Conformational Analysis of Dipeptide-Derived Polyisocyanidesmate.tue.nl/mate/pdfs/3377.pdf · 2004-01-14 · Conformational Analysis of Dipeptide-Derived Polyisocyanides JEROEN J

Conformational Analysis of Dipeptide-DerivedPolyisocyanides

JEROEN J. L. M. CORNELISSEN,1 W. SANDER GRASWINCKEL,1 ALAN E. ROWAN,1

NICO A. J. M. SOMMERDIJK,2 ROELAND J. M. NOLTE1,2

1Department of Organic Chemistry, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands

2Laboratory for Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB,Eindhoven, The Netherlands

Received 20 January 2003; accepted 17 March 2003

ABSTRACT: The conformational properties of polymers derived from isocyanodipeptideshave been investigated with a combination of model calculations, X-ray diffraction, andcircular dichroism spectroscopy. Depending on the configuration of the side chains,defined arrays of hydrogen bonds along the polymeric backbone are formed. This leadsto a well-defined conformation as, for example, expressed in the formation of lyotropicliquid-crystalline phases and increased helical stability. Upon the disruption of thehydrogen bonds by a strong acid, a less well-defined macromolecular conformation isobserved. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 1725–1736, 2003Keywords: biomimetic; chiral; conformational analysis; modeling; polyisocyanides

INTRODUCTION

The function of biopolymers, such as proteins,RNA, and DNA, is strongly related to their sec-ondary structure. Similar correlations have beenfound between the physical properties of syn-thetic polymers and the conformations of theirmacromolecular chains.1 In particular, helix for-mation has recently received considerable inter-est because it can be used to control the organi-zation of synthetic macromolecules at differenthierarchical levels.2–6

Polyisocyanides are a member of this class ofhelical polymers and have the exceptional feature

that every carbon atom in the polymer backboneis provided with a substituent. On the basis ofmolecular models, Millich7 proposed a 41 helicalconformation for the main chain in polyisocya-nides. Experimental evidence for the helicalstructure was first provided by Nolte and cowork-ers;8,9 with chromatography they were able toresolve the polymer of achiral tert-butyl isocya-nide into the two optical antipodes. The opticalactivity in this case was solely originating fromthe conformation of the polyisocyanide backbone,which was stable even at elevated temperatures.By the application of Ni(II) as a catalyst, a largenumber of polyisocyanides have been preparedusing different approaches to create an excess ofeither left- or right-handed helices.10

The conformation of polyisocyanides with sidechains sterically less demanding than thosepresent in poly(tert-butyl isocyanide), however, isstill under debate. Computational studies11–14

have indicated that the 41 helix, particularlywhen bulky substituents are present, is the mostfavorable conformation. More recently, this con-

This article includes Supplementary Material availablefrom the authors upon request or via the Internet at http://www.interscience.wiley.com/jpages/0887-624X/suppmat/2003/41/11/v41.1725.html.

Correspondence to: J. J. L. M. Cornelissen (E-mail:[email protected])

Correspondence to: N. A. J. M. Sommerdijk (E-mail:[email protected])Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 41, 1725–1736 (2003)© 2003 Wiley Periodicals, Inc.

1725

formation was recognized as a local minimum,whereas the so-called syndio conformation wasconsidered to be the absolute minimum.15 Exper-imental investigations toward the conformationof polyisocyanides are limited. Green et al.16

showed that sterically unencumbered polyisocya-nides have a limited persistence length of approx-imately 3 nm. In the case of polyphenylisocya-nide, a combination of gel permeation chromatog-raphy, light scattering, and X-ray diffractionrevealed that the native polyisocyanide has arigid-rod character, but the polymer slowly pre-cipitates from solution as a random coil.17 Thesedata suggest that the helix inversion barrier inpolyphenylisocyanide is not sufficiently high tocreate a stable helical conformation at room tem-perature, and as a result of the nickel(II)-cata-lyzed merry-go-round polymerization mecha-nism,10 the 41 helix is initially formed as thekinetic product.17

In many biopolymers, a combination of (nonco-valent) interactions is required to maintain a sta-ble secondary structure in solution. In the field ofhelical polymers, examples of the combined use ofsuch interactions are rare, and in the reportedcases, mainly steric interactions have been usedto realize a high helix inversion barrier.4,18–20

