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Triazole-linked polyamides and polyesters derived from cholic acid†

Olga Ivanysenko, Satu Strandman and X. X. Zhu*

Received 22nd March 2012, Accepted 19th April 2012

DOI: 10.1039/c2py20168b

A new class of rigid polyamides and polyesters bearing amphiphilic

bile acid functionalities in the main chain have been synthesized from

the heterofunctional precursors by copper(I)-catalyzed azide–alkyne

cycloaddition (CuAAC). The polymers synthesized under homoge-

neous conditions show high thermal stabilities and Young’s moduli,

depending on their structure.

The use of natural compounds is a promising way to prepare novel

polymers for biomedical applications.1 Bile acids are endogenous

steroids present in large quantities in the human body (�250 g, 40%

of which is cholic acid) and they form micellar aggregates in the

digestive tract to assist the solubilization, digestion, and absorption of

fats and lipids.2 They are commercially available at low cost with

enantiomeric purity, which makes them desirable starting materials

for polymer synthesis.3,4 Bile acid moieties can be incorporated in

polymers as pendent functionalities attached via the hydroxyl group

at the C3-position5,6 or the carboxylic acid group at the 24-position of

the steroid skeleton.7,8 They can also be included in a polymer as end

groups9,10 and crosslinkers11 or as the core unit in star-shaped poly-

mers.12 Polymers with bile acid units in the main chain have been

obtained through methods such as acyclic diene metathesis poly-

merization of bile acid-based dienes,13 entropy-driven ring-opening

polymerization of bile acid diene-derived macrocycles,14 and poly-

condensation reactions.15–17 Cholic acid (CA) has been shown to be

an interesting building block formain chain-functional polymers with

potential applications as biomaterials and sensors.18 However, the

polycondensation of CA under harsh conditions led to branched

oligomers,15 and milder conditions in the presence of coupling

reagents or an enzyme (lipase) afforded oligomers with low molar

masses (2800–3200 g mol�1).17,19 Therefore, other synthetic strategies

are of interest.

The highly efficient copper(I)-catalyzed azide–alkyne cycloaddition

(CuAAC) has become an attractive method for synthesizing novel

triazole-linked polymers with a variety of functional groups.20

Although polyesters containing bile acids bearing a spacer between

the steroid skeleton and the triazole have been made with both

CuAAC and its thermally-induced catalyst-free alternative,21,22

Department of Chemistry, University of Montreal, CP 6128, succursaleCentre-ville, Montreal, QC, H3C 3J7, Canada. E-mail: julian.zhu@umontreal.ca; Fax: +1-514-340-5290; Tel: +1-514-340-5172

† Electronic supplementary information (ESI) available: Detaileddescription of the materials, characterization methods, and thespectroscopic data. See DOI: 10.1039/c2py20168b

1962 | Polym. Chem., 2012, 3, 1962–1965

polyamides are often the materials of choice for high-performance

applications. In addition, the rigidity of the monomer unit can

influence both the reactivity in step-growth polymerization and the

thermo-mechanical properties of the polymers. In response to this

need, we have synthesized cholic acid-containing polyamides bearing

rigid triazole links without any spacer groups, where the azidation

takes place directly on the C3-position of the bile acid skeleton. For

comparison purposes, we have made polyesters with the same

strategy and compared the thermal and mechanical properties of

both polyamides and polyesters containing bile acids in the main

chain. The polymer synthesis is simple and straightforward, and may

be applicable to other bile acids and related natural compounds,

though only examples for cholic acid are shown in this report.

The synthetic procedure for heterofunctional cholic acid deriva-

tives containing both alkyne and azide groups is shown in Scheme 1

and described in the ESI†.

Both alkyne and azide functionalities are introduced to the same

molecule to avoid problems of stoichiometry in the polymerization.23

First, alkyne-functionalized cholanamide 2a and cholanoate 2b are

synthesized through the amidation or esterification of carbodiimide-

activated cholic acid in DMF. The following activation by tosylation

Scheme 1 Reaction scheme for the synthesis of main-chain cholic acid-

based polyamides and -esters via copper-catalyzed azide–alkyne

coupling, starting from cholic acid (1).

