Structures of cyclic amides

3oumaI

of Molecular

Structure

413

Elsevier Publishing Company, Amsterdam. Printed in the Netherlands

STRUCTURES

OF CYCLIC

AMIDES.

PART

1, MONOMERIC

SPECIES*

H. E. HALLAM AND CHRBTINE M. JONES

of

Department

Chemistry,

Uniitersify

Coifege

of Swansea,

Singleton Park> Swansea ( WaZes)

(Received December 4tb, 1967)

INTRODUCTION

Although the trans planar configuration (I) of the peptide link has long been accepted as the predominant conformation in protein structures’, the cis configuration (II) has been proposed2 for some of the residues of fibrous proteins.

trans configuration has also been recognised as predominant in N-monosubstituted straight-chain amides3y4 and in cyclic amideP (III) for ring sizes ~27. More recent work by Luck’ and Shablygin et al.’ confirms that for n< 7 the -CO-NHgroup is constrained to adopt the cis configuration (IV) but for n = 7 The

uIx)

UXZI

the two isomers co-exist in comparable proportions. Recent studies of the amide group in N-monosubstituted amides by Lumfey Jones9 and in anilides by Suzuki et aI.‘* have established the co-existence of cis and trans rotimers in extremely dilute solutions in Ccl,. The relative concentrations of the two forms have been shown to depend upon the size of the amide-nitrogen and carbonyl-carbon substituent and of those groups adjacent to them. Lumley Jones’ results suggest that for the cis and trans isomers of the N-monosubstituted amides to co-exist, the largestgroups which can be accommodated together on one side of the peptide link are an ethyl and an isopropyl group. The studieS described here were initiated to determine the steric conditions Soectroscoav. Seatember * Pa-r gmsentedat the 9th Europeari Congress on Molecular -c---m---r*, _Madrid_______ _-~__----1967. J. Mol.

Structure,

1 (1967-68) 413-423

414

H. E. HALLAM,

C. M. JONES

for the co-existence of cis and trans isomers in cyclic amides and to establish the solvent sensitivity of their v(N-H) frequencies.

EXPERIMENTAL

Spectra were recorded with a Perkin-Elmer 225 spectrometer using conventional liquid cells. Frequency values of sharp bands have a precision of f 1 cm- 1 and relative shifts one of 0.5 cm- ‘. Solvents were either Spectrosol grade or reagent grade, distilled before use until their b.p.s agreed with literature values, All were rigorously dried with the appropriate drying agents, stored over molecular sieves, and checked for purity by GLC. Research samples of the n = 3-7 and 9-11 lactams were obtained from B.A.S.F., Ludwigshafen, by courtesy of Dr. Werner Luck. Pelargolactam was synthesised in these laboratories by the method of RuZiCka et al.‘l; the crude lactam was twice sublimed at - 100” and 0:3 mm to give a product of m.p. 138-141”.

RESULTS AND DISCUSSION

Before describing our results we list the criteria which can be set up (see, for example, refs. 9 and 10) for the presence or absence of the cis and trans forms of the monomeric amide group. In the 3~ region the following seem to be definitive: (a) v(N-H) monomeric. The trans form gives a sharp peak in the range 34703440 cm- ’ in dilute Ccl, solutions, the cis form a similar absorption 2040 cm- ’ lower. In the 6~ region the amide II band has also been used as an indication of the presence of the trans conformation. (b) Amide II. 1570-1510 cm-‘. Huisgen6 et al. found this to be absent in lactams for n-_(6 but consistently present when nZ8. For the transition stage n = 7, a weak absorption was observed in CHCl s solution indicating the presence of about lO-15% trans isomer. The work of Beer et al.“, however, suggests that the amide II absorption is present in some cis lactams but is very weak. v(N-H) frequencies of monomeric laciams Our spectra of the 3/r region for the n = 3-11 lactams at about 0.002 k in Ccl4 solutions are shown in Fig. 1. These clearly demonstrate the reversion of cis to trans as n increases beyond 7 and the ring becomes flexible. An interesting feature which arises for the n = 7 compound is a quartet of monomeric v(N-H) frequencies. For the n = 8-11 lactams the trans band appears as a well-resolved doublet and a weak band is found at a position-corresponding to a cis conforma3. Mol. Structure, 1 (1967-68) 413-423