Recently, we have shown that the presence ofwell-defined hydrogen-bonding arrays betweenthe side chains of peptide-based polyisocyanidescan lead to stabilization of the helix structure ofthese polymers.21 In this article, we describe inmore detail the physical properties of polyisocya-nides prepared from alanyl–alanine-based andalanyl–glycine-based monomers (Chart 1).22 Theconformations of these polymers are discussed inconnection with their ability to form extendedarrays of hydrogen bonds that stabilize their sec-ondary structure.2–6,21 The physical properties ofpeptide-based polyisocyanides previously re-

Chart 1

1726 CORNELISSEN ET AL.

ported by our group (Chart 1) are reinterpreted,particularly in relation to the presence of hydro-gen bonds between their side chains.

RESULTS AND DISCUSSION

Characterization of the Polymer Structure

For the polyisocyanopeptides derived from L-ala-nyl-L-alanine (L,L-PIAA), L-alanyl-D-alanine (L,D-PIAA), and glycyl-L-alanine (L-PIGA), NMR andIR spectroscopic investigations indicate that hy-drogen bonds are present between the amidegroups in the polymer side chains; for the L-ala-nyl-glycine-based polymer (L-PIAG), no indicationfor the presence of these hydrogen bonds wasfound.22 In these studies, the single-crystal X-raystructure of L-isocyanoalanyl-L-alanine methyl es-ter (L,L-IAA) served as a reference point.21 Forthis monomer, the presence of an intermolecularhydrogen-bonding array (Fig. 1) resulted in acharacteristic NOH stretching vibration in thesolid-state IR spectrum (�NH � 3279 cm�1),whereas no hydrogen bonding was observed in achloroform solution. The IR spectra of the poly-mers all showed NOH stretching vibrations inthe range of 3260–3300 cm�1, both in solutionand in the solid state, implying that they possessa structure in which the side chains have a hy-drogen-bonding arrangement similar to thatfound in the crystal structure of L,L-IAA and, im-portantly, that this arrangement is preserved insolution. Further confirmation of the presence ofhydrogen bonds came from 1H NMR spectra. Allthe resonances assigned to the amide protons of

the isocyanopeptide moieties were significantlyshifted downfield by 1.5–2.5 ppm upon polymer-ization, and this is indicative of very strong hy-drogen bonding. In neither IR nor 1H NMR spec-tra were any signals detected corresponding toamide groups not participating in hydrogenbonds. The absence of the hydrogen-bonding ar-ray in the case of L-PIAG is tentatively explainedby a diminished preorganizing capacity of the gly-cine group in the polymerization reaction.22 Theincreased rotational freedom of the glycine seg-ment in comparison with that of an alanine onemight account for this difference.

As a result of the hydrogen bonds between theside chains, these polyisocyanopeptides are veryrigid, and individual macromolecules could be vi-sualized by atomic force microscopy.23 The lattermethod was used to accurately measure their con-tour lengths, from which the absolute molecularweights could be deduced.21,22 The rigid characterof these polymers is also reflected in the forma-tion of a nematic liquid-crystalline (LC) phase ina concentrated (�10% w/w) solution of L,L-PIAAin CHCl3, as was indicated by the birefringence ofthis solution visualized between crossed polariz-ers (Fig. 2).21 The observed characteristic finger-print texture points to a cholesteric arrangementof the macromolecules,24 as frequently observedfor concentrated solutions of stiff single-handedhelical polymers.25

Figure 1. (A) Single-crystal X-ray structure of L,L-IAA showing three stacked molecules and the intermo-lecular hydrogen bonds21 and (B) schematic represen-tation of the hydrogen-bonding arrays between the sidechains in L,L-PIAA.

Figure 2. Optical micrograph between crossed polar-izers of a 10% (w/w) solution of L,L-PIAA in CHCl3. Inthe diluted solution, the optical rotation amounted to[�]D � 338°.22 For the LC phase, a pitch of 17 �m andan optical rotation of [�]D � �44,000° were observed24 h after sample preparation. These values eventuallybecame 9.2 �m and [�]D � �72,000°, respectively, after40 h of standing (see the Experimental section for mo-lecular weight data).

