Molecular interactions in conjugates of dicarboxylic acids and amino acids

Journal of Molecular Structure 661-662 (2003) 239–246 www.elsevier.com/locate/molstruc

Molecular interactions in conjugates of dicarboxylic acids and amino acids Alfred Kolbea,*, Carola Griehlb, Simone Biehlerb a

Institut fu¨r Physikalische Chemie der Martin-Luther-Universita¨t Halle-Wittenberg Mu¨hlpforte 1, D06108 HalleSaale, Germany b Institut fu¨r Biotechnologie der Fachhochschule Anhalt, Bernburger Strasse 55, D06366 Koethen, Germany Received 18 April 2003; revised 18 May 2003; accepted 2 July 2003 Dedicated to Professor Dr.-Ing. Bernhard Schrader in respect of his scientific work and his political engagement

Abstract Vibrational spectroscopic studies have been performed to obtain information regarding intermolecular forces acting in conjugates formed by dicarboxylic en-acids (fumaric acid, maleic acid) or their monobenzyl esters with esters of amino acids in the crystalline state and in solution. – NH groups, – COOH groups, and COamide groups have turned out to be the preferred carriers of those molecular interactions, which are the driving forces to form associates. These associates are mostly different in the crystalline state and in solution. The dimerisation of the molecules via the – COOH groups is suppressed in the preponderate number of cases in these molecular arrangements. The different behaviour of the substances is discussed in detail. q 2003 Elsevier B.V. All rights reserved. Keywords: Amino acid conjugates; Molecular arrangement; Hydrogen bonding; IR and Raman spectroscopy

1. Introduction In the course of our investigations on peptides [1,2] we have turned our interest to special amino acid conjugates, which exhibit excellent properties for interacting with other molecules by forming hydrogen bonds. In order to describe this behaviour, which is generally of great importance in biological systems, vibrational spectroscopy may be used in simple model systems as a powerful method. In our special case we have investigated methyl esters of amino acids [alanine (Ala), phenylalanine (Phe), and proline * Corresponding author. Tel.: þ49-34603-20651; fax: þ 49-3455527028. E-mail address: [email protected] (A. Kolbe).

(Pro)], conjugated with maleic acid (Mal) or fumaric acid (Fum) or their benzyl esters. The vibrational spectra allow us to deduce the molecular interactions in the crystal and in solution in detail. The results are presented in the following.

2. Experimental The synthesis of N-(cis-b-carboxyacryloyl)-amino acid ester (I, II and III) (the formulae of the substances characterized by roman numerals are given in Table 1) was performed by using standard acylation procedure with maleic anhydride. N-(trans-b-carboxyacryloyl)phenylalanine methylester (IV) has been obtained by

0022-2860/03/$ - see front matter q 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0022-2860(03)00446-0

3430m,br 3399st

3272w*br

(II) Mal-(L)Phe-Ome cryst Raman lines of the crystal In CH2Cl2 Partly N and/or O-deuteriated cryst IR

3450w, br

3243st

3396st 3450w, br

3280vw, br 3245m

In CH2Cl2

3233m

3394m

(IIa) Mal-(D,L)Phe OMe cryst IR

3450m, br

3252st

(III) Mal-(L)-Pro-OMe neat

3550m

3470m

2500m,br

2500m,br 2369m CO2 excluded 2531

3412m

1751st 1751vvw 1741st

1713sh 1714sh 1724st

1701st 1704st

1644st, 1633sh 1633st 1636st

1559vs 1576w 1607st

1534m

1745st 1744vw 1744st 1745st

1736m 1736vw

1706m, 1713sh 1706st sh, 1713 1725st 1705m, 1713sh

1640m, 1630sh 1630m,sh 1639 1635m 1640m, 1630sh

1590sh 1603m 1608st 1590sh

1555st 1584m 1530st 1553st

1744st

1724st

1635m

1607st

1531m-st

1766vs

1707vs

1640st

1572sh

1547st

1748st

1718st

1572m

Raman lines of the neat compound (IV) Fum-(L)-Phe- OMe cryst Raman lines of the crystal In CH2Cl2 (V) Mal(OBzl)-(L)-Ala-OMe cryst Raman lines of the crystal In CH2Cl2 (VI) Mal(OBzl)-(L)-Phe-OMe cryst Raman lines of the crystal In CH2Cl2