This journal is ª The Royal Society of Chemistry 2012

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and subsequent azidation of one of the hydroxyl groups of cholic acid

derivatives does not require protective group chemistry, as the

equatorial hydroxyl group on C3-position is more reactive than the

highly sterically hindered hydroxyls on the axial C7- and C12-posi-

tions of cholic acid (see numbering in Fig. 1).24 In addition, the bulky

tosylate group is less reactive towards the hydroxyls than smaller

groups, such as triflate or mesylate,25 increasing its selectivity towards

the C3-position. This also helps to avoid the chromatographic puri-

fication step of the tosylate prior to the azidation, thus improving

the yield.24

The nucleophilic substitution of the tosylate by an azide is

conducted at a slightly elevated temperature (45 �C) to improve the

solubility of sodium azide (NaN3) in DMF. Mild conditions are

required to avoid side reactions, such as unintentional polymeriza-

tion, but lead to longer reaction times. As reported earlier, an

inversion in the configuration of equatorial 3a to axial 3b occurs

during the reaction of the tosylate with sodium azide (Scheme 1),

typical for an SN2 substitution.24 The 1H NMR signal of the CH

proton at the C3-position is a clear indicator of the stereochemistry as

well as of the progress of the reaction: the signal of the equatorial 3a

proton of 2a and 2b at 3.18 ppm is a broad multiplet (Table S1†)

while that of the axial 3b proton of 4a (Fig. 1) and 4b (Fig. S3†) at

3.99 ppm is sharper, similar to the axial CH protons on positions C7

and C12. No change in the chemical shift was observed for the latter

Fig. 1 1H NMR spectra of the heterofunctional monomer 4a (bottom)

and of the corresponding polyamide 5a (top) in DMSO-d6. The insets

correspond to the expanded spectral regions marked with dashed lines.

This journal is ª The Royal Society of Chemistry 2012

signals, confirming that only the hydroxyl group at C3-position was

substituted. The structures were verified by 13C NMR and FTIR

spectroscopy, as well as by mass spectrometry.†

The reaction conditions of the polymerizations of heterofunctional

cholic acid derivatives 4a and 4b by step-growth azide–alkyne

coupling (Scheme 1) are summarized in Table 1. The 1H NMR

analysis of 5a in DMSO-d6 confirms the formation of 1,4-disubsti-

tuted triazole rings through the emergence of characteristic signals

from the triazole ring proton at 7.90 ppm and a proton at positionC3

adjacent to the triazole at 4.59 ppm, as well as the disappearance of

signals of the alkyne group at 3.06 ppm and the C3-proton adjacent

to the azide group at 3.99 ppm (Fig. 1). Additional proof of the

formation of main-chain cholic acid-functional polymers was shown

by the FTIR spectra of the polytriazoles. The bands of compound 4a

at 3306 and 2095 cm�1 (Fig. S1†) disappear in the spectrum of the

polyamide 5a after the polymerization, indicating that most of the

–C^CH and –N3 groups have been transformed to triazole rings.

For all polymers, the size exclusion chromatographic (SEC)

analysis shows a monomodal molar mass distribution (Fig. S2†) and

a relatively low polydispersity index (PDI # 1.7). The polyamide 5a

and the polyester 5b havemolarmasses of 23 900 and 25 500 gmol�1,

respectively, corresponding to a degree of polymerization of over 50

in both cases (Table 1). This indicates that there is no significant

difference in the reactivities of compounds 4a and 4b. The polymer-

ization of 4b is accompanied by the disappearance of 1H NMR

resonance signals of an alkyne group proton at 3.51 ppm and

aC3-proton adjacent to the azide group at 3.99 ppm, as well as by the

emergence of signals from a triazole ring proton at 8.17 ppm and

a C3-proton adjacent to the triazole at 5.10 ppm (Fig. S3†). Owing to

their highmolarmasses, neither polyamide 5a nor polyester 5b shows

the azide and alkyne end group signals in the 1H NMR (Fig. 1 and

S3†) and FTIR spectra (Fig. S1†).