DIPEPTIDE-DERIVED POLYISOCYANIDES 1727

Powder X-Ray Diffraction (PXRD)

The diameters of the macromolecular rods in thesolid state were determined for L,L-PIAA, L,D-PIAA, and L-PIGA with PXRD. Diffraction pat-terns displaying sharp signals were observed(Fig. 3), which pointed to a regular crystallizationof well-defined macromolecular rods.26 The differ-ences observed in the peak intensities and peakwidths between patterns obtained from powdersand from films spun from CHCl3 solutions may beattributed to local differences in the ordering ofthe rods and/or the presence of solvent molecules.Macromolecular diameters were calculated fromthe diffraction patterns obtained form both typesof specimens. The recorded reflections fitted bestwith an orthorhombic arrangement of the poly-mers (see the supplementary material). With thismodel, the diameters were determined to be 15.9Å for both L,L-PIAA and L,D-PIAA and 16.6 Å forL-PIGA.

Model Calculations

Two different macromolecular conformationshave been proposed for polyisocyanides,10 the 41helix7–14 and the so-called syndio conformation(Fig. 4, top and middle). Clericuzio et al.15 calcu-

lated that the latter conformation is thermody-namically more favorable. In the syndio confor-mation, two adjacent imine groups are in oneplane, which makes an angle of approximately90° with the plane of the next two imine groups.When initially a 41 helix was assumed for bothL,L-PIAA and L,D-PIAA, calculations suggested afinal structure in which the macromolecular rodshad a calculated diameter of 15.8–15.9 Å, a heli-cal pitch of 4.6 Å, and an average spacing betweenthe side chains n and n � 4 of 4.7 Å. In thesecalculations, the polyisocyanides were treated asa polymeric spring of which the extension andcompression elongated or shortened the polymerbackbone and consequently narrowed or widenedits diameter (Fig. 4, bottom). The calculated side-chain spacings of 4.7 Å resulting from this itera-tive procedure match very well with the spacingof 4.728 Å between the amide groups found in thecrystal structure of the monomer L,L-IAA. Thediameters obtained for the macromolecular rodsare in excellent agreement with those determinedexperimentally by PXRD (15.9 Å).27 For L-PIGA,the diameter was calculated to be 16.3–16.5 Å,again in good agreement with the value of 16.6 Ådetermined experimentally (discussed previously).Calculations on L,L-PIAA and L,D-PIAA were alsoperformed with the syndio model, in which the

Figure 3. PXRD patterns of (A) L,L-PIAA as a cast film,(B) L,L-PIAA as a powder, (C) L,L-PIAA as a cast filmafter treatment with TFA, (D) L,D-PIAA as a cast film,(E) L-PIGA as a cast film, and (F) L-PIGA as a cast filmafter the heating of the polymer at 60 °C for 1 h inCHCl3.

Figure 4. Models representing the 41 helical confor-mation of a 20-residue polyisocyanide (top) and thesyndio conformation of a 12-residue polyisocyanide(middle). A schematic representation of the relation-ship between the relative length and diameter of ahelix is also shown (bottom).


NOCOCON dihedral angles were kept close to180° to maintain the conjugation of the adjacentimine groups (Fig. 4, middle). This, however, ledto an average spacing between side chains n andn � 4 of 5.5 Å, which is too large for the formationof well-defined hydrogen bonds; therefore, thesyndio conformation was discarded as being ofrelevance in these polyisocyanopeptides.

Circular Dichroism (CD) Spectroscopy

The helical structure of polyisocyanides can bestudied by CD spectroscopy, which monitors then–�* transitions of the backbone imine functionsresiding in the wavelength range of 250–350nm.28 The direct determination of the macromo-lecular helix sense of polyisocyanopeptides with

this technique is, however, hampered by side-chain contributions to the Cotton effects originat-ing from the backbone n–�* transitions. Never-theless, by a comparison of the CD spectrum of anL-alanine-based polyisocyanide containing a so-called spectator group (i.e., a diazochromophore)with the CD spectra of other L-alanine-based poly-isocyanides, a right-handed (P) helical backbonegeometry has been assigned to these polymers.29

For the polyisocyanodipeptides in which hydro-gen-bonding arrays between side chains n and n� 4 are present, that is, L-PIGA, L,L-PIAA, andL,D-PIAA, the CD spectra display a single strongCotton effect centered around 315 nm (Fig. 5). ForL-PIAG, which does not have well-defined hydro-gen-bonding arrays, the band at 315 nm is absent,

Figure 5. CD and UV–vis spectra in CHCl3 of (A) L,L-PIAA, (B) L,D-PIAA, (C) L-PIGA,and (D) L-PIAG.


and instead a couplet with lower intensity can beobserved.

