On the electronic structure and odours of esters of the isothiocyanic acid

J. theor. Biol. (1975) 49, 37%383

On the Electronic Structure and Odours of Esters of the Isothiocyanic Acid PETER LINDNERAND OLLE M/~TENSSON

Department of Quantum Chemistry, Uppsala University, Box 518, S-751 20 Uppsala I, Swedent (Received 30 January 1974) The electronic structure of the esters of the isothiocyanic acid is calculated in an iterative extended Htickel method. Contour diagrams of the valence electron density are given. The odour character of these molecules is discussed in terms of the electronic structure obtained and the theories of smell put forward by Amoore and Wright respectively, 1. Introduction

There are many questions concerning the detailed mechanism behind an odour impression which are still unsettled (Wright, 1964; Ohloff & Thomas, 1971). Besides the complex process of information transfer from the primary ceils to the final odour experience in the brain, there is the uncertainty about the structure of the receptor sites on the molecular level. One way of approach to these questions is to investigate the odorant molecules by themselves. We thus look for possible common properties of electronic origin for molecules with the same odorant behaviour. These investigations will shed light on possible structures of the receptor sites and also on the question about the transfer of odorant information from the molecule to the primary cell. The molecular properties we are specifically interested in are: (1) The space-filling property and the local distribution of electron charges as given by the electron density function. (2) The local and overall electric polarizability of the molecule. (3) The thermal vibrations of the molecule. Recently (Lindner & Mhrtensson, 1972) we commented on the bitter almond odour of the benzaldehyde type and its connection with the electronic structure of the compounds. We pointed out some similarities in their spacefilling properties by means of level diagrams of the valence charge distribution. J" Supported by the Swedish Natural SciencesResearch Council. 377

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r'. L I N D N E R AND O. M/~RTENSSON

This was in accord with the stereochemical theory of odour proposed by Amoore (1952, 1970) and the generally accepted idea that the "boundaries" of a molecule are given by the outer contours of the valence electron density. This model neglects the possible deformation of the molecule coming from the interaction between molecule and receptor site. A measure of this deformation is given by the polarizability of the molecule or parts of it in an electric field. There is evidence that the lower vibrational modes (50-500 cm- 1) have a positive correlation with the odour characteristics of the molecule (Wright, 1964). These frequencies together with the space-filling model by Amoore seem to be the main "odour parameters" of a molecule. The acid strength of the molecule and its odorant behaviour for some carboxy acids may be of importance for the olfactory response ofLocusta migratoria (see Kafka, 1970, for an experimental report). In the present work we present results for the esters of the isothiocyanic acid. These are of the general form (R-NCS). The usual "mustard oil" is obtained for R equal to the allyl group (CH2CHCH2). 2. Odour of the Mustard Oil Type Natural "mustard oil" which is isolated from mustard seeds consists mainly of allyl isothiocyanate which has the characteristic smell of mustard. Phenyl isothiocyanate (phenyl mustard oil) has a very similar odour. NCS

I

Hc#C'fH HC%cICH Extensive studies of the variation of odour with substitution in phenyl isothiocyanate have been carried out by Dyson (Dyson, 1926, 1928, 1929, 1931). As for the benzaldehyde series one finds a displacement of odour towards the anis type on para substitution. The size of the group introduced in the phenyl isotldocyanate molecule seems also to be of importance. Substituting the para hydrogen atom by the aldehyde group changes the odour to that of heliotropine. For benzaldehyde we know that 3-hydroxy-4-methoxyl substitution gives vanilline, while 3,4-methylenedioxyl substitution gives heliotropine. Whether the corresponding substitutions in phenyl isothiocyanate gives a transfer to vanilline and heliotropine odour types is unknown to us.

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The dependence of the odour type on the size of substituents in the ortho and meta positions is also pronounced. A chlorine atom in ortho position has a small effect on the "mustard oil" odour, while a bromine atom in the same position gives a more anis like odour. An iodine atom in meta position also changes the odour type towards anis, while a methoxyl group leads to a harsh pungent odour. Metasubstitutions of chlorine, bromine or methyl groups increase the pungency of the odour. The isothiocyanate group is very different from the aldehyde group. The sulphur atom creates a rather bulky neutral or slightly positive end. The nitrogen atom is the site of a negative net charge and its bonds are distinctly polarized. In the following we shall analyze the isothlocyanate group in more detail with regard to its valence charge density. Especially we shall be interested in changes, if any, induced by different substituents in the phenyl ring. 3. Method of Calculation and Results

We have used an iterative extended Hiickel method to calculate the valence charge densities. The charge densities obtained by this method seem to be quite realistic as compared with ab initio results (see e.g. Alml6f & MArtensson, 1971). The details of the iteration procedure are given elsewhere (Karlsson & Mftrtensson, 1969). The parameter values used can also be found in that paper. The essence of the method is the calculation of molecular orbitals as linear combinations of atomic orbitals = Y'.

