Synthesis of an azide–thiol linker for heterogeneous polymer functionalization via the “click” reaction - Thuy Thu Truong

Journal of Science and Technology 55 (1B) (2017) 152–159 SYNTHESIS OF AN AZIDE–THIOL LINKER FOR HETEROGENEOUS POLYMER FUNCTIONALIZATION VIA THE “CLICK” REACTION Thuy Thu Truong1, Ha Tran Nguyen1, 2, * 1Faculty of Materials Technology, HCMUT–VNUHCM 268 Ly Thuong Kiet Street, Ward 14, District 10, Ho Chi Minh City, Vietnam 2Materials Technology Key Laboratory, HCMUT–VNUHCM 268 Ly Thuong Kiet Street, Ward 14, District 10, Ho Chi Minh City, Vietnam *Email: nguyentranha@hcmut.edu.vn Received: 30 December 2016; Accepted for publication: 3 March 2017 ABSTRACT In this study, the synthesis of a telechelic linker bearing both azide and thiol functional groups was described. The reaction conditions were investigated to optimize the reaction yield. The product was analyzed using thin layer chromatography (TLC) and proton nuclear magnetic resonance (1H NMR). The employment of the obtained azide–thiol linker in heterogeneous polymer “click” functionalization was demonstrated for the first time, which was monitored by an online FT–IR method. The obtained telechelic azide–thiol linker is envisioned to be useful chemical tools to link macromolecular chains via orthogonal click reactions. Keywords: azide, thiol, “click” reaction, polymer functionalization. 1. INTRODUCTION Organic azides are well–known as an important and versatile class of chemical compounds. They are considered as powerful precursors for reactive species such as nitrenes, aziridines, triazoles, triazolines and many others, as well as can be easily transformed into amines, isocyanates and other functional groups [1]. Especially, they have received significantly increasing interest as valuable and versatile reagents within the concepts of “click” chemistry. In the “click” chemistry aspect, organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science [1]. Click chemistry has become the catchphrase whenever conjugation of different molecules to each other is desired [2]. Molecular biologists, and material and polymer chemists have rapidly picked up this type of chemistry and adapted it to match their needs in life sciences, polymer science and materials science. In many cases, “click” reactions fulfil the aim to join two different molecules in an efficient way. This is especially true for macromolecular chemistry, where the challenge is to be able to perform click chemistry with polymers, e.g. preparing block cop [3] inc bet com bet thi com to ort exp lin ins iso tow het 2.1 wi Fis 2.2 kg an po mo eth for foa (2. atm dic olymers by . Recently, luding reac ween nitrile pounds [1 ween thiols In this stu ol functiona plexity of link many p hogonal clic eriment by ker in this r tance orthog thiocyanate ard macro erocyclic sy . Materials All chemi thout furthe her Chemic . Synthesis An Allyl– m–3) based allyl loadi lypropyleneo lecular weig er), toluene mulation, w m follows a Figure (Chlorom 1 g, 32 mm osphere fo hloromethan using click– efforts have tion of azid oxides and –3]. Other and electron dy, we are i l groups. I the macromo olymer chai k reactions, simultaneou esearch is e onal azide– or thiol–acr molecular nthesis [7]. cals were of r purificatio als and used of 4–(azidom functionaliz on polyethe ng of 0.5 xide–based ht diol cont diisocyana hich was ca previously 1. Synthetic s ethyl)benzyl ol) in 55 m r 24 h at 8 e was adde chemistry t been made e groups w alkynes and highly clean –deficient fu nterested in n this cont lecular arch ns together where multi s addition o nvisioned to alkyne react ylate reactio diversity i 2. MAT reagent gra n. All the s as received. ethyl)benz ed PU foam r polyols we mmol.g–1. triols with aining the al te, and wa lculated on reported pro cheme of the alcohol (2. L of DMF 0 °C. After d and the so o link two ch to the appli ith substitu thermal cli , fast and nctional gro the synthesi ext, a parti itecture by b [4]. Concep ple conjuga f the reagen be linker ions orthogo n pathways n peptide ERIALS AN de quality o olvents wer yl alcohol ( (open cell re develope A mixture molecular lyl functiona ter as a ch the basis o