The difference between these spectra and theones obtained either experimentally10 or theoret-ically (by calculations)15 for aliphatic polyisocya-nides may be attributed tentatively to an effect ofthe side chains on the n–�* transitions of theCAN chromophores. Because of the hydrogenbonds, the amide carbonyls within one particulararray all point in the same direction (Fig. 1). Thiswill locally result in the formation of a large per-manent dipole, which will strongly influence then–�* transitions of the nearby imine groups. Al-though the electronic transitions of the amidefunctionalities cannot be observed directly be-cause they are masked by the solvent absorptions,our present hypothesis is that the ordering ofthese amides is reflected in the imine n–�* tran-sitions.

Unfolding the Secondary Structure of the Polymers

Because the helical structure of the polyisocyan-opeptides appears to be directly related to thepresence of well-defined hydrogen-bonding arraysalong the polymer chain, it was anticipated thatthe disruption of these arrays would lead to dis-tinct changes in the secondary structure andproperties of these polymers. The strength of hy-drogen bonds in solution is strongly dependent onthe type of solvent and usually decreases withincreasing temperature. As the well-defined hy-drogen-bonding arrays between side chains n andn � 4 in the polymers are reflected in the intenseCotton effects, CD spectroscopy was used to studythe effects of changes in these two parameters onthe polymers.

The addition of polar hydrogen-bonding sol-vents such as methanol and dimethyl sulfoxide toPIAA solutions in CHCl3 did not lead to any no-ticeable changes in the CD spectra, and neitherdid the addition of a solution of urea in CHCl3.For L,L-PIAA, it was found that the addition of anexcess of trifluoroacetic acid (TFA) was requiredto disrupt the hydrogen-bonding arrays, leadingto a decrease in the Cotton effect at 312 nm andeventually resulting in a weak negative signal[Fig. 6(A)]. In the case of L,D-PIAA, this decreasewas so fast that no intermediate state could bedetected. The stepwise addition of smalleramounts of acid allowed the recording of the in-termediate spectra [Fig. 6(B)], which showed thatthe strong signal at 307 nm vanished and two newsignals appeared, that is, a positive peak with

��max � 361 nm and a negative signal with ��max� 275 nm.30–33 Also, in the ultraviolet–visible(UV–vis) spectra, significant changes were ob-served; for L,L-PIAA, the band at 308 nm broad-ened and shifted to longer wavelengths. Upon theaddition of TFA, a similar redshift was observedin the UV–vis spectrum of L,D-PIAA; however, inthis case, a more narrow absorption band re-mained, suggesting that this polymer retained aregular structure. This is supported by the higherintensity of the preserved CD signals and thepresence of an isodichroic point at 335 nm, whichindicates that the breaking of the hydrogen bondsinduces a transition to another discrete conforma-tion.30–33 The structural changes induced by TFAon L-PIGA were so fast even in the presence ofsmall amounts of acid that it was impossible toobtain reproducible intermediate spectra; onlythe complete loss of the Cotton effect could beobserved. The absence of a defined hydrogen-bonding array in L-PIAG was further confirmedby the absence of any observable change in thechiroptical properties of this polymer upon theaddition of TFA.

In the IR spectra, the acidification was accom-panied by a small shift of the amide NH vibrationto higher wave numbers. In a representative ex-ample of L,L-PIAA, this shift is �� 23 cm�1, andit is accompanied by the appearance of a shoulderat � � 3395 cm�1, which suggests a weakened orless well-defined type of hydrogen-bonding pat-tern.