3311st

2900br

3500w

3416m

1740st 1736w 1741st

3390v br

3275v br

1743st

3416st

3293st

3258st *

3369st, sharp 3412m

3300m

(VII) Mal(OBzl)-(L)-Pro-OMe neat Raman neat In CH2Cl2 In CCl4 (VIII) Fum(OBzl)-(L)-Ala-OMe cryst. Raman lines of the crystal In CH2Cl2 (IX) Fum(OBzl)-(L)-Phe-OMe cryst Raman lines of the crystal In CH2Cl2 (X) Fum(OBzl)-(L)-Pro-OMe Raman neat In CH2Cl2

*Only at low temperature near 240 8C.

1741st 3250m In this

3328st 3415st, sharp 3329st 3416st

1741v,st

1736m

1716st

1661w

1629m, 1646m*, 1619m* 1626st

1694m 1685st 1712w

1656st 1676sh 1682st

1645m 1646m 1654w

1542m 1603w

1715m 1734vw 1719st

1674m 1657vw 1677m, 1670sh

1634m 1630w 1624st

1539m 1580w 1550m

1661st

1632m 1605m 1624m

1584w 1540m

1743st

1729m 1729w 1717m

1741t region 1742st 1751st

1721st practically 1725st 1728st

1754st 1754w 1741st

1711st 1710m 1726st

1751st 1752w 1742st

1715st 1713m 1725st

1725w 1741st

1726st

1676/1660m

1586w 1510m

1512st, 1500sh 1523m 1506m

1654st

1631st Raman 1634st 1647sh

1674st 1681vs

1640st 1639st 1650w

1606w

1540st 1588vw 1514st

1673sh, 1679sh 1674st

1638st 1638st 1682st

1604m

1541st 1585w 1511st

1662w 1656m

1627w 1628st

1604vw

1589vw

no

line 1637sh

A. Kolbe et al. / Journal of Molecular Structure 661-662 (2003) 239–246

(I) Mal-(L)-Ala-Ome cryst Raman lines of the crystal In CH2Cl2

240

Table 1 The wave numbers of bands (IR absorptions) and lines (Raman signals) are given in the region of interest for amides in cm21. OMe means O-Methyl. The intensities and some properties of the bands and lines are given by st, m, w, br, sh, sp, v, meaning strong, medium, weak, broad, shoulder, sharp, and very, respectively. The Raman lines in the CH str. region are not given

A. Kolbe et al. / Journal of Molecular Structure 661-662 (2003) 239–246

cis/trans isomerization of (II) in high-boiling solvents as xylole. N-(cis-b-alkoxycarbonylacryloyl)-amino acid esters (V and VI) were prepared from (I)- and (II)-caesium- or triethylammonium salts with alkylhalides in acetonitrile. The synthesis of (VII) is more successful via DCC – DMAP activation of 1-proline with alkyl alcohol. The preparation of N-(trans-balkoxycarbonylacryloyl)-amino acid esters (VIII), (IX) and (X) has been achieved by cis/trans isomerization of (V), (VI) and (VII) with piperidine in ether [3]. IR measurements were done on the Bruker IFS 25 FT instrument. 32 runs were collected to calculate one spectrum. NaCl cells with different thickness were used up to 1 mm, but in most cases the thickness amounts to 0.25 mm. Crystals were investigated using the KBr technique. CH2Cl2 and in one particular case CCl4 were used as solvents. Raman measurements, done on crystalline or neat compounds only, were performed on a Bruker IFS 66 FTIR spectrometer equipped with a Raman FRA 106 module. The Raman laser frequency was 1064 nm. 250 mW laser power was applied and 100 scans were accumulated in 1808 alignment for each spectrum.

