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SUBSTITUENT EFFECT ON REACTIVITY 7 0 3

Die Elution obiger Verbindungen kann entweder durch Messen der Extinktion im Bereich zwischen 325 und 340 nm oder durch Dünnschichtchromatographie einiger /A von jeder Fraktion auf Kieselgel (DC-Fertig-platten ohne Fluoreszenzindikator, Merck) mit Toluol/ Äthanol = 95/5 und Lokalisieren der Flecken unter der UV-Lampe verfolgt werden (7?/-Wert von 8: 0,47, von 4: 0,32). 2-Methoxy-6.7-dimethylnaphtalin

8,6 g 2-Hydroxy-6.7-dimethylnaphtalin werden in 100 ml 10-proz. KOH gelöst. Unter Rühren tropft man 4,8 ml Dimethylsulfat zu. Nach beendeter Zugabe wird noch 30 Min. bei Zimmertemperatur weitergerührt und dann 30 Min. im siedenden Wasserbad erwärmt. Nach dem Erkalten wird das Produkt abgesaugt, mit Wasser gewaschen und an der Luft getrocknet. 4,4 g Rohpro-dukt. Aus dem Filtrat kann nach Ansäuern unumge-setztes Ausgangsprodukt zurückgewonnen werden. Nach

Umkristallisieren aus absolutem Äthanol 3,5 g. Durch Lösen in Äther, Adsorption an Kieselgel und Chromato-graphie an einer kurzen Säule von Kieselgel mit Pe-troläther als Fließmittel 2,8g (30% d. Th.). Schmp. 105-106°.

Ber. C 83,87 H 7,52, Gef. C 83,86 H 7,39.

Dr. L I N TSAI, Bethesda, U.S.A., danke ich für hilf-reiche Diskussionen. Doz. Dr. B. F Ö H L I S C H , Institut für Organische Chemie der Universität Stuttgart, bin ich für die Aufnahme der NMR-Spektren und Hilfe bei der Interpretation Dank schuldig. Ferner danke ich Frau A N D R E E B A U E R - D A V I D u n d F r l . C A R M E N V A R E L A -B L A N C O für ihre Mithilfe bei der Durchführung der Versuche. Diese Arbeit wurde von der Deutschen For-schungsgemeinschaft und dem Fonds der Chemischen Industrie unterstützt.

Substituent Effect on Reactivity of Alkyl Thiolacetates F. DUTKA, A . F. M Ä R T O N , a n d P. VINKLER

Central Research Institute for Chemistry of the Hungarian Academy of Sciences, Budapest, Hungary

(Z. Naturforsch. 26 b , 703—707 [1971]; received Mardi 29, 1971)

Kinetics of catalyzed acyl group exchange between acetic-l-14C anhydride and alkyl thiolace-tates was investigated. The exchange is not accompanied by chemical reaction and demonstrates the full equivalency of anhydride acyl groups in the process. The rate of exchange is lowered by increasing branching rather than lengthening in S-alkyl substituents. The role of catalyst and struc-tures of possible intermediates are interpreted. Upon existing linear structure-reactivity relationship a common mechanism involving sulfur atom as the reaction site seems to be operative.

The effects of variations in structure upon rates of hydrolysis have been reported for a number of alkyl acetates and thiolacetates. Although these stu-dies allow some generalization to be made1, the comparative kinetics of ester and thiolester reactions are not well understood. There are also some dif-ferences in views on the effect of the S-alkyl group on thiolester reactivity 2 ' 3.

Independent of the order of thiol components, alkyl thiolacetates tend to undergo acyl exchange with acetic-1-14C anhydride in nitromethane by the catalytic effect of L e w i s acids. Under the same

Sonderdruckanforderungen an Dr. F. DUTKA, Zentralfor-schungsinstitut für Chemie d. Ungarischen Akademie d. Wissenschaften, Budapest II., Pusztaszeri üt 57 — 69.

1 K . A . CONNORS and M . L . BENDER, J. org. Chemistry 2 6 , 2498 [1961].

2 P . N . RYLANDER and D . S . TARBELL, J. A m e r . chem. Soc. 72,3021 [1950].

experimental conditions, primary and secondary alkyl acetates are unreactive towards acetic anhy-dride 4 while tertiary acetates suffer a chemical change simultaneously with the isotopic exchange5. This finding shows a marked difference in acetate and thiolacetate reactivity and offers further possi-bility to obtain a better understanding of the chemi-cal properties of thiolesters.