With increasing temperature, similar changesin the CD spectra were observed for these poly-mers, with the exception of L-PIAG. The latterobservation is in line with the absence of hydro-gen-bonding arrays in this particular polymer. Inthe case of L-PIGA, the intensity of the Cottonband at 321 nm [Fig. 7(A)] decreased significantlyfaster with increasing temperature in comparisonwith the reduction of the same bands in thePIAAs [Fig. 6(C,D)]. The absence of sterically de-manding groups next to the imine moieties in thepolymeric backbone of this polymer could explainthis effect. After the heating of L-PIGA for 1 h at60 °C in CHCl3, IR studies revealed that hydro-gen bonds were only partially retained, resultingin a pattern similar to that found for L-PIAG.22

The observed nonlinear decrease of the Cottoneffect centered around 321 nm and the increase ofthe absorption band at 346 nm [see Fig. 7(B)]indicate that the unwinding of the helical back-bone is a cooperative process. For the PIAAs, par-tial reversibility was found in this cooperative


unwinding (not shown) when the temperaturewas lowered after it had been raised first stepwiseto 55 °C; this suggested a higher helix inversionbarrier of these polymers in comparison with L-PIGA. This implies that the breaking of the hy-drogen bonds in L,L-PIAA does not immediatelylead to complete unfolding of the helical back-bone; however, after a period of cooling, the well-defined starting situation will not be regained,possibly for entropic reasons.

PXRD patterns were recorded for samples ofL,L-PIAA and L-PIGA in which the hydrogen-bonding arrays had been disrupted (discussedpreviously). In contrast to the situation inwhich these hydrogen-bonding arrays were stillpresent, only broad signals were found in thesesamples [Fig. 3(C,F)]. From the observed reflec-tions, polymer diameters of 16.3 and 17.2 Åwere calculated for L,L-PIAA and L-PIGA, re-spectively, under the assumption that the poly-

Figure 6. (A) Changes in CD and UV–vis spectra with the addition of 18.2% (v/v) TFAto a 2.6 mM solution of L,L-PIAA in CHCl3 [CD spectra: (a) before addition, (b) 1 minafter addition, (c) 6 min after addition, and (d) 17 min after addition; UV–vis spectra:(e) before addition, (f) 3 min after addition, (g) 14 min after addition, and (h) 35 minafter addition], (B) changes in CD and UV–vis spectra of L,D-PIAA (initial concentration� 2.2 mM) with the addition of TFA [(a) 0, (b) 2.2, (c) 6.3, (d) 10.0, and (e) 13.5% v/v],(C) CD spectra of L,L-PIAA at different temperatures, and (D) CD spectra of L,D-PIAAat different temperatures.


mers were still present as macromolecular rodswith hexagonal ordering.

These results show that the secondary struc-ture in these polyisocyanodipeptides strongly de-pends on the presence of well-defined arrays ofhydrogen bonds. After disruption of the hydrogenbonds in the side chains, the rotation around thecarbon–carbon bonds in the polymeric backboneis only hindered by the steric bulk of these sidechains. The PXRD patterns obtained for thesepolymers indicate that even in the absence of sucharrays, the macromolecules still behave like rod-like structures with a high degree of organizationin comparison with polyphenylisocyanide17 and

rigid-rod polyphenylene.34 The CD spectrum ob-tained for acidified L,L-PIAA is indeed very simi-lar to that of poly(L-isocyanoalanine ethyl ester)(L-PIA). The same resemblance is observed be-tween these spectra and the CD spectrum of L-PIAG [Fig. 5(D)], for which no defined arrays ofhydrogen bonds were found.22 For L-PIGA, theabsence of a substituent next to the imine moietyleads to a complete loss of excess helical sense;this suggests that in this situation the inversionbarrier is sufficiently low to allow reversal andequilibration of the helices once hydrogen bondsare no longer present.