cedure [8]. azide–thiol li 5 g, 16 mm , and the r cooling the lution was w Th emically di cation of su ted cyclooc ck reaction efficient me ups [4]. s of a telech cularly intri eing able to tually, it is m tion reaction ts [5]. There useful for m nally combi [6]. Such a chemistry, D METHO btained from e of HPLC compound 2 structure, 10 d by Rectice (50/50, w/ weights o l group (1,1 emical blo f the foam d nker (4–(azid ol) was add eaction mix reaction to ashed with uy Thu Truo fferent macr itable metal– tynes, 1,3–d of alkynes w tal–free rea elic linker be guing targe combine mu ore efficien s could be c fore, the sy acromolecu ned with thi telechelic l combinator DS Sigma–Ald grade and w , Figure 1) x10x10 cm, l NV (Wett w) of poly f around 4 ,1–trimethyl wing agent ensity. The omethyl)benz ed to a solu ture was st room temp water (3 x 5 ng, Ha Tran omolecular free click r ipolar cyclo ith azide–co ction is the aring both a t is to incr ltiple click t and elega arried out in nthesized az lar coupling ol–maleimid inker can b ial chemis rich (USA) ere purcha density aro eren, Belgiu ethyleneoxi 000 g.mol– olpropane m were used synthesis o yl mercaptan tion of sodiu irred under erature, 10 0 mL) to re Nguyen 153 segments eactions, addition ntaining reaction zide and ease the reactions nt to use a single ide–thiol s via for e, thiol– e applied try, and and used sed from und 45.4 m), with de– and 1, a low onoallyl for the f the PU ). m azide nitrogen 0 mL of move the Synthesis of an azide–thiol linker for heterogeneous polymer functionalization via the “click” 154 excess NaN3 and DMF. The organic layer was dried over anhydrous MgSO4, and dichloromethane was removed using a rotary evaporator to give the product (yield: 90 %). 2.3. Synthesis of 4–(azidomethyl)benzyl methylsulfonate (compound 3, Figure 1) Methanesulfonyl chloride (2 mL, 25.4 mmol) was added dropwise at 0 °C to a solution of 4–(azidomethyl)benzyl alcohol (compound 2, Figure 1, 2.08 g, 12.7 mmol)) and triethylamine (3.6 mL) in tetrahydrofuran (100 mL). The reaction mixture was then stirred at room temperature for 2 h. After the reaction, 40 mL of deionized water was added and the mixture was extracted with diethylether. The organic layer was washed with 1 N solution of HCl, deionized water, saturated NaHCO3 and deionized water, dried over anhydrous MgSO4, and the solvents were removed using a rotary evaporator to give the product. The product was purified by column chromatography with dichloromethane as eluent (yield: 83%). 2.4. Synthesis of 4–(azidomethyl)benzyl thioacetate (compound 4, Figure 1) Potassium thioacetate (880.6 mg, 7.7 mmol) was added to a solution of 4–(azidomethyl)benzyl methylsulfonate (compound 3, Figure 1, 0.93 g, 3.8 mmol) in tetrahydrofuran (30 mL). The reaction mixture was degassed, refilled with nitrogen gas and refluxed for 3 h. The reaction was quenched with brine, extracted with diethyl ether, washed two times with brine. The organic layer was dried over anhydrous MgSO4, and the solvents were removed using a rotary evaporator to give the product. The product was purified by column chromatography with dichloromethane as eluent (yield: 93%). 2.5. Synthesis of 4–(azidomethyl)benzyl mercaptan (compound 5, Figure 1) (Azidomethyl)benzyl thioacetate (compound 4, Figure 1) was refluxed in methanol, in the presence of concentrated HCl for 3 h. The reaction was quenched with deionized water and extracted with diethyl ether. The organic layer was dried over anhydrous MgSO4, and the solvents were removed using a rotary evaporator to give the product (yield: 99 %). 