The present paper deals with studies on the kine-tics and mechanism of acyl group exchange as well as on structure-reactivity relationship.

3 L . H . NÖDA, S . A . KUBY, and H . A . LARDY, J. A m e r . chem. Soc. 75,913 [1953].

4 L . ÖTVÖS, F . DUTKA, and H . TÜDÖS, A c t a chim. A c a d . Sei . Hung. 43, 53 [1965].

5 F . DUTKA and A . F . MÄRTON, Z . Naturforsdi . 2 4 b , 1 6 6 4 [1969].

7 0 4 F. DUTKA, A. F. MÄRTON, AND P. VINKLER

Experimental section

Materials All thiolacetates were prepared by acylation of the

corresponding thiols 2. Purity of the esters was checked by analytical gaschromatograph. Nitromethane was dried over P205 and fractionated; b. p. 101°/760mm. AICI3 was a reagent grade Merck product and freshly sublimed before use.

Methods All liquid scintillation counting was carried out

using toluene scintillation solutions, prepared by dis-solving 5,0 g of 2,5-diphenyloxazole ("PPO", REANAL, scintillation grade) and 0,5 g of l,4-bis-2-(5-phenyl-oxazolyl) benzene ("POPO", Packard scintillation grade) in 1,0 I of toluene.

Radioactivities were determined using the Packard TriCarb 574 Liquid Scintillation System.

IR spectra were recorded by means of an UR-10 spectrophotometer. In the spectrum of a typical re-action mixture (concentrations: 2 M ethyl thiolacetate, 1 M acetic anhydride and 0,33 M A 1 C 1 3 ) the carbonyl frequencies of the A C 2 0 - A 1 C 1 3 complex (1540 cm - 1

and 1707 cm - 1 ) , of non-complexed acetic anhydride (1750 cm - 1 and 1819 cm - 1 ) and of ethyl thiolacetate (1688 cm - 1 ) were identified.

Gaschromatographic analyses and separations were carried out by using Carlo Erba models (Fractovap GV. and Fractovap P), resp.

Kinetics The procedure is described here for one particular

run and it is typical of that used throughout. A1C13 (0,033 M) was dissolved in nitromethane (25 ml) and then acetic-l-14C anhydride (0,100 M) introduced into the yellow solution. The almost colorless solution ob-tained and a solution of alkyl thiolacetate (0,200 M) in nitromethane (30 ml) were thermostated separately at 45,0 + 0,1°. At zero time the solutions were mixed rapidly and the total volume supplemented to 100 ml by addition of nitromethane kept also in the same thermo-state. Stirring of the reaction mixture started without delay. Samples (10 ml) were removed at appropriate times (the first at zero time) with a syringe and in-jected quickly into a flask cooled by liquid air. After addition of freshly distilled aniline (0,1 ml) the mixture was allowed to stand for 10 min at room temperature. Acet-l-14C-anilide was crystallized by cooling in liquid air and separated by filtration. After repeated (usually three times) recrystallization from water its activity remained constant.

Specific activities of samples taken at zero time and separate experiments demonstrated no reaction of thiolacetates with aniline under these contitions. (In all cases aniline was used in amounts smaller than equi-valent to Ac20).

In several experiments thiolacetates were also sepa-rated gaschromatographically from the mother liquor obtained after filtration of acetanilide and their acti-vities measured.

Isotope exchange Kinetics of acyl exchange was followed by measuring

the decrease in the specific activity of labelled acetic anhydride in the form of acetanilide. Rates of exchange (Re) were calculated from the equation suggested by M C K A Y 6, taking into consideration that the number of exchanging groups in acetic anhydride was two.

Results

The catalyzed acyl exchange reaction between alkyl thiolacetates and acetic-1-14C anhydride has the following characteristics:

1. The exchange is not accompanied by any che-mical reaction as was shown by gaschromatographic analysis of the reacting system.

2. The specific activities of the equilibrated pro-ducts are closely identical with the calculated values based on the assumption that both acetyl groups of acetic anhydride take part in the exchange.

3. The specific activities at equilibrium are de-termined exclusively by the concentrations and not affected by the sequence of mixing reactants.