Effects of the Side-Chain Configuration

For the polyisocyanopeptides previously dis-cussed, the presence of a hydrogen-bonding arraybetween the amide groups is in all cases (i.e.,L,L-PIAA, L,D-PIAA, and L-PIGA) accompanied bya strong positive Cotton effect around � � 315 nmattributed to a right-handed (P) helix, whereas forthe polyisocyanides in which these arrays wereabsent (i.e., L-PIAG and L,D-PIAA after TFA treat-ment), CD spectra were obtained lacking this sig-nal. For polyisocyanopeptides derived from ala-nyl–serine35 and alanyl–histidine36,37 preparedin the past by our group, similar differences in CDspectra were observed, including differences be-tween the two stereoisomers of poly(isocyanoala-nyl serine methyl ester), L,L-PIAS36,37 and L,D-PIAS, and between the two stereoisomers of poly-(isocyanoalanyl histidine methyl ester), L,L-PIAHand D,L-PIAH (Fig. 8). The CD spectra of L,L-PIASand L,L-PIAH show a strong Cotton effect around310 nm in analogy to those of L,L-PIAA, L,D-PIAA,and L-PIGA, whereas such a Cotton effect is ab-sent in the spectra of L,D-PIAS and D,L-PIAH,which show more of a resemblance to the spec-trum obtained for L,D-PIAA after treatment withTFA and the spectrum of L-PIAG.38 Although theprecise structures of these polymers were neverelucidated, we tentatively attribute these differ-ences to the presence of hydrogen-bonding arraysin the former two polymers and the absence ofsuch arrays in the latter two. For the alanyl–serine-derived polymer, this explanation is sup-ported by the differences in the intrinsic viscosi-ties ([�] � 4.1 vs [�] � 0.35) and observed poly-merization times (�30 vs 240 min) determined forL,L-PIAS and L,D-PIAS, respectively; this suggeststhat the first polymer has a better defined confor-mation, that is, including the hydrogen-bondingarrays, than the second.39 Similar differences

Figure 7. (A) CD and UV–vis spectra of L-PIGA withincreasing temperature (the arrows indicate the direc-tions of the changes) and (B) relative intensities ofselected CD and UV–vis bands as a function of temper-ature.


were found between the intrinsic viscosities andpolymerization times of L,L-PIAA and L-PIGA.

The differences in the polymerization times be-tween polymers that form such hydrogen-bondingarrays and polymers that do not, in tandem withthe fact that the Ni(II)-catalyzed polymerizationreaction is kinetically controlled, suggest that thepreorganization of the monomers with respect tothe growing chain is an important factor in deter-mining the polymer structure.22 In this scenario,the interaction between the growing chain andthe incoming monomer will depend on both the

steric bulk and the configuration of the mono-meric unit and will be reflected in the polymer-ization time and in the properties of the resultantpolymers (i.e., the absence of hydrogen bonding inL-PIAG).

CONCLUSIONS

Polyisocyanides derived from dipeptides canhave, depending on the precise configuration ofthe constituting amino acids, a highly defined

Figure 8. CD spectra of (A) L,L-PIAS,36,37 (B) L,D-PIAS,36,37 (C) L,L-PIAH,35 (D)D,L-PIAH,35 and (E) poly(L-isocyanoalanyl-L-O-acetyl histidinol) [D,L-PIAH(OAc)].36,37


conformation maintained by hydrogen-bondingarrays formed between amide functionalities inthe polymer side chains. From a combination ofspectroscopic data, powder diffraction, and modelcalculations, an extended 41 helical conformationis proposed for these polymers in which hydrogenbonds are present between side chains n and n� 4. On the basis of the data obtained, it is ex-pected that the integrity of these macromolecularhelices is largely determined by a delicate inter-play between steric and hydrogen-bonding inter-actions between the monomer and the growingpolymer chain. For L,L-PIAA and L,D-PIAA, thehelix inversion barrier is large compared withthat of L-PIGA, which is caused by a combinedeffect of the sterically demanding substituentsand the stabilization by the hydrogen bonds. Forthese polymers, LC properties have been ob-served that support the idea that these macromol-ecules have a well-defined structure.

Similar to the denaturation of proteins, thedisruption of the hydrogen bonds by an increasein the temperature or by a treatment of the poly-mers with a strong acid leads to a less well-de-fined macromolecular conformation. The presenceof hydrogen-bonding arrays along the polymericbackbone is reflected in the intense Cotton effectsthat are present around 315 nm in the CD spec-tra. This technique, therefore, is a powerful toolfor studying the conformation of these peptide-derived polyisocyanides. Indeed, upon the disrup-tion of the hydrogen bonds, drastic changes in theCD spectra are found.