STRUCTURES -O-002&

OF MONOMERIC

in 2cm

-aOOCSM

cells

m

._rl SIC.”

cm-’

--

CYCLIC

n -_-_____3

____

in lcm ce& .LC^ IP2.2

hkl

--___

--W...“-__--4

415

AMIDES

_ 10

cm-*

2

3

5

___-

___I

.

.._8_____

7

9

to

I IV

j

Fig. I. 3~ and 6,~ region spectra of lactams in Ccl,. Fig. 2. 3~ region of capryllacram in representative solvents of Table 2.

TABLE

1

z’(N-HI

FREQUENCrrS

(IN CITx)

OF LACTAMS

I

(CH,),

1

CO-NH

M 0.002 J?# Ccl,

SOLUTIONS

AND

2 cm P.hx-HLENGTHS n

3 4 5 6 7 8 9 10 11

Band

3455 3418.5

3360 sho 3385 Y. w. 3430

3461.5 3471.5 3470.5 3464 3467

3457 3458 3455 3452.5

3442

3417.5 3415.5

3410 3397 3397 w

tion (Table 1) for n =t8. Signsof a doubletarealsofoundwithsomeof thecis lactams and then = 8 and 10 &tams showa shoulderon thehid-frequency sideof thetrstns doublet. Severalof thesefeatureshave also beenreportedby Shablyginet al. in a work which appeared?in.the courseof our investigations,However,thereare SW: J. Mol.Structure, 1 (1967-68)

413-423

416

H. E.

HALLAM,

C. M. JONES

era1 discrepancies between our results and theirs and they give little discussion of the structures which give rise to the multiple bands. In an effort to determine the orientations of the four confo~ations of caprylfactam and the two trans forms of the n = s-1 1 lactams we have made a comprehensive study of the solvent sensitivity of all four moilomeric absorptions and of representative cis and trans structures (Fig. 2, Table 2). TABLE 2 W-H)

STRETCHING

FREQUENCIES (Cm-‘) tl=5

Band

CCl,FCCSF= n-Hexane ccl* C&l, CHCI, CHCl&HCI, CHsCls C% CHBrs C,H,CI CH,CIC!H,CI C,H,Br C,H, C,H,N% Toluene o-Xylene Mesitylene CH,CN Ethyl acetate Acetone Dioxan Di-n-butyl ether Diethyl ether

DMSO

3434 3430 3421 3418 3417.5 3419 3410 3419 3413

n=

7

n=8

skew 1

skew 2

cis f

cis N

3467 3465 3461.5 3460.5 3458 3454 3451 3451.5 3449 3443

3447 3444 3442 3441 3439 3437 3434 3433 3433 343 1 3430.5 3428 3423.5 3424 3420.5 3417 3413.5

3423.5 3420 3415 3415 3406 3403 3402 3405.5 3395 3403 3392 3400 3387 3406 3390 3382 3367

3404

3415

3416.5 3414 3410 3399.5 3394 3388 3382.5 3379.5 3351.5 3352 3350.5 3264.5

OF LACTAMS IN VARIOUS SOLVENTS

3434 3433 3429

3396 3397 3395 3393 3394 3392 3385 3387 3392 3390

3390 3380 3378

3389 3403’ 3378 3376

3306*

3370

3350 3340 3340

tram I

tram If

3474 3470.5 3466

3462 3458 3456.5

3464

3458

3452.5

3450 3449 3450 3445 3448 3446 3444 3439 3433 3435 343 1 3426 3402 3409 3394 3379.5 3380 3375.5 3297.5

l The bands are assigned to skew or cis by comparison with the trans and cis bands of n = 8 and n = 5 respectively.