(1)

P

where the atomic orbitats qSj,(r) are Slater type functions for each valence electron. fb~(r) = N r "-1 e-°SYtm(O, rp). (2) The coefficients co, are determined by the secular equations /t

where the matrix elements of the effective one-electron Hamiltonian are approximated in the usual way h.. =

; valence state ionization energy of atomic orbital

1"75 h,v -- <~,lhl~> = - 2 - s,v(h,,+h,~)

(4)

where su, = (~b~,lq~,) is the overlap integral and the charge iteration goes through huu.

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P. L I N D N E R A N D O. M,~RTENSSON

In the present context we are interested in the density contour for the valence electrons OCC

p(o = Xf l,,(r)l

(s)

The non-iterative extended Hiickel method gives an over-polarization of the bonds between atoms with large electronegative difference. This is damped to a realistic level by the charge iteration. We have found that the outer contours of the charge density is practically unaltered by the iteration. This is depicted in Fig. 1 and Fig. 2 for methyl isothiocyanate.

2.0

......................................................

?, C t~

k5

-3'0

I

l

I

I

I

-2"0

-I.0

0"0

['0

2"0

3-0

4;0

5.0

6'0

7.0

Oislance (au)

FIG. 1. Total valence charge density of the - N C S group in methylisothiocyanate. Perpendicular to the plane containing C-NCS. Iterative extended Hiickel method. The outer contour represents the density 0"01 el/au 3. The following are for 0'03, (0'03) 0'30, 0"35 (0.05) 0"50, 0"70 (0"20). The figures in parentheses indicate the steps between contours.

We made a series of calculations on the isothiocyanic acid itself, HNCS, and on some of its esters (methyl, allyl, phenyland o-chlorophenyl). It turned out that the valence charge density in the - N C S group is practically unchanged throughout this series of esters and coincides with the one in the acid itself. The n-electron densities were then separated and compared. For all compounds considered we got the same agreement as found for the total densities. In Fig. 3 we give the contour diagram for the methyl ester. This invariance of the charge densities was somewhat unexpected. Especially we would have expected changes in the n-densities when going from the acid to one of the phenyl esters.

381

ELECTRONIC STRUCTURE AND ODOUR 3.0

2,0 i

I-O o.o

i::3

~

"--.L..gJ)/I]F

"

:.. ..; j ~,

°

I

!!

-I.0

.-.~_--2.0

_.... •

-I.0

.......

................................

I 0-0

I 1.0

~.-~.__~.i..

, ................

I 2.0

...

I 3.0

I 4.0

5.0

6.0

7"0

8,0

9.0

Distonce (ou)

FIG. 2. Same as in Fig. 1 but without charge iteration,

2'0

ii° 1

2 -3.0

o I -2.0

.............. I -I,0

1 0-0

1 1,0

l 2,0

I 3-0

I 4.0

I 5-0

I

6-0

7'0

Distance (au)

FIG. 3. n-electron charge density of the -NCS group in CHa-NCS. Perpendicular to the molecular plane. Noniterative extended Hiickel method.

On the other hand one finds a similar behaviour also in many other cases. In a bond forming process between two molecules the outer density contours are essentially unchanged except in the region where the molecules are in contact. This seems to hold even for systems where the charge densities close to the atoms undergo large changes.