3. Results The IR and Raman spectroscopic values (Table 1).

4. Discussion Before starting a compound by compound discussion based on the wave numbers given in Table 1, it should be mentioned that the assignment of the main interesting bands will not be uncomplicated. Because our interest is strongly directed to the region of double bonds, we have to take into account that sometimes there may exist a vibrational coupling of the different CO vibrations with each other and also the CyC bond may participate in this interaction. This coupling depends in part on the geometric arrangement of the molecules. Greater separation of the characteristic groups in the molecule and orthogonal direction of vibrations of similar frequencies to each other diminish their possibilities to couple vibrationally with each other and thus, fortunately, in the case presented here rather characteristic signals can very

241

often be found. Most of the discussion given here is based on the changes of frequencies in the dissolving process, but in this procedure also conformational changes may occur, sometimes pretending changes in hydrogen bonding. Further, it should be mentioned that a special situation is met here, concerning the COamide band and the CyC double bond band. In the case of maleic acid and its derivatives, possessing a cis arrangement at the CyC double bond, the CyC double bond appears in the region between 1635 and 1665 cm21, but in the trans arrangement its position is between 1665 and 1695 cm21 [3]. Thus it may happen that sometimes the wave number of the CyC vibration is lower and sometimes is higher than that of the COamide vibration. Examples for this behaviour will be encountered in particular when discussing the spectra of the compounds (I), (II), and (IX). The correct assignment is supported by Raman spectroscopy, differentiating between the differences in polarisibilities of the characteristic groups and the changes of them on vibration. In the spectra of the crystalline compound (I) we had expected to find an arrangement of dimers associating via the carboxylic groups. But we have found that the strong band at 1751 cm21 shows practically no counterpart in Raman, but the band at 1701 cm21 and the line at 1704 cm21 correspond to each other. This result is rather surprising, because we had learned from other spectra, which we have given in part in a former publication [4], that the carboxylic groups of associated dimers do not appear in the Raman spectrum. If this rule also holds here, then the associate carboxylic CO band of the dimer has to possess an improbably high frequency, which we have neither found in our earlier work nor in the spectra given in collections like [5], or no dimer can be formed by the COOH groups in this case. This opinion is supported by the fact that the IR spectrum of the crystal does not show the well-known broad absorption structure in the region near 2800 cm21, which could be taken as characteristic for the –COOH dimerisation. Thus the band at 1751 cm21 is assigned as a COmethylester band and the band at 1701 cm21 as the CyO absorption of the carboxyl group. The broad band near 3430 cm21 is interpreted as an indication of an unspecific interaction of the OH group with other groups of the molecule in the crystal. In order to illuminate this situation the spectrum of the solution

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has been taken into account. The main changes on dissolving (I) are that the rather sharp NH band at 3233 cm21 of the crystal is strongly shifted to 3399 cm21, the position of a free band in accordance to the behaviour of the dNH band which is shifted from 1559 to 1534 cm21. Simultaneously the carboxylic CO band is shifted from 1701 to 1724 cm21. This means that an interaction between the carboxylic CO group and the NH group exists in the crystal, which is broken at dissolving. The molecular arrangement in the crystal, which is ruled by hydrogen bonding, excludes the ester CO group (1751 cm21) in spite of its high polarity (proved by its low Raman intensity) from any direct interaction. On the other hand, the ester CO band is shifted on dissolving from 1751 to 1741 cm21. Thinking in terms of the Badger Bauer rule [6] this is formally an indication that in solution this group is subject of a stronger interaction than in the crystal, but this shift may be a consequence of a dipol –dipol interaction with the solvent. Evidently the breakdown of the intramolecular NH – OCcarboxyl interaction on dissolving may allow the OH group to interact very strongly with the CO amide group originating a shift of this band to 1607 cm21. The band remaining in solution at 1636 cm21 —as in the crystal- is taken as an representation of the CyC bond. In agreement with the shift of the COamide band the intensity of the OH band is shifted as a very broad band to 2500 cm21, which is representative for a very strong intramolecular hydrogen bond in a seven membered ring. We have found an analogous situation in intramolecular hydrogen bonds formed by PO –HO groups in seven membered rings [7]. Considering the change of the spectra, on dissolving this molecule undergoes probably a transformation of one intramolecularly bonded structure into another intramolecularly bonded one. As mentioned above, in contrast to the situation in solution, the existence of the CyC double bond in the crystal is only convincingly documented by a sharp (CyC)– H line at 3055 cm21, but the CyC double bond itself appears in the IR spectrum only at 1633 cm21 as a weak shoulder of the band at 1644 cm21, but in the Raman spectrum the intensity ratio at this position is inverse. In the case of (II) like in that of (I) no carboxylic dimer seems to be formed in the crystal. Although there exist a large similarity between the spectra of (I) and (II) in the IR spectrum of crystalline (II) there

