Spectrochimica Acta Part A 61 (2005) 1321–1326

Conformation of some biologically active aromatic ureas

Boriana Hadjieva, Sonia Ilieva, Diana Cheshmedzhieva, Boris Galabov∗

Department of Chemistry, University of Sofia, 1 James Bourchier Avenue, 1164 Sofia, Bulgaria

Received 15 July 2004; accepted 15 September 2004

Dedicated to Prof. J.R. Dung on the occasion of his 70th birthday.

Abstract

Experimental IR spectroscopic data for the N–H stretching mode frequencies for several types of tri-substituted ureas containing benzyland/or phenyl substituents as well as theoretical results from B3LYP/6–31G(d,p) computations on selected compounds provide sufficientevidence to determine the conformational state of these molecules. Two types of N–H bands may be found the spectra: (a) A type band due toa classicaltransconformation (trans I) of the CO NH structure; (b) B type band arising from an alternativetransform (trans II), in whichthe N–H band is involved in a hydrogen bond like interaction with the aromatic ring at the neighbouring nitrogen atom (benzyl or phenylsubstituents). The N–H band oftrans I CO NH structure is observed at frequencies higher than 3460 cm−1, the actual position dependingo eda©

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su1abcstawgasat

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andcalcom-cturenalalso

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n weather the non-substituted N–H group is linked to aryl or alkyl substituents. The N–H band of thetrans II rotameric structure is observt 3430–3420 cm−1.2004 Elsevier B.V. All rights reserved.

eywords:Substituted ureas; Conformation; DFT calculations; IR spectroscopy

. Introduction

A number of substituted urea and thiourea derivatives werehown to possess pronounced herbicidal, plant growth reg-lating and cytokine activity[1–3]. A number of 1-alkyl--benzyl-3-aryl(or alkyl) ureas were recognized as cytokinentagonists (anticytokinins)[4,5]. It has been shown that theiological activity of urea and thiourea derivatives is stronglyorrelated with their conformational state[6]. The presenttudy aims at establishing the dependencies between IR spec-ral characteristics and conformational state of biologicallyctive tri-substituted ureas containing a benzyl moiety asell as aryl and alkyl substituents. For comparison analo-ous structures with phenyl instead of benzyl moiety werelso investigated. This work is an extension of our previoustudies on the relationship between structure and biologicalctivity as plant-growth regulators of substituted ureas and

hioureas[1–5].There has been a continuous interest in applying IR

nd NMR spectroscopies in characterizing the conforma-

∗

tional equilibrium in different types of substituted ureasthioureas[7–27]. The interest is determined by the biologiactivities of many representatives of these classes ofpounds as well as because of the closeness of their struwith amides and thioamides. Ab initio and density functiotheory computations on selected urea derivatives werereported[28–30]. The electronic structure results provideclear framework for analysing the relationship between stroscopic data and conformation.

2. Experiments and computational details

The aromatic ureas studied were synthesized by thaction of isocyanates with amines[31]. The structural formulas of the compounds are given inTable 1. The infraredspectra were recorded on a Perkin-Elmer 983 G spectroat a slow speed in dilute tetrachloromethane solutions.recorded frequencies are accurate to±1 cm−1.

Density functional theory computations at B3LYP31G(d,p) level[32–34]were carried out to optimise the g

Corresponding author. Tel.: +359 2 6256421; fax: +359 2 9621913.E-mail address:galabov@chem.uni-sofia.bg (B. Galabov).

ometry and evaluate properties of the conformers for severalcompounds from the series studied. A scaling factork= 0.946

386-1425/$ – see front matter © 2004 Elsevier B.V. All rights reserved.oi:10.1016/j.saa.2004.09.020

1322 B. Hadjieva et al. / Spectrochimica Acta Part A 61 (2005) 1321–1326

Table 1N–H stretching mode frequencies in some trisubstituted ureas in CCl4

No. Compound �N–H cm−1

A B

1 3463 3423

2 3462 3420

3 3468 –

4 – 3430

5 – 3430

6 3463 –

7 3483a –

a From reference[7].

for B3LYP/6–31G(d,p) vibrational frequencies was used. Allcalculations were carried out using the Gaussian 98 programpackage[35].