2.6. Thiol–ene functionalization of the allyl–functionalized PU foam Photo–initiation reaction was performed at room temperature, where 4– (azidomethyl)benzyl mercaptan (compound 5, Figure 1) and 2,2–dimethoxy–2– phenylacetophenone (DMPA) were used as the thiol compound and UV light initiator, respectively. General procedure: in a two–necked glass flask, the allyl–functionalized PU foam (about 1x1x1 cm, allyl concentration of 8.75 mM) was charged with the solvent and thiol compound. The React–IR silicon probe was dipped in the reaction solution, and a regular stirring of the reaction mixture was maintained to avoid bringing bubbles to the surface of the probe. After addition of the photoinitiator, the reaction flask was irradiated at room temperature by a 365 nm UV light (9x9 watt bulbs, intensity of 6 mW.cm–2). The azide conversion was indicated by a decrease in absorption intensity of the azide asymmetric stretching vibration at 2200 cm–1. The thiol–ene reaction conversion was calculated corresponding to the azide conversion and the 4–(azidomethyl)benzyl mercaptan to allyl molar ratio used for the reaction. Thuy Thu Truong, Ha Tran Nguyen 155 2.7. Characterization 1H NMR spectra were recorded with TMS as an internal reference, on a Bruker Avance 300 at 300 MHz at Institute of Chemistry–VAST, Ha Noi. Time–resolved online ATR FT–IR spectra were recorded on a React–IR 4000 Instrument (Mettler Toledo AutoChem ReactIR) equipped with a silicon ATR probe (SiComp, optical range 4400–650 cm–1) at National Key Lab for Polymer & Composite (HCMUT–VNUHCM). For online monitoring, the silicon probe was introduced into a two–necked glass flask containing the reaction mixture and spectra were recorded every 1 min for the first 30 min and then every 2 min. The solvent spectrum was recorded at the reaction temperature and subtracted to enhance the signal of the reaction species. 3. RESULTS AND DISCUSSION 3.1. Synthesis of 4–(azidomethyl)benzyl mercaptan The azide–thiol linker (4–(azidomethyl)benzyl mercaptan) was prepared according to a four–step procedure as shown in Figure 1. In the first step, 4–(azidomethyl)benzyl alcohol (compound 2, Figure 1) was prepared from 4–(chloromethyl)benzyl alcohol (compound 1, Figure 1) by treatment with excess sodium azide in dimethylformamide at 80 °C under an inert atmosphere. This applied synthetic route is halide displacement by azide ion [9]. In the second step, the hydroxyl group of 4–(azidomethyl)benzyl alcohol reacts with methanesulfonyl chloride with triethylamine as the catalyst to transform to the methylsulfonate group (step II, Figure 1). The methylsulfonate group of compound 3 was then converted in to the thioacetate group via the reaction with potassium thioacetate (step III, Figure 1). Finally, the thioacetate group of compound 4 was transformed to the thiol group upon reflux in methanol under an acidic condition to yield the final product (compound 5, Figure 1). The product of each step was purified by column chromatography. Analysis of azide ions using LC–MS was not feasible because of their low molecular weight and strong background interference in this range [10]. Therefore, the products were analysed by 1H NMR. Figure 2 shows the 1H NMR spectrum of three intermediate products, i.e. 4–(azidomethyl)benzyl alcohol, 4–(azidomethyl)benzyl methylsulfonate and 4–(azidomethyl)benzyl thioacetate, and the final product 4–(azidomethyl)benzyl thiol. All the peaks in each spectrum could be assigned to the corresponding structures of the products. Regarding the synthesis procedure, except for step II, the other three steps resulted in products (after purification via column chromatography) in relatively good yields (above 90 %) when employing reaction conditions previously reported in the literature [11–13]. However, for step II, the yield was low (below 40 %), inspite of the application of conditions previously reported for mesylation of the alcohol with methanesulfonyl chloride [14]. For this step, the reaction conditions, i.e. the feeding temperature and the reactant molar ratio, were observed to influence strongly the reaction yield. With the use of methanesulfonyl chloride to 4–(azidomethyl)benzyl alcohol molar ratio of 2, the reaction yields obtained at two feeding temperatures, 0 °C and room temperature, were compared. It was found that the yield was enhanced by approximately two times, from 42 % to 83 % when methanesulfonyl chloride was added dropwise at the lower temperature (Table 1, Entries 1 and 3). It was likely that low temperature suppressed considerably side reactions during the formation of the reactive sulfonyl–tertiary amine complex, which, in turn, reacted with the alcohol to give the sulfonate. In fact, reaction temperatures of 0–5 °C have also been Sy 15 suc cat con me an inc 83 (az wa pro [15 an F nthesis of an 6 cessfully ap alytic tertia version, a thanesulfon d 5. As sho reasing this % was o idomethyl)b s attributed duct in a s ]. Therefore d feeding tem igure 2. 