appear four bands between 1750 and 1700 cm21, namely a strong one at 1745 cm21 exhibiting a shoulder at 1736 cm21, and a medium strong one at 1706 cm21 exhibiting a shoulder at 1713 cm21 and additionally one medium strong band at 1640 cm21 also with a shoulder at 1630 cm21. In the Raman spectrum the bands at 1745 and 1736 cm21 show only extremely weak counterparts, but a strong line appears at 1706 cm21 possessing as in IR a shoulder at 1713 cm21. The intensity relation of the medium strong pair of lines at 1640 and 1630 cm21 inverts in comparison to the situation in IR. This is taken as a supporting indication that the band (shoulder) at 1630 cm21 is a manifestation of the CyC double bond. Because NH – OC interaction does not suppress the Raman intensity of the CO line strongly [5], 1713 and 1706 cm21 will be frequencies of associated carboxylic CO groups. Evidently these two bands possess a common root as the bands at 1745 and 1736 cm21 also and the splitting may be due to conformational effects. Namely on dissolving, both groups degenerate to one band in each case, but the vibration at 1745 cm21 is not affected in its position at all by dissolving. Therefore this group also should not be a partner of hydrogen bonding. A broad OH band appears in the crystal with low intensity near 3450 cm21, possibly representing an unspecific interaction of the OH group with other parts of the molecule. The NH vibration is represented by a rather sharp and intense band at 3243 cm21, evidently an associate band, which is shifted to 3396 cm21 on dissolving, now representing a free group. In the same procedure the band at 1555 cm21 in the crystal, assigned as a dNH, is shifted to 1530 cm21, exhibiting the classical behaviour of deformation frequencies in hydrogen bonding on their opening. Consequently the molecular state in the crystal may be as best described as governed by an intramolecular interaction of the NH group with the carboxylic CO group, which is shifted on dissolving from 1706 to 1725 cm21. The appearance of a new band in solution, namely at 1608 cm21, can be taken as an indication of an interaction between the OH group and the COamide group, the vibration of which now is shifted to this position, and as in (I) the remaining band at 1635 cm21 represents the CyC double bond. In accordance with this interpretation there appears a broad band of medium intensity at 2500 cm21,

A. Kolbe et al. / Journal of Molecular Structure 661-662 (2003) 239–246

Fig. 1. Probable arrangements of (I) (R ¼ CH3 ) and (II) (R ¼ CH2C6H5) in the crystalline state (a) and in solution (b).

