Insect Bioclwm., 1977, Vol. 7, pp. 483 to 485. Pergamon Press. Printed in Great Britain.

EFFECTS OF RING UNSATURATION ON THE ACTIVITY OF PROPYL CYCLOHEXANEACETATE

AS AN ATTRACTANT FOR THE GERMAN COCKROACH

R. SUGAWARA,* Y. TOMINAGA,* and T. SuzuKr[" *Institute of Applied Biological Chemistry, University of Tsukuba, Sakura-mura, Niihari-gun, Ibaragi-ken,

300-31, Japan tLaboratory of Pesticide Chemistry, Tokyo University of Education, Meguro-ku,

Tokyo, 153, Japan

(Received 4 April 1977)

Abstract--Effects of modifications including ring unsaturation on the activity of propyl cyclohexaneace- tate to attract the German cockroach were comparatively tested in field conditions. The test compounds were arranged in the decreasing order of activity as follows: propylcyclohexaneacetate > propyl 3-cyclo- hexenylacetate > propyl 2-cyclobexenylacetat~propyl cyclohexylideneacetate/> propyl n-hexanoate > propyl 1-cyclohexenylacetat~phenyl acetate.

The result was interpreted by postulating a multipoint attractant-receptor interaction that includes the axial CH bonds in the ring, the terminal methyl group in the side chain and the ether oxygen in the ester group.

I N T R O D U C T I O N

PROPYL CYCLOHEXANEACETATE, a synthetic attractant to the German cockroach, was regarded to consist of a head (cyclohexane ring) and a tail (a side chain containing ester linkage). In the preceding paper (SUGAWARA et al., 1976), the tail was variously modi- fied and the change of activity was followed. A model was proposed for the binding of the attractants to the receptor site. In the present paper, unsaturation was introduced into the ring as a means of evaluating the contribution of the ring to the effective interac- tion.

MATERIALS AND METHODS

Test materials I-Cyclohexenylacetic acid was obtained by condensing

cyclohexanone and cyanoacetic acid (COPE et al., 1963), followed by hydrolysis of the resulting nitrile. 2-cyclohex- enylacetic acid was prepared from 3-bromocyclohexene by malonic acid synthesis (MOFFETT, 1963). 3-cyclohexenylace- tic acid was derived from 3-cyclohexenyl aldehyde via reduction (BRowN, 1951), halogenation (NOLLER and BAN- NF.RT, 1934; BRODV and BOGERT, 1943) and carboxylation by Gringnard reaction. The starting aldehyde was prepared by Diels-Alder condensation of butadiene and acrolein. The cyclohexenylacetic acids prepared as above as well as phenylacetic acid were esterified with CI-C5 n-alkanols and purified with distillation and chromatography to a GLC purity higher than 96%. 1-cyclohexenylacetic esters were contaminated by more or less than 10% of cyclohexy- lideneacetates which could not be removed by the conven- tional procedures. Thus, to check its influence on the ac- tivity, propyl cyclohexylideneacetate was prepared by an Wittig reaction between 0,0-diethyl carbopropyloxymethyl-

phosphonate and cyclohexanone (WADSWORTH and EMMONS, 1973) and included in the test. Propyl n-hex- anoate was also included because its side view profile resembled that of propyl cyclohexaneacetate.

Test procedure Various combinations of chemicals were tested compara-

tively. The tests were carried out, and the results were ana- lyzed as described in the preceding paper (SUGAWARA et

al., 1975).

RESULTS

A peak in activity was attained with propyl ester in each of the n-alkyl homologous series of the unsa- turated acids. Thus, comparative experiments among different unsaturations were run with propyl esters. In runs A and B (Table 1), propyl 3-cyclohexenylace- tate (II) appears somewhat less active than propyl cyclohexaneacetate (I). From runs A, B, C, and D, (II) is definitely superior to the otherwise unsaturated

'esters. To it follows propyl 2-cyclohexenylacetate (III), propyl cyclohexylideneacetate (IV) and even propyl n-hexanoate (VII). They may be ranked at a same level of activity (runs C and E). Propyl l-cyclohexenyl- acetate (V) and propyl phenylacetate (VI) sustained considerable loss in activity (run F). The overall order of attractancy may be arranged as (I) > (II) > (III)==(IV) >I (VII) > (V)==(VI).

D I S C U S S I O N

The ranking in attractancy obtained above was in- terpreted in terms of a multipoint interaction of the

483

484 R. SUGAWARA, Y. TOMINAGA AND T. Suzum

Table 1. Effects of ring unsaturation on the attraction of propyl cyclohexaneacetate to the German cockroach

Run Avg no./trap* Avg no./trap*

Combination of Dose (,ul) Combination of Dose (ltl) compounds (Replicates) Run compounds (Replicates)

o.ot 0.05 0.5 0.05 o. z 0.5 (10) (10) (to) (10) (10) (6)

Untrearea 6.6a 5.8b 7.7c Untreotea 7.4b 7.7b 4.7c O O

C3 CH2C--O--CHzCH2CH 3 ( I ) II.9a 21.4a 34.4a CH2~--O--CH2CH2CH~ ( I ) 25.3a 33.1a 42.8a

O O

( 3 © ' A CH~C--O--CHzCH2CHI5 (Y) 14.0a 4.8b 12.5bc B CH2C--O--CH2CH2CH3 11I) 14.0ab 21.4ab 32.0ab

O 0

C ) " Q " CHiC--O--CH2CH2CH 3 (llI) 8.9a 12.5ab 22.5ab CHiC--O--CH2CH2CH!5 (~t) 17.4ab 17.5b 16.8bc

O O © " CHzC--O--CH2CH2CH) (]~: 13.1a 19.3a 22.7ab HC--O--CH2CH2CH 3 (W) 12.9ab 14.2b 10.0bc