1H N methy azide–thiol plied by Ta ry amine/K2 n excess yl chloride t wn in Tabl reactant rat btained. Ho enzyl alcoh to undesirab mall quantit , the methan perature of MR spectra lsulfonate, 4– linker for he nabe et al. CO3 system use of m o 4–(azidom e 1 (Entries io from 1 to wever, furt ol molar rati le side form y has often esulfonyl ch 0 °C were c of the synthes (azidomethyl terogeneous to efficiently [15]. On t ethanesulfon ethyl)benzy 2–4), by f 2, a signific her increas o to 5 led to ation of 4– been observ loride to 4– hosen as the ized 4–(azido )benzyl thioa polymer fu tosylate an he other ha yl chlorid l alcohol m ixing the fe ant increase e of the m a moderate (azidomethy ed in the u (azidomethy optimum co methyl)benz cetate, and 4– nctionalizatio d mesylate nd, to obtai e was ne olar ratio w eding temp of the react ethanesulfo decrease of l)benzyl chl sual method l)benzyl alc nditions for yl alcohol, 4– (azidomethyl n via the “cl 2–alkyn–1– n complete cessary. Th as varied b erature at 0 ion yield fr nyl chlorid the final yi oride [15]. S using triet ohol molar r this reaction (azidomethyl )benzyl thiol. ick” ols using reaction us, the etween 1 °C and om 34 to e to 4– eld. This uch by– hylamine atio of 2 step. )benzyl 3.2 rea wa po ph be int pro qu of thi (on of 4– irr IR an giv foa the Entry F t 1 2 3 4 . Demonstr “click” fun To demon ction for po s employed lyurethane ( enylacetoph aring alkene roduction o cess of th antification the unreacte ol compoun –line) FT–I the azide sig Figure 3. Sch surface modif Figure 4 (azidomethy adiation. A peak during d the corresp en in Figure m (having n model “cli Table 1. S eeding emperature (° 30 0 0 0 ation of th ctionalizat strate the ap st–functiona as a model PU) foam vi enone (DMP functional f trimethylo e PU, acc of the functi d model thio d is preserv R analysis th nal as an ind ematic illustr ication via th a shows l)benzyl th 3D online F the reaction onding plot 4b & c. It s o allyl grou ck” compou ynthesis yiel C) Methan (azidom e applicatio ion plication of lization of p compound a the “click” A) as photo groups in th lpropane m ording to onalization d l compound ed during th e reaction s ication of it ation of the sy iol–ene “click model “c an FT–IR iol, DMPA T–IR water under UV of the amou hould be no p) was also nd due to it ds of step II ( esulfonyl chlo ethyl)benzyl 2 1 2 5 n of the az the synthes olymeric m to be coup thiol–ene r initiator und e hard segm onoallyl eth a previousl egree can b in the react e reaction b olution can s concentrat nthesis of the ” reaction usi lick” compou spectrum and the fall plot, sho irradiation fo nt of model ted that a bla performed, i s absorption Th Figure 1) at v ride to 4– alcohol molar ide–thiol lin ized 4–(azid aterials, this led to penda eaction, in th er UV irradi ents (Figure erdiol in th y reported e performed ion mixture. etween the be used to c ion. allyl–functio ng 4–(azidom nd in this sud of the allyl–functio wing the de r the thiol c compound nk reaction ndicating no on the PU uy Thu Truo aried conditio ratio Yield purifi ker in hete omethyl)ben obtained az nt allyl gro e presence o ation. The c 3) has bee e feed of t procedure by monitor As the azid thiol and all onveniently nalized PU fo ethyl)benzyl y. reaction nalized PU crease of th oupling reac as a function on a regular decrease in foam. Clea ng, Ha Tran ns. (after column cation) (%) 42 33 83 63 rogeneous zyl thiol in ide–thiol co ups of a cro f 2,2–dimet ross–linked n synthesize he polycond [8, 16]. G ing the conc e group of th yl groups, a monitor the am [8], follo thiol compou solution co foam bef e characteris tion to the P of reaction unfunctiona the concent rly, compar Nguyen 157 polymer a “click” mpound sslinked hoxy–2– PU foam d by the ensation enerally, entration e azide– n in situ intensity wed by nd as a ntaining ore UV tic azide U foam, time are lized PU ration of ed to the Sy 15 pre foa qu “on F 4– 4–( pre op cou gro me lin 1 2 3 4 5 