All exhibit the pattern of solvent shifts found for v(N-H) absorptions13 and yield straight lines when their relative shifts, Av/v = (v~~~--v,)/v~~~,are plotted against the corresponding shifts of v(N-H) of pyrrole, the %tandard” N-H absorption. As the solvating power of the solvent increases the bands are seen to merge so that the upper part of some of the plots becomes a little doubtful, but the major bands can be identified with some certainty and provide extremely good plots (Fig. 3). These confirm that all absorptions arise from H-N stretching vibrai tions. Taking the eskblishkd structures first we see that caprolactam (n = 5, .T. MaL

Sfrucfure,

1 (1967-68j 413-423

STRUCTURES

OF MONOMERIC

CYCLIC

AMIDES

Coprinloctom

‘*Q

Fig. 3. Relative shifts of z0M-I) bands of (a) caproIactam (cis I), (b) capryllactam (skew II), (c) caprinlactam (trans II), plotted against the corresponding shifts of @I-H) pyrrole_ For soIvent numbering, see Table 2.

cis) shows a regular frequency lowering with no anomalies and a slope S = 2.00. For caprinlactam (n = 9, trans) the higher trans-I absorption soon merges into the dominant trans-IL band which progressively moves to lower frequencies giving an identical S value = 1.98. These values can be compared with thoseI for N-methylacetamide, 1.49, and N-ethylacetamide, 1.59, which are thus more solvent sensitive

than the cyclic

structures,

What

perhaps

is surprising

is the identical

sensitivity of the cis and trans conformations. For the four bands of capryllactam (n = 7) it would appear that band I is somewhat more sensitive (S- 1.8) than band II (S = 2-16) and therefore gradually merges with band II as the solvent polarity increases. The same behaviour is observed for the cis doublet except that cis-II is extremely solvent-insensitive (S- 3.5). This suggests a conformation whose N-H is shielded from solvent interaction. In the most polar solvents the quartet merges into one broad band, The solvent in which the bands just coalesce may represent a situation in which the four different solvated conformers possess similar vibrational frequencies, but more probably it means that only one conformer (solvated) predominates. The fact that such shifts only yield meaningful plots for one case (Fig. 3b), that of band II, means that essentially only one species is present in these polar solvents. A similar conclusion has also been reached in the case of the cis-trans conformational equilibria in para-substituted acetanilides, as a result of IR solvent studies15 which are corroborated by dipole moment. studies in benzeneI and in dioxane”. J. Mol. Strucrure, 1 (1967-68) 413-423

418

H. E. HALLAM,

C. M:JONES

Sfrziciures of monomeric iactams In discussing the structures of the cyclic amides there are two main factors to be considered_ Firstly, the stabihsation due to deloealisation of the nitrogen p orbital and the carbonyl K orbital which is at a maximum when the amide group is planar,. whethe t in ihe cis or the tram conformation, SecondIy, the constraint imposed on the $oupicg by the ring. The foilowing structures are discussed in terms of these considerations and an inspection of both spacefilling and flexiblerod stereomodzls. 2-~yr~;fidone (n = 3). It would appear that the -CO-NH- group is unable to adopt a fully planar cis toleration without introducing some strain into the system. The 3455 cm-’ value of the v(N-H) frequency is anomalous for cis compounds being raised as a consequence of ring strain and possibly also due to non-planarity. +&x?ridone (or ~-~ai~r~~ac~~rn)(n = 4). Two planar cis conformations can be readily constructed which appear to be strainfess, an envelope (V) and a boat form (VI)