4. The distribution of radiocarbon at equilibrium is unanimously determined by concentrations of acyl compounds, irrespective of whether acetic an-hydride or thiolacetate is the originally labelled spe-cies.

5. Plotting l o g ( l - F ) vs. time6 perfect linearity is obtained at 45° ; at higher temperatures a slight deviation from linearity appears in the initial stages of the exchange (plots are not shown).

6. Increasing amounts of A1C13 enhance the rate of exchange but do not affect the value of equili-brium specific activity.

7. The exchange rate (Re )is first order with respect to each of the reactants as shown in Fig. 1.

2.0

t o

10

0 0 0,2 OA 0.6 Cj X C2 * Cj

Fig. 1. Effect of concentrations of reactants on the rate of acyl exchange.

6 H. A. C. MCKAY, Nature [London] 142, 997 [1938] ; J. Amer. chem. Soc. 65, 702 [1943].

7 D. COOK, Canad. J. Chem. 37, 48 [1959].

SUBSTITUENT EFFECT ON REACTIVITY 7 0 5

Thiolacetate 105 k Mol - l sec - 1

Methyl 14,20 Ethyl 2,83 n-Propyl 2,53 n-Butyl 1,81 {-Propyl 0,65 i-Butyl 0,16

C H s - 1 4 C = 0 > 0

C H , - 1 4 C = 0

ALCLO CH» - 14CO ® • CH, - 14COOAlCLQ.

Table 1. Rate constants for acyl exchange of thiolacetates with acetic-l-14C anhydride in nitromethane at 45,0 ± 0,1°.

(Here , c2 and c3 are the concentrations of an-hydride, thiolester and A1C13, respectively.) The over-all third-order nature of the exchange is consi-stent with the rate equation

Re = k [acetic anhydride] [thiolester] [A1C13]. 8. The reactivity of thiolacetates falls with in-

creasing + 1 effect of S-alkyl substituents (Table 1) (rate constants k were calculated from the former equation).

9. Under the same experimental conditions ZnCl2

is a more effective catalyst of acyl exchange than A1C13 . This rapid exchange was not followed kineti-cally.

Discussion

Complexes of A1C13 with carbonyl compounds are generally believed to play an important role in acy-lation reactions. Unreactivity of thiolesters towards acetic anhydride in the absence of A1C13 also demon-strates the key-role of this species in acyl exchange. Principally, A1C13 can coordinate with thiolacetate or acetic anhydride present in the system. Carbonyl frequencies in the IR spectrum of the reaction mix-ture suggest the only formation of Ac20 • A1C13 com-plex under the given circumstances. Actually, trans-acylation should take place between this complex and thiolacetates. Presumably, A1C13 serves to polarize the anhydride sufficiently so that transfer of CH3CO® to the reactant can occur. Complexes of A1C13 with acyl halides were found to exist in nitro-benzene as a mixture of oxocarbonium ion salt (b) and donoracceptor complex (a) 7. Analogously, the equilibrium of these forms may be present in nitro-methane solution of AC20-A1C13 even if it lies far to the left:

8 G. OLAH, F r i e d e l C r a f t s and Related Reactions, Interscience Publishers, New York 1964. Vol. Ill, p. 1009.

9 L . J. ANDREWS and R . M . KEEFER, Molecular C o m p l e x e s in Organic Chemistry, Holden-Day Inc., San Francisco 1964, p. 163.

The energy difference between the two structures is not large8 and the ion CH3CO® or the ion pair CH3CO® • A1C130C0CH3® (b) rather than complex (a) is the species which takes part in the acylation 9. Supposing that ionization of the reactive complex occurs prior to acyl transfer 10, acyl exchange may take place through an oxonium (c) or sulphonium (d) intermediate:

O 14CO —CH,

O —14C —CH, C H 3 - C - S - R II ©

CH,—C — SR

Catalytic cleavage of ethers and thioethers by acyl halides is explained by a similar mechanismn. There are two alternative mechanisms for decompo-sition of the intermediates yielding exchanged pro-ducts: alkyl or acyl fission. Alkyl fission of the intermediates is hardly expected because it would imply real chemical reaction affording oxygen esters (by reoombination of the alkyl cation with the ace-tate moiety of the complex) and thioacetic anhy-dride. Acyl exchange, however, was found not to be accompanied by any chemical change. On the other hand, acyl fission of the oxonium structure would lead to unchanged initial reactants.