The polymerization of compound 4awas also carried out in a tert-

butanol–water (t-BuOH–H2O) mixture catalyzed by CuSO4$5H2O/

sodium ascorbate (SA) under nitrogen atmosphere. A few minutes

after commencing the reaction (�15 min), the polymer formed

started to precipitate. The stirring was continued for 120 h. After

purification, polymer 5a0 was found to be poorly soluble in common

organic solvents, such as chloroform, dichloromethane, or tetrahy-

drofuran, but dissolved in DMF and DMSO. As a result, the molar

mass (Mn) was low (5200 g mol�1, Table 1), likely due to the poor

solubility of the polyamide formed in t-BuOH–H2O. Since the

molecular weight in this case was relatively low, it could also be

estimated by 1HNMRanalysis (Table 1) by comparing the integrated

area of the alkyne end group signal at 3.06 ppm to the triazole signal

in the main chain at 7.90 ppm (Fig. S4†). In comparison, the poly-

merization of 4a in dry DMF at 80 �C with CuBr/PMDETA as the

catalyst, where no precipitation occurred, led to a 5-fold increase in

the molar mass of the polyamide.

Thermogravimetric analysis (TGA), differential scanning calo-

rimetry (DSC), and dynamic mechanical analysis (DMA) were

conducted on polymer films cast fromDMF solutions (100mgmL�1)

to study the effect of the chemical structure on the thermal behavior

of the polymers. Thermograms and calorimetric curves of the

samples are presented in the ESI (Fig. S5†) and the results are

summarized in Table 1. All polymers show high resistance to thermal

degradation with degradation onset temperatures Td $ 307 �C, thepolyamides being more thermally stable than the polyester. The glass

transition temperatures (Tg) determined by DSC are in the range of

Polym. Chem., 2012, 3, 1962–1965 | 1963

Table 1 Polymerization conditions and the properties of the polymers

Entrya Mnb/g mol�1 Mw/Mn

b DPc

Tge/�C

Tdf/�C Eg/MPaDSC DMA

5a 23 900 1.69 51 161 � 0.6 155 � 2.0 372 � 3.0 659 � 295b 25 500 1.63 54 137 � 0.8 139 � 1.5 307 � 6.0 282 � 265a0 5200 1.48 11, 10d 167 � 1.6 N/A 365 � 4.0 N/A

a Polymerization was catalyzed by CuBr/PMDETA in DMF at 80 �C for 120 h (5a and 5b) or by CuSO4$5H2O/sodium ascorbate (SA) in a t-BuOH–H2Omixture at 60 �C for 120 h (5a0). b Mn andMw: number- and weight-average molar masses obtained from SEC analysis. c Degree of polymerization.d Calculated from 1H NMR data. e Glass transition temperature determined by differential scanning calorimetry (DSC) and dynamic mechanicalanalysis (DMA). f Temperature corresponding to the onset of decomposition in thermogravimetric analysis. g Young’s modulus measured fromstress–strain curves at 30 �C.

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137–167 �C.None of the polymers exhibitedmelting transition below

the degradation temperature, which points to the amorphous nature

of the materials. This behavior corresponds well with that of a rigid

polyester prepared by the direct polycondensation of cholic acid,

which showed low crystallinity.19 Our earlier observations of main

chain-functional bile acid-based polymers also showed the amor-

phous character.26 The triazole linker may contribute to the high Tg

through its proximity to the steroid skeleton imposing strong steric

constraints in the polymer backbone and thus increasing the chain

rigidity, as well as through hydrogen bonding.20b The replacement of

the amide linker by an ester in the polymers of similar molar masses

(5a and 5b) decreased the Tg by ca. 24 �C and the Td by ca. 65 �C(Table 1), indicating the higher rigidity and thermal stability of the

polymers containing the amide bonds capable of hydrogen bonding.