presenting the intramolecularly (there is no dependence on concentration) bonded OH group. The dissolution process means for the molecules of (I) and (II) in main the transformation given in Fig. 1. Two other facts should be mentioned: Firstly, in the crystalline state of (I), as well as of (II), the CH bands appear in similar shape and similar size like the NH band. In order to make sure the existence of only one NH interactive bond, (II) was partially deuteriated. The IR spectrum of the crystal of (D – II) exhibit only one ND band at 2369 cm21, proving that in fact the NH group forms only one species of hydrogen bonds. Secondly the racemic mixture (IIa) shows in the crystalline state nearly dramatic changes in its IR spectrum compared with the enantiomeric compound (II). This means that (II) and (IIa) form different diastereoisomers by association. In the IR spectrum of (IIa) the position of the carboxylic CO band at 1707 cm21 and the behaviour of the OH band which is more intense and broader than in the crystal spectrum of (II) may be taken as an indication of a dimerisation via the carboxyl groups, but this case was not investigated in detail. In solution there is no difference between the racemic compound and the pure enantiomer. In the substance (III) there is no NH group to stabilize the molecular structure by hydrogen bonding. This may be a reason that this substance exists only as an oil. The spectra of this pure oil and that of the solution do not differ. The spectroscopic behaviour of the COOH-groups of (III) is analogous to (I) and (II): this means that there is no indication of – COOH dimerisation. The OH band exhibiting clearly a threefold structure lies between 3400 and 3600 cm21. At room temperature there is one COamide band (1629 cm21), but on decreasing the temperature there appear two additional bands as ligands of this band at 1646 and at 1619 cm21, whereas the positions of the bands at 1748 and 1718 cm 21 remain

243

unchanged, thus indicating that the COamide group is a centre of molecular interaction. The two additional bands may only be explained by considering other arrangements. Firstly, the OH group may be free, documented by the nOH at 3550 cm21 at room temperature, where the nCO amide appears at 1629 cm21. Secondly, it may form an intramolecular bridge with the nitrogen atom in the proline ring-in this case the wave number of the COamide band is affected by conformational isomerism and/or, less probably, by the attack of the OH group on the proline nitrogen atom and is shifted to 1646 cm21, exhibiting the n OH at 3470 cm21 and, additionally, an intramolecular OH – COamide interaction characterised by the position of the amide band at 1619 cm21 and nOH at 3412 cm21 can exist. The situation concerning cis– trans isomerism of the CO – NH group may be still not definitely clear, but we refer in our considerations to the paper of Andrews [8], where the existence of a cis isomer of the amide group is pointed out. The assignment of the OH bands follows from the better agreement of temperature behaviour of the bands at 1619 and 3412 cm21 on the one hand and 1646 and 3470 cm21 on the other. The arrangements are outlined in Fig. 2. The compound (IV) seems to be more inclined to form dimers in the crystal. Although in this case there appears a strong NH band at 3311 cm21, additionally an associated OH group appears as a broad band with its centre near 2900 cm21. A rather broad band at 1694 cm21 may be assigned as the carboxylic CO dimer band, showing no direct counterpart in the Raman spectrum. Further there are two other CO bands, at 1740 cm21 (methyl ester) and the split COamide band at 1645 cm21 and at 1656 cm21. In the Raman spectrum there appear two other lines, having no counterpart in IR, namely at 1685 cm21 and at 1676 cm21. They are representations of the CyC double bond. On dissolving in methylene chloride

Fig. 2. Probable arrangement of (III) in the dissolved resp. liquid state.

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A. Kolbe et al. / Journal of Molecular Structure 661-662 (2003) 239–246

the broad OH band disappears in favour of a weak band near 3500 cm21, in fact a free band, and there remain 3 clearly separated CO bands at 1741 cm21 (methyl ester), 1712 cm21 (carboxylic acid) and a band at 1654 cm21. The NH band is shifted to 3416 cm21, indicating that also in this case the NH group is of great importance for the molecular interaction in the crystal. But steric reasons deny the possibility of forming an intramolecular hydrogen bond in this molecule, particularly a COamide – HN interaction. Therefore we postulate in the crystal lattice an intermolecular COamide – HN interaction perpendicularly to the main axes of the dimers simultaneously with the existence of –COOH dimers. The Fig. 3 should describe the state of the crystal. There is no prominent interaction in the dissolved state. Now we turn our interest to (V). From now a carboxyl group does not exist in the molecules. Instead of the characteristic bands of this group now a benzyl ester CO band has to appear. In the IR spectrum of the crystal in the double bond region there are four bands, at 1743, 1715, 1674 cm21, and at 1634 cm21, and, in another region, an overlap of two very broad (Dn1/2 < 300 cm21) NH bands, showing their maximum positions near 3390 and 3275 cm21. According to these broad bands also the bands at 1634 and at 1674 cm21 are rather broad as the dNH at 1539 cm21 also. This means that in the crystal the interaction field is not very homogeneous for all molecules. The spectrum of the solution may make

