are not correlated by the Hammett relationship.

TABLE 111 Isomer distributions in the aluminum chloride catalyzed acylation of toluene

in ortho-diclorobenzene with substituted benzoyl chlorides at 20 "C (*)

Substituents % ortho YO (meta+para)

4 Me 3.9 96.1 3.4 diMe 7.3 92.7 3.5 diCl 5.0 1.3 meta 93.7 para

(*) Initial concentrations: acylating compound 0.094 M, toluene 0.706 M.

Additivity of substituent effects

It is very customary to accept that, within the precision of the Hammett relationship itself, substituent effects in polysubstituted compounds behave additive, provided steric effects and direct resonance interaction between substituents mutually in ortho- or para-positions are excluded.

In this respect 3.5-disubstituted benzoyl chlorides constitute the compounds of choice in order to examine the cumulative substituent effect.

Such study requires however a linear relationship between the reactivity parameter (logklk,) and the substituent parameter (e.g. Zo), in order to judge the eventual deviations observed.

In case of failure of the Hammett relationship such a study consists in correlating the reactivities of multiply substituted compounds with the sum of the reactivities of the singly substituted compounds. In the case of additivity a theoretical slope of unity should be obtained.

Such analysis of the relative reactivities of the 3.5- and 3.4-disubstituted compounds of the reaction series has been carried out in figure 4. Inspection of this figure reveals that all disubstituted compounds may be regarded to behave as expected from the existence of an additive substituent effect, except the dihalogeno-benzoyl chlorides (i.e. whether or not both halogens appear in meta-positions with regards to the functional group, or when one substituent occupies also the para-position). Comparing figure 4 with figure 3, it will be seen that just these compounds are respon- sible for the curvature in the Hammett plot.

This observation may confirm the view [lo] that additivity of substituent effects is limited to reaction series which fit the Hammett relationship.

In fact, it was hoped that the deviating behaviour of these substituents was corrected by use of the substituent effect of the same substituents in the same reaction. It may therefore be concluded that the individual deviating effects have been amplified in the most electron deficient compounds, rather than being summed up.


DISCUSSION

In the previous paper [I] two alternative interpretations were advanced to account for the observed results: firstly it could be assumed that throughout the reaction series the same single step (a-correlated) is rate determining in an otherwise complex reaction, but that the concentration of an intermediate is governed by a pre-equilibrium step (a+-correlated). The other interpretation supposed a gradual change in the rate determining step with otherwise constant mechanism throughout the reaction series, assuming that the measured rate constant is actually a composite quantity depending on the rate and equilibrium constants of several reaction steps.

These interpretations represent in fact, actually accepted views 111, 121.

+ O,!

(

- 0.'

0 3C1- 5C1

3C1-5Br

3Br - 4Br

3 C1-5 Me 3 c1 - 4 Cl 3Er- 4C1

3 3 0 r - 4 M e C1-4 Me J 3Me- 4Br 3Me-4C1

3Me- 5Me 9 f -

-0.5 0 + 0 5 .+ 1.0

Fig. 4 - Examination of the additivity of substituent effects in the Friedel-Crafts acylation of toluene with 3,4- and 3,5-disubstituted benzoyl chlorides in ortho-dichlorobenzene.

The first interpretation can now definitely be ruled out, in that it is shown (fig. 3) that the Hammett relationship fails to correlate the relative reactivities of the meta- substituted members of the reaction series. Indeed, for these compounds, the electro- philic substituent constant a+ is, within experimental error, equal to the Hammett substituent constant a , and thus a linear pa-relationship would have to be obtained for the meta-substituted members of the reaction series.

As to the second interpretation, we are forced, in order to interpret our results to assume that this change in rate determining step may as well include a changein


‘1-

mechanism of the reaction: by this we understand a complex reaction wherein several reaction paths are possible, e.g. several acylating species, and wherein the relative importance of the reaction paths is governed by the substituent, solvent and temperature.

An indication of the likelihood of this assumption may be found in the non-additive behaviour of these members of the reaction series which show the greatest deviation of an eventual meta-regression line.

This situation points to the existence of a new interaction mechanism between substituent and reaction center, as brought about by a new reaction center or a supplementary mechanism of the reaction.

I

- 0

0 --e

Fig. 5 - Behaviour of the second order rate constant in the course o f the reaction of various disubstituted benzoyl chlorides with toluene in the presence of aluminum chloride in ortho-dichlorobenzene solution.

This means that the second order behaviour of the reaction represents an approximation of the true course of the reaction, expressed by apparent second order rate constants. Indeed, the rate constants are known to depend on the initial concentration


of the acylating compound [13]. But it has been common practice, since Steele [14], to discuss all features of the Friedel-Crafts acylation reaction in terms of second order rate constants [15-18]. In fact, the reaction of the unsubstituted benzoyl chloride in apolar and polar solvents with benzene or toluene, can very closely be approxi- mated by a second order treatment of the concentration-time data.