Reasonably, a mechanism involving sulphonium intermediate (d) should probably be operative in the exchange. Sulphonium salts form more readily and are more stable than oxonium salts. Partitioning of the sulphonium intermediate to reactants and ex-changed products by acyl fission takes place without producing new chemical species. Acyl fission in the exchange of t-butyl thiolacetate is not unexpected since, in sharp contrast to the behaviour of t-butyl acetate, the acid catalyzed hydrolysis of the sulfur analogue proceeds entirely by cleavage between the sulfur atom and the carbonyl group 2.

Radioactivity originally present in acetic an-hydride, is equally devided into acetyl and acetoxy group of the complex. Transacylation through the above mechanism, however, involves only the acetyl

1 0 H . C . BROWN and F . R . HENSEN, J. A m e r . chem. Soc . 8 0 , 2 2 9 1 [ 1 9 5 8 ] ; 8 0 , 3 0 3 9 [ 1 9 5 8 ] .

1 1 R . L . BURWELL, JR., C h e m . Reviews 5 4 , 6 1 5 [ 1 9 5 4 ] .

7 0 6 F. DUTKA, A. F. MÄRTON, AND P. VINKLER

group of the reactive complex. On the other hand, the value of specific activity at equi-librium is independent of the amount of A1C13

and demonstrates the participation of both acyl groups of acetic anhydride in the exchange. It can be concluded, therefore, that a com-plete acyl exchange also occurs between the complex and non-complexed anhydride. The precise pathway of this process has not been clarified as yet. Conse-quently, no detailed mechanism can be given for the over-all exchange reaction. At any rate, in this stage acetyl groups of the non-complexed acetic anhydride should be incorporated into the acetyl and acetoxy group of the L e w i s acid complex with equal chance. This can be realized by a dissociative equi-librium between the reactive complex and its con-stituents or by displacement of the complexed an-hydride from the adduct by non-complexed acetic anhydride. In this manner the full equivalency of anhydride acyl groups in the over-all process which is unambigously proved by exact linearity of log (1 — F) vs. time until the equilibrium isotope distribution can be explained. Difference in the reac-tivities of acyl groups would create a curvature in this plot as pointed out in complex exchange reac-tions 12. Furthermore, it is quite evident that this step may not be rate determining because of the dependence of the observed exchange rate on the structure of thiolesters.

As can be seen from Table 1 the reaction rate decreases with the increasing + / effect of 5-alkyl substituents. About the same sort of reactivities seems to be obtained in the cleavage of dialkvl ethers by acyl chlorides in the presence of ZnCl2 13. The question arises whether the rate of formation of the sulphonium intermediate or its rate of reaction is the kinetically important step. Apart from possible steric effects, a process with rate determining for-mation of the intermediate would produce the re-versed reactivity sequence of thiolesters. Therefore the reaction rate is determined by the concentration of the intermediate and by its specific rate of reac-tion.

Rate constants k for acyl exchange can be cor-related with the Taft substituent constants (Fig. 2 ) : In agreement with our experimental evidence, this

1 2 A . C . W A H L and N . A . BONNER, Radioactivity A p p l i e d to Chemistry, J. Wiley and Sons, Inc., New York 1951, p. 11.

13 W. L. GUYER and R. E. DUNBAR, Proc. nat. Dakota Acad. Sei. 11, 26 [1957].

t o>

-5

-6

Fig. 2. Relationship between log ke and substituent constants in acyl exchange reaction of thiolacetates at 45°. In Fig. 2

linear free energy relationship supports a common mechanism in the series studied, the rate controlling step being governed solely by polar effects. The posi-tive sign of the reaction constant Qe* indicates that the exchange is facilitated by low electron density on the reaction site. Rate determining attack on the sulfur atom would result in a reaction constant with minus sign.

The same relationship was found to be effective in the hydrolyses of alkyl thiolacetates catalyzed by acids or bases 2. A comparison of the corresponding reaction constants (£e=6 ,5 ; £h® = 1,46; £>Hoe = 3,40) exhibits remarkable differences. Although these processes were carried out under different experi-mental conditions, the greater value of £>e* indicates a large sensitivity to the nature of substituent and is at least partly due to the fact that the reaction centre is nearer to the substituent14 in exchange reactions than in hydrolyses.