O.I 0.5 1.0 0.5 5NO (12) (10) (6) (6) (6)

Untreoted 7.7b 4.3b 7.0b UntrecLtecl 5.7b 5.8c

0 O. IL ~ II

~m/CH2C--O--CH2CH2CH3 ('~II) l l.2ab 8.5b 1 4 . 7 a b CH2C--O--CH2CHzCH:5 ('iF) 7.5b 9.8bc

O O

C CHC-O--CH2CHaCH~I (1~) ll.2ab 9.3b ll.3ab D CH2C--O--CH2CHzCH:s (llI) 14.8b 26.2ab

O 0 fl ~ II ~CH2C--O--CH2CH2CH, ('nr) 10.4ab 13.8ab 13.8ab ~ /~eH2C--O--CH2CH2CH, (~} 37.3a 39.8a O 0

~.~CH2~--O--CHzCHzCH 3 liT) 21.4a 24.6a 23.0a F--,,/~Q_j~CHz~_O_CH2CH2CH , (lZI} 6.3b l l.3bc

0.5 1.0 5.0 5.0 25.0 (10) (10) (6) (10) (6)

UnrreQted 12.2a 3.0b 1 . 8 b Untret.ea 6.5b 1.0b

0 ° ,., O ° CH2C--O--CH2CH2CH3 21.5ab 1 2 . 8 a CH2~--O--CH2CHzCH a (~') 15.7ab 16.5a

© o E HC--O--CH2CH2CH3 (~') 14.5a 29.2a 18.7a F CHzC--O--CHaCH2CH3 (~ZI) 19.7ab 21.0a

0 0 II II

~_//CH2C--O--GH2CH2CH3 ('~1 20.7a 20.lab 13.2a \ /CH2C--O--CH2CH2CH 3 (~) 25.6a 23.8a x . . . . J

* Any pairs of means followed by the same letter in a column are not significantly different at the 5~ level of confidence.

attractant molecules with the receptor site through their axial (or pseudoaxial) bonds in the ring (ELt~L, 1962), ether oxygen and terminal methy group.

In reference to Fig. 1, (I) and (II) have one set of structural features in common; the side chain which lies in the plane of the ring and the axial hydrogens at C2 and C6 which point at the receptor. Owing to the planar arrangement, the axial hydrogens at C2 and C6, the ether oxygen and the terminal methyl group will gain access together to the receptor site. The activity of (II), that approximates to that of (I), suggests the axial bond at C4 is not so important as those at C2 and C6. Double bonds will not partici- pate in the binding to the receptor..(III) retains, the

planar shape but lacks one of the axial hydrogens at C2 and C6, and thus becomes less potent. In (IV), the axial hydrogens remain intact, but the side chain, which still runs in parallel with the receptor face, is forced aside from the long axis of the molecule. Fur- thermore, the ether oxygen gets aloof from the sur- face. Either or both of these aspects of deformation will be the cause of the fall in activity. In (V) and (VI), the side chain bend away from the receptor face, and thus the Simultaneous interaction of the three parts of the molecules becomes impossible. In (VII), the unfavourable defect in half of the ring must have been compensated to some extent by higher volatility and flexibility of the molecule.

Ring unsaturation effects on the German cockroach 485

3 0

\ RECEPTOR SITE ( I ) (~.)

o ,o

('V) {'V'I )

Fig. l. Side elevation views of propyl cyclohexaneacetate (I), propyl 3-cyclohexenylacetate (II, propyl 2-cyclohexenylacetate (lII), propyl cyclohexylideneacetate (IV), propyl 1-cyclohexenylacetate (V) and

propyl phenylacetate (VI), in interaction with the receptor site.

The attractant molecules will fit into the comple- mentary cavities over the receptor site, which either naturally occurs or have been induced by the stimu- lants (BELLEAU, 1964). For this effect, the ether oxygen will operate through induction forces or hydrogen bond. whereas methyl and methylenes, through hydrophobic interactions (Nr~MET~Y, 1967) and Van der Waals forces. In view of the distance specificity of the last mentioned force (SALEM, 1962; DObD, 1976), the ---~H's which come closer to the receptor surface will be more efficacious. They will be the ter- minal methyl group and the axial bonds at C2 and C6; their manipulations except ---CH 3 ~ C1 caused significant decrease in activity. Thus they will provide the 'favourable side' of the molecules that was referred to in the preceding paper (SuGAWARA et al., 1976).

In the above discussion, consideration was not given to the equatorial bonds which also disappeared by the ring unsaturation, because the CH bonds on the olefinic carbons do not so much change from the equatorial bonds in spatial direction.

R E F E R E N C E S

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N~MI~TrtY G. (1967) Hydrophobic interactions, Anoew. Chem. (int. Ed.) 6, 195-206.

NOLLER C. R. and BANNERT R. A. 0934) The synthesis of unsaturated fatty acids. Synthesis of oleic and elaidic acid. J. Am. chem. Soc. 56, 1563-1565.

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SUGAWARA R., Ktn~mARA S., and MUTO T. (1975) Attrac- tion of the German cockroach to cyclohexyl alkanoates and n-alkyl cyclohexaneacetates. J. Insect Physiol. 21, 957-964.

SUGAWARA R., TOMINAGA Y., KOBAYASHI M., and MUTO T. (1976) Effects of side chain modification on the ac- tivity of propyl cyclohexaneacetate as an attractant to the German cockroach. J. Insect Physiol. 22, 785-790.

WADSWORTH JR. W. S. and EMMONS W. D. (1973) Ethyl cyclohexylideneacetate. In Organic Synthesis Coil. (Ed. by BAUMGARTEN H. E.) 5, 547-549. John Wiley, New York.