A haIf chair conformation

(VII)

in which the amide group is not completeIy planar is also a strainless structure. There are clear signs of amonomer ~(~-~)doublet for this factam; the strong band at 3418.5 crnvi we assign to structure VII and the very weak band at 3385 cm-l to small amounts of structure V and/or VI. Further evidence in favour of configuration VII is that a recent X-ray diffraction study” has shown this to be the crystal structure of ar-chloro-S-valerolactam. Caproktczm (n = 5). At least two planar cis conformations. of envelope and boat type are possible as is afso a non-planar buckled structure corresponding to WI. Only- one monomeric v(N--ET) is observed, at 3430 cm-l, which we assign L Mol. Sriucture,I (1967-68) 413-423

STRUCTURES

OF MONOMERIC

CYCLIC

AMIDES

419

to One of the cis Iljlanare~n~or~t~~ns on the basis that there can be little strain in a 7”membered ring and that delocalisation, will be dominant. E~~~~~~~f~~ (n = 6;). The additionai C atom gives more flexibility but still ins&Ecient for the amide group to adopt a tr~sco~~~~on. A planar cis grouping can exist in a puckered ring ~&~~espondingto IX) and a boat-type canfurmation (corresponding to X). These appear to be delineated by the 341?.5~?410 cm - ’ dauMet_ Capryriactam (n = 7). From the evidence” of the amide II absorption the n = 7 ring has for some time been accepted as the stage at which the ring is sufficiently flexible to allow the peptjde link to adopt its preferred trans conformation and to co-exist with the cis form. Our dilute solution studies of v(N-H) indicate the presence of four rather than two conformations. A similar v(N-H) quartet was found by Shablygin et a1.8 and assigned simply to two cis and two trans structures. Lack? assigns the bigher-frequency pair of his 2v(N--H) overtone frequencies to two trans c~~g~rations corresponding to the N-I-I bond facing inwards (III) or outwards (VIII)

from the ring. EIe mentions the possibility of a similar interpretation for his cis doublet but nut surprisingly does not press the suggestion of a cis ~un~~rmatiun with both gr~~.~psfacing inwards in a ring of size n = 7. Our finding of a similar splitting for the n = 6 lactam renders such an interpretation even more unacceptable. We find that the n = 7 ring is sufficiently supple for several puckered strainfree planar cis amide structures to exist but it is impossible to have one in which the grouping is ‘“inside”’the ring. In the puckered str~~cture(IX) the N-H bond is freely accessible and on the basis of solvent sensitivity we would assign the band at 3415.5 cm-’ to this conformation.

a9

The boat-type c&Grmation

@Cl brings a methylene hydrogen stifliciently close

H. E.

420

HALLAM,

C. M. JONES

to the N-H group to cause appreciable hindrance to solvation and allows us to assign the 3397 cm-’ band to it. A strainless planar trans structure is not possible but several skew structures (approximately 45” from trans) are. Delocalisation energy is unlikeiy to overcome ring constraint in this system and we feel the structures are better described by skew rather than trans. One such puckered structure gives a readily accessible N-II and can account for the solvent-sensitivity of the 3461.5 cm-” band. Its position is also more compatible with a skew structure since a strained trans configuration would cause the frequency to rise above 3470 cm-‘, the value in the strainifree structures of the higher lactams. A boat-type skew structure causes some steric hindrance of the N-H link and we suggest is responsible for the 3442 cm-’ absorption. n = 8-11 iuctams. The n = 8 ring appears to be the first in which a planar traus configuration can be strainless. The two structures proposed by Luck7 are now feasible, i.e. N-H “inwards” or “outwards” and we take these to account for the trans doublet in all these lactams. The separation in all cases (9-14 cm-l) is insufficient to allow the solvent-sensitivity criterion to be used on each component but the main peak shows the expected behaviour (e.g. Fig. 3~) for a free v(N-H). An additional feature observed for the n = 8 compound in dilute Ccl, solutions is a weak absorption at 3397 cm-’ which we attribute to the co-existence of cis-isomers. It corresponds to about 5% cis molecules and adds support to the recent findings of Lumley Jane=-’ for the N-substituted amides. Indications of a weak absorption in this vicinity were occasionally found for the n = 9-l 1 compounds and may also indicate traces of cis monomers. For the n = 8 lactam also, Shablygin et al8 report four v(N-H) frequencies in the monomer range. We have repeatedly checked this and are unable to reproduce their findings; nor do we find a v&=0) doublet which woufd be expected to accompany a Y(N-H) quartet. Two of their bands (3472 and 3457 cm-‘) are identical to ours and, if it is very weak (they give no indication of intensities), so does their band at 3395 cm-’ agree with ours at 3397 cm-‘. We can only assume their 3430 cm- 1 feature is due to an impurity, possibly of caprolactam. v(C= 0) frequencies ~amide I) of ~onu~eric