Branching alkyl groups affect the rate of ex-change to a greater extent than do substituents with non-branching chain (Table 1). Similar tendency appears in acylation reactions. Unfortunately, quan-titative data on thiol acylations are fairly sparse. According to available results15 the esterification constants markedly decrease with the increasing order of thiol. An estimated value of the reaction constant for esterification (q* = 6) shows a sub-stituent sensitivity similar to acyl exchange. Thus the mechanism of acyl exchange resembles thiol acylation rather than thiolester hydrolysis.

The unreactivity of primary and secondary alco-hol acetates towards acetic anhydride may partly

14 R. W. TAFT and I. C. LEWIS, J. Amer. chem. Soc. 80, 2436 [1958].

NITRIL ALS INTRAANULARE GRUPPE 7 0 7

be attributed to the importance of the resonance

/ ° e

form CH, —C as compared to thiolesters: > 0 - R

this makes the alkyl oxygen more positive and pre-vents attack by the acyl cation. In this type of elec-tron-releasing conjugation, sulfur is not as effective as oxygen16, therefore, electron density on sulfur 15 A. CHABLAY, C. R. hebd. Seances Acad. Sei. 263, 15

[1966].

is decreased to a lesser extent. Binding of the elec-trophile derived from the reactive complex on the acyl oxygen of esters may result in exchange only by alkyl fission. It seems likely that the extraordi-nary behaviour of tertiary alkyl acetates5 can be interpreted by their tendency to suffer alkyl fission.

The superiority of thiolacetates over oxygen ana-logues appears more unequivocally in acyl exchange than in catalyzed hydrolyses.

1 6 C . K . INGOLD and E . H . INGOLD, J. d i e m . Soc . [ L o n d o n ] 1 9 2 6 , 1 3 1 0 ; E . L . HOLMES and C . K . INGOLD, 1 9 2 6 , 1 3 2 8 .

Sterische Wechselwirkungen im Innern cyclischer Verbindungen, 18 1

Nitril als intraanulare Gruppe Steric Interactions of Inner Atoms in Cyclic Compounds, 18

The Nitrile Group as an Intraanular Substituent

FR I T Z V Ö G T L E , M ICHAEL ZUBER u n d PETER NEUMANN

Institut für Organische Chemie der Universität Heidelberg und Institut für Organische Chemie der Universität Würzburg

(Z. Naturforsdi. 26 b, 707—709 [1971]; eingegangen am 19. Märe 1971)

Cyclophane, Konformationsanalyse, Nitril-Gruppe, Protonenresonanz, Sterische Wechselwirkungen

The bridged aromatic compounds 1 — 3 with internally projecting nitrile groups have been pre-pared. The cyclophanes 1 and 3 are conformationally rigid due to steric hindrance of the inner cyano groups; 2 shows partial conformational mobility.

Das Problem, Nitrilgruppen so zu fixieren, daß sie ins Innere eines Ringsystems hineinragen, ist aus verschiedenen Gründen von besonderem Interesse: Einmal sind sterische Wechselwirkungen der kova-lent gebundenen Cyanogruppe kaum untersucht wor-den, obwohl ihre lineare Gestalt geometrisch beson-ders übersichtliche Verhältnisse mit sich bringt. Zum anderen besteht — insbesondere bei Anwesenheit mehrerer intraanularer Nitrilgruppen im Molekül — die Möglichkeit intramolekularer elektronischer und chemischer Wechselwirkungen.

Wir berichten im folgenden über Darstellung und Eigenschaften der ersten Cyclen mit intraanular2

fixierten Nitrilfunktionen.

Sonderdrudeanforderungen an Dozent D r . FRITZ VÖGTLE, Institut für Organische Chemie der Universität Würzburg, D-8700 Wurzburg, Landwehr.

1 2 3

Darstellung der Cyclophane

Die Metacyclophane 1 und 2 wurden nach einer früher3 mitgeteilten Methode durch Umsetzung von 2.6-Bis-brommethyl-benzonitril mit den Dinatrium-Ver-bindungen von Dithioresorcin bzw. von a),co'-Dimer-capto-m-xylol nach dem Verdünnungsprinzip erhalten.

1 1 7 . M i t t . : F . VÖGTLE U. R . LICHTENTHALER, Chemiker -Ztg. 94, 727 [1970].

2 V . PRELOG, W . K Ü N G U. T . TOMLJENOVI6, Helv . chim. A c t a 45,1352 [1962].