A similar effect of the chemical structure on Tg was observed with

cholic acid and lithocholic acid-based main chain-functional poly-

ester–amides and polyesters bearing long alkyl spacers between the

bile acid moieties, where both amide linkers and multiple hydroxyls

of cholic acid increase the Tg values significantly.14 As expected, the

absence of a spacer between the steroid skeleton and the azide leads to

an increased Tg for the triazole-linked polyester.21

Fig. 2 shows the evolution of the storage modulus E0 of polyamide

5a and polyester 5b films with temperature, allowing the determina-

tion of Tg from the onset of the slope. The results are well in accor-

dance with those determined by DSC (Table 1). Linear stress–strain

responses are observed for both polymers (Fig. S6†) with high values

of Young’s modulus (Table 1), characteristic for brittle polymers with

amorphous character or low crystallinity. The polyamide has a higher

Fig. 2 Evolution of the storage modulus of polymers 5a and 5b with

temperature determined by DMA at a frequency of 1 Hz. Measurements

were made on rectangular samples (4 � 10 mm), with a preload force

of 0.01 N, an amplitude of 2 mm, and a temperature sweep rate of

2 �C min�1.

1964 | Polym. Chem., 2012, 3, 1962–1965

Young’s modulus than the polyester, confirming the enhanced

hardness of the material caused by the amide bonds. The modulus

of 5a at 30 �C is comparable to that of a main chain-functional

lithocholic acid-based polyester–amide bearing two amide bonds per

repeating unit.14 This further emphasizes the importance of the

chemical structure of linkers on the mechanical properties of the

polymer, but also warrants studies on triazole-linked polymers based

on other bile acids.

Conclusions

In summary, both polyamides and polyesters based on cholic acid

have been successfully synthesized via triazole-links through cop-

per(I)-catalyzed step-growth polymerization in high yields; among

them the polyamides weremade for the first time, and their properties

have been compared. These polymers are thermally stable up to

$307 �C with high glass transition temperatures and Young’s

moduli, depending on the chemical structure of the linker (amide

versus ester). The polyamides tend to have higher Tgs and higher

moduli than their polyester counterparts.

This family of triazole-linked polymers may be further expanded

by the inclusion of other bile acids and other related steroids, such as

lithocholic, deoxycholic, oleanolic, or ursodeoxycholic acids, and the

thermo-mechanical properties can be tuned by derivatives of hydroxy

fatty acids.14a The microwave-assisted copper-mediated azide–alkyne

coupling may help to shorten the reaction time and to obtain bile

acid-based polymers with higher molar masses.27 It may also be

interesting to explore the use of solvent- and catalyst-free strategies

for these monomers since methods such as thermal azide–alkyne

cycloaddition have already proved to be effective in synthesizing

main chain-functionalized polymers and polymer networks.22,28

Abbreviations

DMF

This

Dimethylformamide;

DMSO

Dimethyl sulfoxide;

PMDETA

N,N,N0,N0 0,N0 0-Pentamethyldiethylene

triamine;

Acknowledgements

Financial support fromNSERC of Canada, the FQRNT of Quebec,

and the CanadaResearch Chair program is gratefully acknowledged.

journal is ª The Royal Society of Chemistry 2012

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The authors are members of CSACS funded by FQRNT and

GRSTB funded by FRSQ.

Notes and references

1 (a) M. Vert, Prog. Polym. Sci., 2007, 32, 755–761; (b) S. Y. Wong,J. M. Pelet and D. Putnam, Prog. Polym. Sci., 2007, 32, 799–837;(c) J. K. Oh, D. I. Lee and J. M. Park, Prog. Polym. Sci., 2009, 34,1261–1282.

2 A. F. Hofmann, News Physiol. Sci., 1999, 14, 24–29.3 E. Siev€anen, Molecules, 2007, 12, 1859–1889.4 J. E. Gautrot and X. X. Zhu, J. Biomater. Sci., Polym. Ed., 2006, 10,1123–1139.

5 (a) Y. H. Zhang and X. X. Zhu, Macromol. Chem. Phys., 1996, 197,3473–3482; (b) D. Avoce, H. Y. Liu and X. X. Zhu, Polymer, 2003,44, 1081–1087.