3. Results and discussion

The principal correlations between vibrational frequen-cies and conformational state of the ureido grouping in ureasand thioureas are well established[10–17,26,28]. The as-signments are mostly based on earlier correlations betweenconformational isomerism and vibrational frequencies estab-lished by Russell and Thompson[36], Suzuki et al.[37] andHallam and Jones[38]. It was shown that the position ofthe N–H stretching band in the IR spectra is directly linkedto the rotational isomerism of theCO NH moiety. Thefollowing main rotameric forms of this grouping have beenestablished:

ationf efT t

15–30 cm−1 lower than thetransband[10–17]. In most casesof dialkyl, alkylaryl, and diaryl ureas containing two NHgroups, only a single N–H stretching band is experimentallyobserved[10–17].

Two monomeric N–H stretching bands have been found inurea derivatives containing bulky substituents[12,13]. It wasdiscussed that steric hindrance in such molecules causes arelative stabilization of bothtrans and cis rotamers of the

CO NH grouping resulting in the appearance of N–Hbands originating from these structures.

Two NH stretching bands were also found in the infraredspectra ofortho-hydroxyphenyl andortho-halogenophenylsubstituted ureas[14,16,18,19]. The higher frequency band isassigned to N–H bonds adjacent to the alkyl or unsubstitutedphenyl groups, while the lower frequency band is attributedto N–H bond involved in hydrogen bonding with theortho-hydroxy orortho-halogene substituents in the aromatic ring.

In the present study the IR spectra of several trisubsti-tuted aromatic urea derivatives in dilute CCl4 solution wererecorded. The respective structures are shown inTable 1to-gether with the recorded experimental N–H stretching modefrequencies. As already emphasized, the established probefor the conformational state of the ureido grouping is theN–H stretching mode frequency. In the spectra of 1-alkyl-1-benzyl-3-phenyl ureas (compounds 1 and 2,Table 1) twowell-defined N–H bands are observed though just a singleN ev-i ota-t Cls ratured –Hb -a othert unds4 nd.T ed ast d tot e ob-s giono l-3-p

ob-s rpre-t theya s thed tiont zyl-1 veralp al-t withr areliT rma-t of are

In absence of steric hindrance the preferred conformor NH CO in ureas istrans. The typical frequency rangor the N–H stretching mode frequency is 3445–3430 cm−1.he NH frequency for thecis conformers is usually a

–H bond is present in the molecules. This is a cleardence for the existence of equilibrium between two rional forms at ambient temperature in the non-polar C4olvent. These results are somewhat unexpected. Liteata show[10–16]that in tri-substituted ureas a single Nand corresponding totrans NH CO conformation is usully observed. The experimental spectra of the several

ri-substituted ureas studied in the present work (compo–7,Table 1) also contain just one N–H stretching mode bahe observed N–H bands in these systems are assign

ypes A and B bands. The assignment is simply relatehe frequency intervals in which the respective bands arerved. The infrared spectra in the N–H stretching ref 1-benzyl-1-methyl-3-phenyl urea and 1-benzyl-1-ethyhenyl urea are shown inFig. 1A and B.

The type A band in the substituted benzyl ureas areerved at a higher frequency range. The dominant inteation of these higher frequency bands in ureas is thatre due to non-planar conformations. In order to asseseviation from planarity in these derivatives density func

heory computation at B3LYP/6–31G(d,p) level for 1-ben-methyl-3-phenyl urea were performed. There are seossible rotameric forms of the compound that arise from

ernative orientations of the methyl and benzyl moietiesespect to the CO group aside from the conformers thatinked to thecis and trans forms of the CO NH group-ng. The theoretical data obtained are presented inTable 2.he computations reveal that two stable transoid confo

ions, termedtrans I and trans II, can be formed. The tworms in the case of 1-benzyl-1-methyl-3-phenyl urea