Fig. 3. Probable arrangement of (IV) in the crystalline state.

the situation more comprehensible. On dissolving the broad NH bands of the crystal are transformed into three bands, a rather sharp one at 3416 cm21 and two associate ones, namely at 3293 cm 21 and at 3258 cm21. Concurrently, the NH deformation band (1539 cm21 in the crystal) is split into three bands (1550, 1512 cm21 and a shoulder at 1500 cm21), also indicating the existence of three differently acting NH groups. Both ester CO bands are practically not affected by the dissolving process. Thus here could not be a breakdown of any interaction involving these CO bonds. In the double bond region only the COamide band is clearly shifted, namely down to 1624 cm21, but also the vibration near 1670 cm21 may be originated by a part of the molecules, indicating the formation of a cis arranged amide group, which is the prerequisite for a dimerisation via a double NH – OC amide interaction. All these changes give only tentative proposals for the molecular arrangement in the crystalline state, but in solution the three NH bands are taken as indications of definitely different molecular arrangements. The band near 3416 cm21 should represent free molecules. Other possible arrangements are the dimerisation via a double NH – OCamide interaction or an intramolecular hydrogen bonding of the NH group to the single bonded oxygen of the benzylester. A splitting of the band at 1212 cm21 in solution (not mentioned in Table 1) may support this idea. The threefold splitting of the different dNH vibrations can then be understood. It should be mentioned, that the intensity ratios of the NH bands are only weakly dependent on temperature, if at all. This means, that the steric arrangement exhibiting a free NH group will be energetically nearly equal to the other, which is stabilized by molecular interactions. Surprisingly the intensity of most of the Raman lines of this compound is very low. Fig. 4 should describe the situation in the solution of (V) and (VI) and with the right hand sketch also the situation in the crystals of (VI). Similar interactions can be found in the compound (VI). But here a rather sharp NH band at 3369 cm21 in the crystal is subject to change on dissolving and splits into three bands, one near 3250 cm21, the next at 3300 cm21 and the other at 3412 cm21, but no band of the potential acceptor groups is shifted to higher wave numbers. This can be interpreted in terms of an intermolecular NH – NH- hydrogen bond chain in

A. Kolbe et al. / Journal of Molecular Structure 661-662 (2003) 239–246

245

Fig. 4. Probable arrangement of (V) (R ¼ CH3) and (VI) (R ¼ CH2C6H5) in the dissolved state. The right hand sketch represents also the arrangement in the crystalline state of (VI).

the crystal, but the band at 1661 cm21 also can be taken as a strong indication of two s-cis arranged amide groups forming a dimer via an eight membered ring. In contrast to (V) on dissolving the CO wave number of the benzyl ester is shifted from 1729 to 1717 cm21 and the position of COamide from 1632 to 1624 cm21. Steric reasons do not allow an intramolecular COamide-HN hydrogen bond. But in a part of the molecules the existence of an intramolecular hydrogen bond between the NH group and the CO group of the benzyl ester may be postulated, substantiated by that shift of the benzyl ester CyO band and-not mentioned in Table 1-of changes of the spectra near 1200 cm21, whereas the methyl ester band does not move from its position at 1743 cm21. The remaining of the band near 1660 cm21 is an indication, that at least a part of dimers as in (V) has survived the dissolving process. The assignment of the two NH bands with the lower wave numbers is uncertain as in (V) too. It should be mentioned that in the Raman spectrum the line at 1729 cm21 is rather prominent, but there is no trace of a line at 1743 cm 21 and, more surprisingly, none of the CyC bond. As we have expected, the substance (VII), which exists only as an oil, shows in its spectra no indication of molecular interaction, but on changing the solvent from CH2Cl2 to CCl4 the COamide band is strongly shifted. This effect may be interpreted by a change of conformation, involving a transformation from a more polar to a less polar state. The single bonds of the maleic skeleton may rotate and further there is the possibility of a change between the axial and