Because the Ni(II)-catalyzed polymerization ofisocyanides is a kinetically controlled process, it islikely that all polymers grown from L-alanine-based monomers have the same stereochemistry.On the basis of this kinetic control and the ob-served properties of the polymers, including theshort polymerization time, high intrinsic viscos-ity, and intense Cotton effects, it is proposed thatthe L-alanine-derived peptide monomers fit betterin the developing polymer helix than monomerswith different configurational properties becausethey can form internal hydrogen-bonding ar-rays.40 As a result of the combination of stericinteractions and hydrogen bonding, subtle differ-ences in the side-chain configuration can have apronounced effect on the formation of the poly-mers, as demonstrated for L,D-PIAA, which can beformed even without the help of nickel(II) ions,that is, by H� catalysis.21

The accessibility of a large number of naturaland unnatural amino acids opens the possibility

of designing and synthesizing a wide array ofwell-defined polyisocyanopeptides and relatedblock copolymers. The arrangement of the sidegroups, resembling the �-sheet peptide motif, pro-vides a stable and robust scaffold to which a va-riety of functional groups can be attached, such asmetal catalysts41 and nonlinear optical chro-mophores.

EXPERIMENTAL

General Methods and Materials

All chemicals were commercial products and wereused as received. 1H NMR spectra were recordedon Bruker AC-100, Bruker WM-200, and BrukerAC-300 instruments at 297 K. Chemical shifts arereported in parts per million relative to tetra-methylsilane ( � 0.00 ppm) as an internal stan-dard. Fourier transform infrared spectra were re-corded on a Bio-Rad FTS 25 instrument. UV–visspectra were measured on a Varian Cary 50 con-centrated spectrophotometer, and CD spectrawere measured on a Jasco 810 instrument. X-raypowder diffractograms were collected on a PhilipsPW1710 diffractometer equipped with a Cu LFFX-ray tube operating at 40 kV and 55 mA. Sam-ples were measured on a silicon wafer between 3and 60°, with a step width of 0.05°. Optical mi-crographs between crossed polarizers were ob-tained on a Jeneval THMS 600 microscope.

Model Calculations

Molecular modeling calculations were carried outwith the CHARMM 4.4 molecular mechanicsforce field (with quanta charm charges) and theQuanta modeling package. Calculations were car-ried out on small oligomers (n � 64, 16 turns ofthe helix) initially possessing a 41 helix. The oli-gomers were preliminarily minimized with molec-ular dynamics (3ps, 273 K) in vacuo. The result-ing minimum energy conformations were subse-quently minimized with molecular mechanics,and this resulted in the presented conformations.Because of end-group effects during the dynamiccalculations, only the central 8 helical turns wereused as a model of the resulting helices.

CD Spectroscopy

CD spectra were measured at ambient tempera-ture in CHCl3. Spectra of the samples to which


acid was added were recorded in 8/1 (v/v) CHCl3/MeOH to prevent precipitation of the polymers.During the temperature-dependent measure-ments, after each interval, the solution was equil-ibrated for 10 min.

Synthesis

The polymers L,L-PIAA [number-average molecularweight (Mn) � 186 kg/mol, polydispersity index(PDI) � 1.4], L,D-PIAA (Mn � 221 kg/mol, PDI� 1.7), L-PIGA (Mn � 120 kg/mol, PDI � 1.4), andL-PIAG were synthesized as described previously.22

The Council for Chemical Sciences of the NetherlandsOrganization for Scientific Research is acknowledgedfor its financial support of J. J. L. M. Cornelissen.

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18. Quantitative theoretical and experimental analy-ses of the helix inversion barrier in polyisocyanateshave been reported; see refs. 19 and 20.

19. Young, J. A.; Cook, R. C. Macromolecules 2001, 34,3646.

20. Ute, K.; Fukunishi, Y.; Jha, S. K.; Cheon, K. S.;Munoz, B.; Hatada, K.; Green, M. M. Macromole-cules 1999, 32, 1304.

21. Cornelissen, J. J. L. M.; Donners, J. J. J. M.; deGelder, R.; Graswinckel, W. S.; Metselaar, G. A.;Rowan, A. E.; Sommerdijk, N. A. J. M.; Nolte,R. J. M. Science 2001, 293, 676.