~aGram~

It is well known (see, for example, Bellamy’s source-book’g) that in cyclic compounds carbonyl frequencies are raised as the ring size is decreased from a 6- to a 4-membered ring_ This is attributed to ring strain although Hall’* prefers an interpretation in terms of the hybridization of the carbon atom in the carbonyl group. As the ring is contracted, the ring bonds to this carbon becomes moredin character, which conforms more s-character in the carbonyl bond. This strengthening of the C= 0 bond will be reflected in a higher force constant and hence a higher vibrational frequency. .T. Mof. Structure,

1 (1967-68)

413423

STRUCTURES

OF MONOMERIC

34567691011

Fig, 4. Plot of v(C=O)

CYCLIC

AMIDES

421

n

of lactams in dilute CCII sob. against n.

Spectra of the lactams in the 6,s region were examined at --O.OOMM in CCI, in 1 cm pathiengths (Fig_ 1). A clear pattern of behaviour of the monomeric v(C= 0) was observed (Fig. 4) including a well-defined doublet for capryltactam. This behaviour paralIels that of the v(N-H) modes and fully confirms the strain invoIved in 2-pyrrolidone and the skew conformations of capryllactam. A skew configuration drasticaliy reduces the p-n overSap and thus the v(C= 0) might be expected to rise towards a “normal” value (> 1700 cm-’ e-f. Chap. 12 of ref. 19). The v(C= 0) for the n = 8-11 compounds are not resolved into doublets corresponding to those of v(N-H) but this is not surprising when the t@&-H) splitting is only 9-14 cm-‘.

Amide N fieqwacies It is impossibie to investigate amide II in extreme dilution in CC& because of strong solvent absorption in this region. We have examined the band at meditmi to high concentrations and the results will be discussed”* in terms of the association characteristics in Part 2. We find a medium band due to monomeric species at 1509 & 4 cm- 1 for compounds with n2_ 8 and the complete absence of this absorption for n s 6. This fufiy confirms the work of Huisgen et al- in the more polar solvent CHCl 3For caprylfactam (fz = 7) we find a very much weaker band at about 1504 cm-’ which from its sJ.ightlydifferent position we can assign to the skew conformations. The very fact that the absorption occurs at all suggests that the skew configurations are closer to trans rather than cis,

The results illustrate the important

of performing extreme dilution studies,

422

H. E. HAL-LAM,

C. M. JONES

preferably in a variety of solvents, when the maximum information on molecular conformations is required, Consequently the cis-trans criteria for cyclic peptide links can now be made more precise. Criteria for the presence of tram und cis_fiirms of the peptide l&k in cycli’c structures with ring sizes b 5 Conformation

Monomer

rrans cis

3480-3450 3435-339s

absorptions

in CC&

1681 f3 167245

150914 absent

If we include the recent studies on anilidesl’ and N-monosubstituted amidesQ, the range for the v(N-H) monomeric in Ccl, overlap slightly and become extended to: trum -CO-NH3495-3434 cm-’ for cyclic and acyclic peptide links 3440-3395 cm-r cis -CO.NHThe thio analogues exhibit4*10s’5 similar conformational equilibria but as they consistently absorb at lower frequencies they should be treated separately. They absorb in the foIlowing ranges: 341 l-3398 cm-r tram -CSNH-CS-NH3378-3368 cm- ’ cis

ACKNOWLEDGEMENTS

We are indebted to the Hydrocarbon Research Group of the Institute of Petroleum for financia1 support and to the S.R.C. for a research studentship (to C.M.J.) and for the grant for the purchase of the spectrometer. We also thank Dr. Werner Luck of B.A.S.F. for so kindly providing the la&am samples and Mr. I. H. Rogers for synthesizing pelargolactam.