382

P . L I N D N E R AND O. M A R T E N S S O N

This is of course in accord with the chemical experience that a substituent in a molecule usually only distorts the outer form of the molecule in a local way. This is the reason why one can talk about - N C S and many other functional groups as if they were invariants. It also gives support to the spacefilling model as one of the main clues in determining the odour of a molecule. Space-filling often seems to be more important than other general chemical properties of the molecule in settling its odour. 4. Discussion and Conclusions

As Amoore has pointed out there is a definite positive correlation between the "stereochemical volume" of a molecule and its odour (Amoore, 1952, 1970). Our results for the "mustard oil" series shows that the functional group in this case, the isothiocyanate group, is unaffected by the type of ester or the substituents in the phenyl esters. As pointed out above there is a change in odour for the substituted phenyl esters which is connected with the size of the substituent and the position of substitution. All this fits well into Amoore's theory. The space-filling theory does not explain how a specific molecule finds its receptor site and how it orients itself with respect to this site. There is in this theory no satisfactory clue to the question of the information transfer from the molecule to the receptor. We thus need other additional molecular "parameters" for a full classification of a certain group of odorant molecules. We are here thinking of groups for which we can talk about a well-defined odorant behaviour. Since conventional chemical characteristics of substituent groups generally seem to be of minor interest for the odorant behaviour, there are definite reasons to believe that properties of the molecule as an entity have to be searched for. The lower vibrational modes of a molecule conslitute such a property. While higher vibrational frequencies usually can be traced to specific groups in the molecule, the modes with longer wavelengths often involve the entire molecule. We thus expect a positive correlation between these lower frequencies and the odorant property. This conclusion was reached by Wright through considerations of the excitation energies available at the receptor sites (Wright, 1964). A systematic investigation of the lower frequencies (below 500 cm-1) in the mustard oil series would be very interesting. The vibrational theory by Wright gives a possible clue to the kind of energy involved in the information transfer process. Finally there is the question of the orientation and binding forces which act between molecule and receptor. Kafka has made some qualitative comments on this (Kafka, 1970). In terms of the usual classification of chemical

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383

binding we could expect effects from electrostatic forces (mainly dipole interactions) and from van der Waals (dispersion) forces. Furthermore there are for many of the odorant molecules possibilities for hydrogen bonding. The dipole moments of the methyl, allyl and phenyl esters of isothiocyanic acid lie around 3-0 Debyes. For p-bromo- and p-chloro-phenyl isothiocyanate the dipole moment is around 1.5 Debyes (Antos, Martvon & Kristian, 1965). This correlates with the mustard oil to anis change of odour type in these molecules. As there is a liquid phase surrounding the receptor sites in most animals the use of an electrostatic model has to be made very carefully. The dispersion forces on the other hand are quite unaffected by the surrounding medium. They are furthermore usually of a strength which corresponds to thermal energies. It is known that they are related to the electric polarizability of the interacting molecules. Higher polarizability leads to stronger bonding power. According to the data by Antos et al. (1965) there seems to be a marked difference in the polarization between the phenyl ester and the metasubstituted phenyl esters on one side and para-substituted phenyl esters on the other side. More data is needed before one can decide if there is in general a correlation or not between polarizability for the whole molecule or parts of it and the odorant behaviour. In conclusion we would like to point out that the discussion of the esters of isothiocyanic acid made here applies to the odorant response in man. The general ideas put down in this paper should also be applicable to insects. For these the odorant response is vital for behaviour and survival. REFERENCES ALMLOF,J. • M.~RTENSSON,O. (1971). Acta Chem. Scand. 25, 1413. AMOORE,J. E. (1952). Perfitm. essent. Oil Rec. 43, 321, 330. AMOORE,J. E. (1970). Molecular basis of odor. Springfield: C. C. Tomas. ANTOS,K., MARTVON,A. ~. K.RISTIAN,P. (1965). Colln. Czech. chem. Commun. 31, 3737. D','SON, G. M. (1926). Perf. essent. Oil Rec. 17, 20. DYSON, G. M. (1928). Perf. essent. Oil Rec. 19, 3, 88, 171, 341. DYSON, G. M. (1929). Perf. essent. Oil Rec. 20, 3, 42. DYSON, G. M. (1931). Perf. essent. Oil Rec. 22, 278. KAFKA, W. A. (1970). Verb. dt. zool. Ges. 64, 174. KARLSSON,G. &: M.~TENSSON,O. (1969). Theor. Chim. Acta 13, 195. LINDNER, P. & M3,RTENSSON,O. (1972). Int. J. quant. Chem. 6S, 363. OHLOFF, G. & THOMAS,A. F. (eds.) (1971). Gustation and OIfaction. London: Academic Press. WRIGHT, R. H. (1964). The Science o f Smell. London: G. Allen and Unwin Ltd.