22. Cornelissen, J. J. L. M.; Graswinckel, W. S.; Ad-ams, P. J. H. M.; Nachtegaal, G.; Kentgens, A.;Sommerdijk, N. A. J. M.; Nolte, R. J. M. J PolymSci Part A: Polym Chem 2001, 39, 4255.

23. Samori, P.; Ecker, C.; Gossl, I.; de Witte, P. A. J.;Cornelissen, J. J. L. M.; Metselaar, G. A.; Otten,M. B. J.; Rowan, A. E.; Nolte, R. J. M.; Rabe, J. P.Macromolecules 2002, 35, 5290.

24. Collings, P. J.; Hird, M. Introduction to LiquidCrystals: Chemistry and Physics; Taylor & Fran-cis: London, 1997.

25. Green, M. M.; Zanella, S.; Gu, H.; Sato, T.; Got-tarelli G.; Jha, S. K.; Spada, G. P.; Schoevaars,A. M.; Feringa, B.; Teramoto, A. J Am Chem Soc1998, 120, 9810.

26. Ballauf, M. Angew Chem 1989, 101, 261.27. In strict terms, the polymer no longer has a 41

helical conformation but instead has a 3910 helicalconformation.

28. van Beijnen, A. J. M.; Nolte, R. J. M.; Naaktge-boren, A. J.; Zwikker, J. W.; Drenth, W. Macromol-ecules 1983, 16, 1679.

29. Cornelissen, J. J. L. M.; Sommerdijk, N. A. J. M.;Nolte, R. J. M. Macromol Chem Phys 2002, 203,1625.

30. In addition to the protonation of the amide groupsand the subsequent disruption of the hydrogen-bonding pattern, the imine groups also can be pro-tonated, and this, in turn, can cause syn–antichanges around the CAN bond. However, thechanges in the chiroptical properties of L,L-PIAAand L-PIGA induced by acid were irreversible uponneutralization of the solution with a base, and sim-ilar, albeit less pronounced, changes in the CDspectra were also found for L,L-PIAA and L,D-PIAAwith increasing temperature (see the text). Thissuggests that these are not likely the result of theprotonation of the imines (see refs. 31 and 32). Ithas been found recently that the acid-inducedchanges in the chiroptical properties of L,D-PIAAcan be reversed completely by titration with a base(see ref. 33).

31. Aharoni, S. M. J Polym Sci Polym Phys Ed 1979,17, 683.

32. Kamer, P. C. J.; Drenth, W.; Nolte, R. J. M. PolymPrep 1989, 30, 418.


33. Metselaar, G. A. University of Nijmegen, Unpub-lished results, 2003.

34. Gin, D. L.; Conticello, V. P.; Grubbs, R. H. J AmChem Soc 1994, 116, 10507.

35. Van der Eijk, J. M.; Nolte, R. J. M.; Drenth, W.;Hezemans, A. M. F. Macromolecules 1980, 13,1391.

36. Visser, H. G. J.; Nolte, R. J. M.; Zwikker, J. W.;Drenth, W. J Org Chem 1985, 50, 3138.

37. van der Eijk, J. M. Ph.D. Thesis, University ofUtrecht, The Netherlands, 1980.

38. Yamada, Y.; Kawai, T.; Abe, J.; Iyoda, T. J PolymSci Part A: Polym Chem 2002, 40, 399.

39. For L,D-PIAA, a high intrinsic viscosity was alsomeasured ([�] � 5.26), whereas for poly(L-isocyano-alanyl ethyl ester), a much lower value ([�] � 0.44)was obtained. In the former case, a polymerizationtime of less than 5 min was found, in contrast to7200 min in the latter case. See Cornelissen,J. J. L. M. Pure Appl Chem 2002, 74, 2021.

40. A similar relation was recognized by Visser et al.,36

although no relationship with hydrogen-made for-mation was found at that time.

41. Knapen, J. W. J.; van der Made, A. W.; de Wilde,J. C.; van Leeuwen, P. W. N. M.; Wijkens, P.;Grove, D. M.; van Koten, G. Nature 1994, 372, 659.


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