SUMMARY

A comprehensive concentration and solvent study has been made of the N-H and C=O vibrational frequencies for the n = 3-11 factams, (C!H. Several new features are reported and the results are discussed in terms of cis, trans and skew configurations of the peptide link. In the case of the IZ= 7 compound four different monomeric conformations, (two skew and two cis), are shown to co-exist. For the n = ‘8 lactam in dilute solution small quantities of cis isomers are shown to co-exist with the. trans isomers. J,.Mol. Srructwe,

1 (196748)

413-423

STRUCTURES

OF MQNOMERIC

CYCLIC

AMIDES

423

Revised IR criteria are presented for cis and tram conformations of the peptide link in cyclic and acyclic amides.

REFERENCES 1 J.DONAH=, Proc. Natl Acud- Sci. U.S., 39 (1953) 470. 2 L. PAULING AND R. B. COREY, Pruc. Nuti. Acad. Sci. U.S., 37 (1951) 256. 3 S. MIZUSHIMA, T. SHIMANOUCHI, S. NAGAKURA, K. KURATANI, M. Tspor, H. BABA AND 0. FUSIOKA,J. Am. C’hem. Sot., 72 (1950) 3490. R. A. RUSSELLAND H, W. THOMPSON, Spectrochim. Acta, 8 (1956) 138. U. SCHIEDT,Angew. Chem., 66 (1954) 609. R, HUISGEN, H. BRADE, H. WALZ AND I.GLOGGER, Chem. Ber., 90 (1957) 1437. W. LUCK, 2. Naturwissensch., 2 (1965) 25. M.V. SHABLYGIN,D.N.SHIGORINAND M.V.MIKHAILOV, Zh. Prikl. S’ektroskopii, 3 (1965) 56. 9 R. LUMLEY JONES,Spectrochim. Actu, 23A (1967) 1745. T. SHIMANOUCHI AND S. MIZUSHIMA, Spectrachim. Acta, 16 (1960) 471. 10 I. SUZUKI, M. TSKJBOI. 11 L. Ru%&cA, M. KOBELT, 0. HAFLIGER AND V_ PREI-OG, Web Chim. Acra, 32 (1949) 544. 12 M. BEER, H.. B. KE.S%ER AND G. B. B. M. S~JTHERLAND,J. Chem. Whys., 29 (1958) 1097. AND H. E. HALLAM, Trans. Faraday SW., 58 (1962) 40. 13 E. A. -ORE 14 E. A. CUTMOREAND H. E. HALLAM, Proc.4th Conference of European Molecular Spectroscopy, Bologna, 1959, Pergamon Press, London, 1961; E. A. CUTMORE, M. SC. Thesis, University of Wales, 1961. I5 L. K. DYALL AND J. E. KEMP, Spectrochim. Act@, 22 (1966) 483, 16 J. W. SMITH,J. Chem. Sac., (196i) 4700. 17 M. GOMEL AND H. LUMBROSO, Bufl.Sot. Chim. France, (1962) 1196. 18 C. ROMERS,E. W. M. RU-I-I-EN,C. A. A. VAN DREEL AND W. W. SANDERS, Acra Cry& 22 (1967) 893, 19 L. J. BELLAMY, Infrared Spectra of Complex Molecules, 2nd ed., Methuen, London. 1958. 20 H. K. HALL, JR. AND R. ZB~EN, 3. Am. Chem. Sot., 80 (1958) 6428. 21 H-E. HALLAM AND C M.Jom,.K. Mol. Srractwe, 1 (1968) 425. J. Mol. Sirucrure, 1 (1967-68) 413423