The use of substituted benzoyl chlorides however, reveals that such treatment of data shows deviations which are function of the substituent in the acid chloride. When these deviations are not very pronounced in the usual graphical representation of the integrated form of the rate expression, by which method the second order rate constants presented here have been obtained, the trends can be amplified by calculating the second order rate constant in the course of the reaction by use of the successive time-intervals for conversion of a constant amount of reactants into reaction products.

Although by this method experimental errors also are enlarged, a real second order rate constant will show up by a statistical repartition of the so calculated values.

Such analysis of data is presented in figure 5 for different members of the reaction series by plotting the second order rate constants against the conversion degree of the reaction. It will be noted that the approximate nature of the second order rate constant increases with increasing electron deficiency of the aromatic nucleus of the benzoyl chloi ide.

An obvious explanation of this observation consists in a gradual change in mechanism of the reaction showing up by an increase of the order of the reaction with respect to the benzoyl chloride-aluminum chloride complex concentration. This effect can be accounted for in a complex reaction, assuming the possibility of the simultaneous operation of at least two potential acylating species.

A second point which emerges from our results is the systematic meta-para dispersion as it appears in the correlations of the relative reactivities (fig. 1 and fig. 3). I t is quite obvious that para-substituents differ predominantly from meta-substituents in their resonance capacity. Therefore it seems very reasonable to accept that ground state resonance stabilization in one of the acylating species must be taken into account in formulating a possible reaction mechanism. In view of the accepted complex reaction mechanism no direct relationship will even be found between the lowering of reactivity and the resonance capacity of the para-substituent [I].

Conclusion

The results hitherto presented demonstrate amply the complex character of the Friedel-Crafts acylation reaction, whose intimate mechanism cannot be described by a simple rate expression. This situation is indeed typical for the reaction of a polar compound in an apolar solvent.

Nevertheless some aspects of the reaction have been elucidated: the failure of the Hammett relationship, as well as the lack of additivity of the substituent effect, both facts indicate that the substituents in a substituted benzoyl chloride complex do not act solely by a simple polar effect on the reactivity of the parent compound, but also bring about a change in reaction mechanism.

The systematic meta-para dispersion, which moreover characterizes the substituent effect, indicates that in one of the reaction intermediates a very important resonance


interaction occurs between the reaction centre and a suitable para-substituent. Therefore it seems evident to award an ionic character to one of the effective acylating species as e.g. in an ion-pair.

The complex pattern of the reaction has hitherto been limited to the role of the Friedel-Crafts acylation complex as such. No effort has been made to judge the kinetic importance of the solvation of this complex by solvent molecules [19]. Nor has any attention been paid to the role of the aromatic hydrocarbon in the courseof the reaction: it has been assumed tacitly that the reaction is of strict first order in the aromatic hydrocarbon. That this does not need to be so, is shown by evidence for associations between Friedel-Crafts addition compounds and aromatic hydro- carbons [20]. Recently the acylation of toluene-antimony trichloride complexes has been reported [21].

As toluene-aluminum halide complexes have also been prepared [22, 231, an extension of this study decidedly must include a careful examination of the kinetic behaviour of the aromatic hydrocarbon, as also of the role of the solvent of the reaction.

EXPERIMENTAL

Experimental procedure and rate constants

The progress of the benzoylation is followed by determination of the amount of hydrochloric acid formed in the reaction: quantitative and instantaneous elimination of the hydrochloric acid is effected by a fast stream of dry nitrogen through the vigorously stirred reaction mixture.

Absorption of the hydrochloric acid in water by scrubbing of the gas stream in an especially designed titration vessel, and titration of the solution gives the rate of production of hydrochloric acid and hence of the benzoylation. The experimental set up has been described in detail, together with a discussion of the experimental method [13].

From these concentration-time data, second order rate constants have been determined in a plot: log ( a - x ) / ( b - x ) versus time, wherein a end b represent the initial concentrations of the aromatic hydrocarbon toluene and the benzoyl chloride - aluminum chloride addition compound respectively. The amount of ketone formed at time t , as determined from its equivalency with the amount of hydrochloric acid evolved at the same time, is represented by x .

As the aim of this paper was merely to determine rate constants for compounds, differing considerably in reactivity, rather than to investigate the justification of second order treatment of the experimental data, most reactions have been followed to 50-60 % of completion. Within this range of conversion of reactants into products, the second order treatment of the concentration-time data by the graphical method outlined, allowed to obtain second order rate constants.

The reproducibility of the rate constants may bejudged from the data in table Tv, wherein for each compound the rate constant is given, followed by the standard deviation obtained from four independent kinetic runs.


TABLE IV Rate constants of the aluminum chloride catalyzed benzoylation of toluene

in ortho-dichlorobenzene solution at 20 "C with substituted benzoyl chlorides (*)

Substituents k2. lo4 1 .mole-l.sec-l

4 Br 6.22+0.02 3 Me4 Br 3.58+0.08 3 C1-4 Br 1.49+0.04 3 Br-4 Br 1.50f0.04

(*) Experimental conditions: toluene 0.706 M, benzoyl chloride-aluminum chloride compound 0.094 M.