6 J. B. Kim, B. W. Lee, J. S. Kang, D. C. Seo and C. H. Roh, Polymer,1999, 40, 7423–7426.

7 I. Idziak, D. Gravel and X. X. Zhu, Tetrahedron Lett., 1999, 40, 9167–9170.

8 H. Liu, D. Avoce, Z. Song and X. X. Zhu, Macromol. RapidCommun., 2001, 22, 675–680.

9 R. Boyce, G. Li, H. P. Nestler, T. Suenaga and W. C. Still, J. Am.Chem. Soc., 1994, 116, 7955–7956.

10 I. S. Kim, S. H. Kim and C. S. Cho,Macromol. Rapid Commun., 2000,21, 1272–1275.

11 (a) X. Z. Hu, Z. Zhang, X. Zhang, Z. Li and X. X. Zhu, Steroids,2005, 70, 531–537; (b) M. A. Gauthier, P. Simard, Z. Zhang andX. X. Zhu, J. R. Soc. Interface, 2007, 4, 1145–1150.

12 J. Luo, G. Gigu�ere and X. X. Zhu, Biomacromolecules, 2009, 10, 900–906.

13 J. E. Gautrot and X. X. Zhu, Angew. Chem., Int. Ed., 2006, 45, 6872–6874.

14 (a) J. E. Gautrot and X. X. Zhu, Macromolecules, 2009, 42, 7324–7331; (b) B. Manzini, P. Hodge and A. Ben-Haida, Polym. Chem.,2010, 1, 339–346.

This journal is ª The Royal Society of Chemistry 2012

15 M. Ahlheim and M. L. Hallensleben, Makromol. Chem. RapidCommun., 1988, 9, 299–302.

16 S. Gouin, X. X. Zhu and S. Lehnert,Macromolecules, 2000, 33, 5379–5383.

17 O. Noll and H. Ritter,Macromol. Rapid Commun., 1996, 17, 553–557.18 E. Virtanen and E. Kolehmainen, Eur. J. Org. Chem., 2004, 3385–

3399.19 F. Zuluaga, N. E. Valderruten andK. B.Wagener,Polym. Bull., 1999,

42, 41–46.20 (a) M. Meldal, Macromol. Rapid Commun., 2008, 29, 1016–1051; (b)

H. F. Chow, K. N. Lau, Z. Ke, Y. Liang and C. M. Lo, Chem.Commun., 2010, 46, 3437–3453; (c) L. Billiet, D. Fournier andF. Du Prez, Polymer, 2009, 50, 3877–3886.

21 A. Kumar, R. K. Chhatra and P. S. Pandey, Org. Lett., 2010, 12, 24–27.

22 W. Li, X. Li, W. Zhu, C. Li, D. Xu, Y. Ju and G. Li, Chem. Commun.,2011, 47, 7728–7730.

23 S. Binauld, D. Damiron, T. Hamaide, J.-P. Pascault, E. Fleury andE. Drockenmuller, Chem. Commun., 2008, 4138–4140.

24 J. K. Denike, M. Moskova and X. X. Zhu, Chem. Phys. Lipids, 1995,77, 261–267.

25 P. J. Stang and A. G. Anderson, J. Org. Chem., 1976, 41, 781–785.26 H. Th�erien-Aubin, J. E. Gautrot, Y. Shao, J. Zhang and X. X. Zhu,

Polymer, 2010, 51, 22–25.27 (a) M. Bardts, N. Gonsior and H. Ritter, Macromol. Chem. Phys.,

2008, 209, 25–31; (b) M. Van Dijk, K. Mustafa, A. C. Dechesne,C. F. Van Nostrum, W. E. Hennink, D. T. S. Rijkers andR. M. J. Liskamp, Biomacromolecules, 2007, 8, 327–330; (c)Y. Nagao and A. Takasu, J. Polym. Sci., Part A: Polym. Chem.,2010, 48, 4207–4218.

28 (a) C. Besset, S. Binauld, M. Ibert, P. Fuertes, J.-P. Pascault,E. Fleury, J. Bernard and E. Drockenmuller, Macromolecules, 2010,43, 17–19; (b) C. Besset, J. Bernard, E. Fleury, J.-P. Pascault,P. Cassagnau, E. Drockenmuller and R. J. J. Williams,Macromolecules, 2010, 43, 5672–5678; (c) J. M. Spruell, M. Wolffs,F. A. Leibfarth, B. C. Stahl, J. Heo, L. A. Connal, J. Hu andC. J. Hawker, J. Am. Chem. Soc., 2011, 133, 16698–16706.

Polym. Chem., 2012, 3, 1962–1965 | 1965