B. Hadjieva et al. / Spectrochimica Acta Part A 61 (2005) 1321–1326 1323

Fig. 1. Infrared spectra (CCl4 solution) in the N–H stretching region of 1-benzyl-1-methyl-3-phenyl urea (A), 1-benzyl-1-ethyl-3-phenyl urea (B), 1-methyl-1,3-diphenyl (C), and 1,1-dimethyl-3-phenyl urea (D).

illustrated inFig. 2. The estimated deviation from planarityfor the CO NH structure is 11–15◦ for these conformers.There is quite significant frequency separation between thetwo transconformations. The higher frequency band (A type

Fig. 2. Thetrans Iandtrans II rotameric forms in the case of 1-benzyl-1-methyl-3-phenyl.

band) is associated with transoid orientation of the alkyl sub-stituent with respect the CO group. Then lower frequencyband (B type band) is due to the second transoid form. Therespectivecisstructure is also a minimum in the potential en-

1324 B. Hadjieva et al. / Spectrochimica Acta Part A 61 (2005) 1321–1326

Table 2B3LYP/6–31G(d,p) optimized energies and calculated N–H stretching frequencies for the three main conformational isomers ofN-phenyl-N′-di-substitutedureas

Conformera E (Hartree) Erel (kcal mol−1) ∠ HNCO(degree)

Calculated�N–Hb (cm−1) Experimental

�N–Hc (cm−1)

trans I trans II cis

1-Benzyl-1-methyl-3-phenyl ureatrNH-cisPh-trMe-cisBe −766.0068222 0.00 168.8 3455 – – 3463 –trNH-cisPh-cisMe-trBe −766.0060888 0.46 165.0 – 3414 – – 3425cisNH-trPh-trMe-cisBe −766.0022664 2.86 11.5 – – 3411 – –

1-Methyl-1,3-diphenyl ureatrNH-cisPh-trMe-cisPh′ −726.6868388 3.59 170.7 3464 – – – –trNH-cisPh-cisMe-trPh′ −726.6925604 0.00 176.9 – 3433 – – 3431cisNH-trPh-trMe-cisPh′ −726.6810015 7.25 10.6 – – 3416 – –

1-Benzyl-1-ethyl-3-phenyl ureatrNH-trEt-cisBe −805.3254919 0.11 179.1 3462 – – 3461 –trNH-cisEt-trBe −805.3256614 0.00 164.6 – 3412 – – 3420cisNH-trEt-cisBe −805.3185951 4.43 10.7 – – 3406 – –

1-Dimethyl-3-phenyl ureatrNH-cisPh-diMe – – 172.9 3463 – – 3465 –

a Formal description of the conformers. The conformation of the respective ureas is expressed by the orientation of the substituents and NH group withrespect to the CO group. For instance: trMe should read trans methyl.

b Scaled with a factor of 0.946 for the best fit to experimental frequencies.c In CCl4 solution.

ergy surface. However, the theoretical computations revealthat the energy of thecis form is much higher than the ener-gies of the respectivetrans I andtrans II forms. Populationcalculations show that the amount of this form will be lessthan 1% at ambient temperature. Thus, it cannot appear inthe respective IR spectrum. The high frequency range for theA type bands (Tables 1 and 2) can be attributed to increasedN–H force constants as result of added alkyl substituents[28]and, partly, to the deviations from planarity of theCO NHgrouping.