Reactants and reaction products

Common reagents: Commercially available aluminum chloride, sublimed, purity at least 97%, has been used as such after pulverization and homogenization in a nitrogen protected ball mill.

Toluene was the purest commercially available one, dried by refluxing over sodium and distillation in an inert atmosphere. Only the middle cut was retained, and its water content was examined by gaschromatographic analysis at 110°C on a 20 % polyethyleneglycol column, connected to a catharometer detector (Carlo Erba, Fractovap model B).

The solvent orthodichlorobenzene, quality purum, was dried by refluxing over diphosphorpentoxide, quickly filtered by suction, and distilled under reduced pressure. The purity of the middle cut was checked by gaschromatographic analysis at 150°C on the same column as used for toluene.

Acids and acid chlorides: The monosubstituted benzoic acids and their benzoyl chlorides were available from a previous investigation [l]. The syntheses of the disubstituted benzoic acids were carried out following conventional routes. The physical constants of the various benzoic acids are in agreement with litterature data.

The benzoyl chlorides were prepared from the pure benzoic acids with pure colorless thionyl chloride, obtained from the commercially available yellowish product by double fractionation through a preparative Sigwart column, rating fifteen theoretical plates. After distillation of the excess of thionyl chloride, the acid chloride was distilled in vacuo.

The physical constants of the benzoic acids and the corresponding benzoyl chlorides are given in table V (*).

Reaction products: The product of the reaction of a particular benzoyl chloride with toluene in the presence of aluminum chloride was isolated from the combined reaction mixtures of several kinetic experiments by steam distillation of the solvent ortho-dichlorobenzene.

Solid benzophenones were isolated from the steam distillation residue by filtration and recrystallized from petroleum ether. Liquid or oily ketones were taken up in

(*) Physical constants determined by A. Storme.


TABLE V Physical constants of disubstiruted henzoic acids, benzoyl chlorides.

p'-methylhenzophenones and their 2.4-dinirrophenylhydrazones (DNPH).

Substituents XY-CEHPCOOH XY-CEHS-COCI XY-CaHrCO-CeH4-Me(p')

BP "C/mm Hg F "C or DNPH. F'C oc n20D

XY F "C

~

3.5 diMe 3 Me-5 CI 3.4 diMe 3 M e 4 CI 3 M e 4 Br 3.5 di I-Bu 3.5 diCI 3 C1-5 Br 3 CI-4 Me 3.4 diCl 3 C1-4 Br 3 Br-4 Me 3 Br-4 CI 3.4 diBr

168-9 178-9 163.5-4.5 208-8.5 213-4 170-1 185-6 193.5-4 199.5-200 202.5-3 218-9 206-6.5 21 4-4.5 229-30

127120 127121 147121 132/17 145120 169121 I34.5/20 149/21 135.5120 134/13 148115 148118 151/11 182/23

1.54618 1.56380 1.55857 1.57639

1.5241 2 27-8

26.5-7.5 32.5-3 1,57290 33.5-4 59-9.5 37.5-8 37-8 68.5-9

74-5 43-4 81-2

100-1 103.5-4.5 (*) 59-9.5 69-70 91.5-2

121-2 123-3.5 91-1.5

114-5 112.5-3

235-6 246-8 234-5 220-2 227-9

237-9 260- I 244-5 235-7 262-3 238-9 229-3 1 246-8

(*) Ketone lost by accident.

benzene, the resulting solution dried over sodium sulfate, and the benzene evaporated. The crude benzophenone was further distilled in vacuo in a microdistillation apparatus.

From each ketone, purified as mentioned, the dinitrophenylhydrazone (DNPH) was prepared and recrystallized from aqueous acetic acid (50 vol. %). The physical constants of the ketones, uncorrected melting point or refractive index at 2OoC, and their dinitrophenylhydrazone, are taken up in the foregoing table V.

ACKNOWLEDGEMENTS

The authors are indebted to the Nationaal Fonds voor Wetenschappelijk Onderzoek ( N . F. W. 0.) for financial support. One of us, (R.V.) predoctoral fellow 1963-1965, thanks the Insrituut ter bevordering van her Watenschappelijk Onderzoek in Nijverheid en Landborrw (I . W. 0. N . L.). The technical assistance in the preparation of the various benzoic acids by R. Wijns, F. Heines, P. Ascoop, R. Gevers, C. Widrs, E. Van Emelen, and W. Bienstman is gratefully acknowledged. Finally the authors wish to express their appreciation to Professor Dr. J. Verhulst for his constant interest and wise advice.

Laboratorium voor Algemene Scheikunde Naamsestraat 96 Leuven (Belgium)

REFERENCES

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Medegedeeld aan de Redaktie, op 16 oktober 1967.

the friedel-crafts acylation reaction iv. multiple substituent effect in the friedel-crafts...

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