equatorial position of the methyl ester group in the proline ring. The remarkable shift of this band on changing the solvent may throw some doubts on the earlier discussion, where this shift has generally been taken as a consequence of changes in hydrogen bonding. But there we have always discussed the change of the COamide band in connection with the variation of the NH bands. We cannot explain the absence of any Raman line in the region of our interest. (A Raman line of the intensity of 0.85 Raman units appears at 703 cm21, Raman lines of 0.02 units are well defined lines.) The possibilities of forming hydrogen bonds are also rather restricted in (VIII). Raman lines and IR bands are coincident and allow a clear assignment of the carbonyl bands at 1754 cm21 (methyl ester), 1710 cm21 (benzyl ester) and 1639 cm21 (COamide). In the Raman spectrum an additional line appears at 1674 cm21, undoubtedly the CyC str. vibration. In the spectra of the compounds (VIII and IX) generally a weak, but clear Raman line is found for the methyl ester bond, a reliable indication of increasing polarisibility of this bond. On dissolving there is a rather dramatic changes in the IR spectra of (VIII) and (IX). The carbonyl band of the methyl ester is shifted only to 1741 cm21, in contrast to the direction of the shift of the benzyl ester band, which is shifted to higher wave numbers to 1726 cm21, but the amide band is shifted up to 1681 cm21, a shift of more than 40 cm21. Concurrently the NH band is shifted from 3328 to 3415 cm21, in agreement with the shift of dNH from 1540 to 1514 cm21.This result may best be

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A. Kolbe et al. / Journal of Molecular Structure 661-662 (2003) 239–246

interpreted by the assumption of the existence of intermolecular hydrogen bonds between the NH and the COamide bonds in the crystal, probably forming dimers. This agrees with the assignment given for (VI), there also such an arrangement (cis conformation of the amide group) has been postulated at a similar position. The shift of the methyl ester CO band to lower wave numbers on dissolving may be due to conformational rearrangements or to interactions with the solvent, but in principle it remains unexplained. As may easily be seen from the spectra, the behaviour of (IX) is strikingly similar to that of (VIII). Therefore its associative behaviour should be equal or at least similar. The spectra of (X), which we could not crystallise, do not give any indication of an remarkable interaction.

5. Conclusions Summarizing, the most interesting feature of our results is, that in only two cases of all substances under investigation in the crystalline state and not at all in the solution an associate dimer via carboxylic groups is indicated. The NH group, formally a weaker proton donor than the OH group, shows in all peptides under investigation a great ability to undergo well defined different interactions. In particular, different hydrogen bonds are formed in solution compared with

the situation in the crystal. These interactions evidently depend in a high degree on the molecular environment. This means, that the reactive behaviour of the substances under investigation generally cannot be deduced from X-ray structure.

Acknowledgments We are indebted to Dr John Shorter, Hull, for making suggestions to the manuscript and to the Fonds der Chemischen Industrie for financial support.

References [1] C. Griehl, A. Kolbe, S. Merkel, J. Chem. Soc., Perkin Trans. 2 (1996) 2525. [2] C. Griehl, H. Jeschkeit, U. Schilken, A. Kolbe, J. Chem. Soc., Perkin Trans. 2 (1990) 47. [3] E. Pretsch, T. Clerc, J. Seibl, W. Simon, Spectral Data for Structure Determination of Organic Compounds, Springer, Berlin, 1983. [4] A. Kolbe, M. Plass, H. Kresse, A. Kolbe, J. Drabowicz, R. Z˙urawin´ski, J. Mol. Struct. 436-37 (1997) 161. [5] B. Schrader, Raman/IR Atlas of Organic Compounds, VCH Weinheim 1995. [6] R.M. Badger, S. Bauer, J. Chem. Phys. 5 (1937) 839. [7] A. Kolbe, M. Plass, R. Z˙urawin´ski, P. Kielbasin´ski, M. Mikolajczyk, Spectrochim. Acta. (2003) In press. [8] P.R. Andrews, Biopolymers 10 (1971) 2253.