The appearance of a second lower frequency band (typeB) in 1-alkyl-1-benzyl-3-phenyl ureas is quite interesting.Though the frequency range for this band indicates the pos-sible appearance of acis CO NH structure, its presenceat ambient temperature is unlikely as discussed earlier. Thusthe band is assigned to a second transoid structure in whichthe aromatic ring of the benzyl moiety is situatedsynto theN–H bond. Such a configuration results in considerable low-ering of the calculated NH stretching frequency in accor-dance with the experiment (type B band). An interpretationof the origin of the B bands can be based on the hypothe-sis proposed in early studies of Suzuki et al.[37,39]. Theauthors investigated the intramolecular interaction betweenthe N–H bond and the phenyl ring inN-methyl-N-phenyl ac-etamide. They suggested that the N–H bond might interactwith the phenyl�-electrons forming a weak hydrogen bond.B d the� ap-p eoryc gestt ggestt

in compounds 1 and 2 of the present series explains in themost plausible way the appearance of two N–H bands inthe IR spectrum in CCl4 solution at ambient temperature.The N–H bands due to the two forms are clearly seen inFig. 1A.

In the IR spectrum of 1-benzyl-1-methyl-3-ethyl urea(compound 3,Table 1) just a single high frequency N–H bandis observed (Table 1). It can be argued that the N–H bond inthis compound is much less acidic compared with the re-spective bond when attached to an aromatic ring. Therefore,an intramolecular interaction between the N–H bond and thearomatic�-electrons in this compound is less likely.

An interesting basis for comparison with the properties ofthe tri-substituted ureas discussed so far is offered by the spec-troscopic characteristics of structural analogues containing asecond phenyl instead of benzyl substituent (Table 1). Thetwo compounds from this group have a single N–H stretch-ing band in the IR spectra at 3430 cm−1. Theoretical com-putations on the respective 1-methyl-1,3-diphenyl urea areshown inTable 2. It is seen that there is significant energydifference between the lowest energytrans II form and thetwo other possible conformers:trans Iandcis.Thus, the the-ory predicts that at ambient temperature thetrans II formwill strongly predominate and the IR spectrum will containabsorption arising from this rotamer only. The prediction isin full conformity with the experimental results (Fig. 1C,T cya ther malld uredp ter-a ted

y analogy such interaction between the N–H bond an-electrons of the aromatic ring in the benzyl moietyears possible. B3LYP/6–31G(d,p) density functional thomputations on 1-benzyl-1-methyl-3-phenyl urea sughat such interaction is realistic. The present results suhat equilibrium betweentrans Iandtrans II conformations

able 1). A single N–H band is observed with N–H frequent 3430 cm−1. The band position is slightly higher thanespective N–H bands in the benzyl derivatives. The sifference can be attributed to geometrically more favoositioning of the benzyl grouping for intramolecular inction of its�-electrons with the N–H bond. The predic

B. Hadjieva et al. / Spectrochimica Acta Part A 61 (2005) 1321–1326 1325

Fig. 3. B3LYP/6–31G(d,p) optimized structure of thetrans II form of 1-methyl-1,3-diphenyl urea.

structure of thetrans II form of 1-methyl-1,3-diphenyl ureais shown inFig. 3.

The influence of benzyl or phenyl moieties situated at oneof the nitrogen atoms in the urea derivatives on the posi-tion of the characteristic band of N–H group situated at theother nitrogen atom of the ureido grouping can be assessed bycomparing the spectroscopic results for the two types of ureasdiscussed so far with tri-substituted ureas that do not containan aromatic ring at the neighbouring nitrogen atom. The IRspectrum of 1,1-dimethyl-3-phenyl urea in CCl4 (Fig. 1D)contains a single N–H band at 3463 cm−1 corresponding toA type bands (compound 6,Table 1). Similarly, a high po-sition for the N–H stretching band frequency is observed inthe spectrum of 1,1,3-trimethyl urea (compound 7,Table 1).In this case the very high value of the N–H stretching bandfrequency can be attributed to the absence of resonance in-teraction between N–H and the aromatic ring that makes theN–H bond more acidic and weaker.

4. Conclusions

Experimental IR spectroscopic data for the N–H stretchingmode frequencies for several types of tri-substituted ureas aswell as theoretical results from B3LYP/6–31G(d,p) computa-t ovides te oft d intm dat ter-a gena f thet hert the

non-substituted N–H group is at the aryl or alkyl substituents.The N–H band of thetrans II rotameric structure is observedat 3430–3420 cm−1.

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