nthesis of an 8 viously pub ms [8], in antification, –line” quan igure 4. Illus solvent (azidomethy azidomethyl) By utiliz pared and timized. Thi ple with an up was exp thod. This o ker of macro . Bräse S. of a Un 5188–52 . Espeel P Matchin . Moses J Chemica . Wong C chemistr 1679–16 . Iha R. K Applicat Material azide–thiol lished study which benz the employm tification of tration of the signal (a) an l)benzyl thiol benzyl thiol a ation of a f the conditi s compound allyl–functi loited as a btained azid molecular c , Gil C., Kne ique Class o 40. ., Du Prez g Recent Pro . E. and M l Society Re . –H., Zimm y: from Me 95. ., Wooley ions of Ort s, Chemical linker for he on the thio yl mercaptan ent of this the reaction FT–IR absorb d online FT–I and the allyl s a function o 4. our–step pr ons of step bearing bo onalized PU useful label e–thiol tele hains via ort pper K., Zim f Compoun F. E. – “C gress and U oorhouse A views 36 (2 erman S. C. rrifield to K. L., Nyst hogonal, “C Reviews 10 terogeneous l–ene post– was used novel azide . ance spectrum R waterfall p –functionaliz f reaction tim CONCLU ocedure, 4– II (mesyl th the azide foam via th ing group f chelic functi hogonal clic REFEREN mermann V ds, Angewan lick”–Inspi ser Expectat . D. – Th 007) 1249–1 – Orthogon click chemi röm A. M. lick” Chem 9 (2009) 562 polymer fu functionaliz as a thiol c –thiol comp of the react lot (b) for the ed PU, and th e observed by SIONS (azidomethy ation of alc and thiol fu e thiol–ene or reaction onal compo k reactions. CES . – Organic dte Chemie red Chemis ions, Macro e growing 262. ality in orga stry, Chemi , Burke D. istries in th 0–5686. nctionalizatio ation of ally ontrol comp ound in this ion mixture a thiol–ene rea e correspondi FT–IR mon l)benzyl th ohol to m nctionalities “click” reac monitoring und is prom Azides: An Internation try in Macr molecules 4 applications nic, polymer cal Commu J., Kade M. e Synthesis n via the “cl l–functiona ound for “ work enab fter subtractio ction between ng mol% of u itoring the az iol was suc ethylsulfona was furthe tion, where by an onlin ising to be u Exploding al Edition 4 omolecular 8 (2015) 2–1 of click ch , and supram nications 4 J., Hawker of Functio ick” lized PU off–line” les facile n of the nreacted ide signal. cessfully te) were r used to the azide e FT–IR sed as a Diversity 4 (2005) Science: 4. emistry, olecular 9 (2013) C. J. – nal Soft Thuy Thu Truong, Ha Tran Nguyen 159 6. Nguyen L.–T. T., Gokmen M. T. and Du Prez F. E. – Kinetic comparison of 13 homogeneous thiol–X reactions, Polymer Chemistry 4 (2013) 5527–5536. 7. Tunca U. – Orthogonal multiple click reactions in synthetic polymer chemistry, Journal of Polymer Science Part A: Polymer Chemistry 52 (2014) 3147–3165. 8. Nguyen L. –T. T., Devroede J., Plasschaert K., Jonckheere L., Haucourt N., Du Prez F. E. – Providing polyurethane foams with functionality: a kinetic comparison of different "click" and coupling reaction pathways, Polymer Chemistry 4 (2013) 1546–1556. 9. Scriven E. F. V., Turnbull K. – Azides: their preparation and synthetic uses, Chemical Reviews 88 (1988) 297–368. 10. Wang L., Dai C., Chen W., Wang S. L., Wang B. – Facile derivatization of azide ions using click chemistry for their sensitive detection with LC–MS, Chemical Communication 47 (2011) 10377–10379. 11. Warrier M., Lo M. K. F., Monbouquette H., Garcia–Garibay M. A. – Photocatalytic reduction of aromatic azides to amines using CdS and CdSe nanoparticles, Photochemical & Photobiological Sciences 3 (2004) 859–863. 12. Yin J., Ge Z., Liu H., Liu S. – Synthesis of amphiphilic copolymer brushes possessing alternating poly(methyl methacrylate) and poly(N–isopropylacrylamide) grafts via a combination of ATRP and click chemistry, Journal of Polymer Science Part A: Polymer Chemistry 47 (2009) 2608–2619. 13. Mizrahi D. M., Omer–Mizrahi M., Goldshtein J., Askinadze N., Margel S. – Novel poly(ethylene glycol) monomers bearing diverse functional groups, Journal of Polymer Science Part A: Polymer Chemistry 48 (2010) 5468–5478. 14. Uenishi J. – Stereospecific Displacement of 1–(Pyridinyl)ethanols with Amines and Thiols via Methanesulfonate Esters; Asymmetric Synthesis of 1–(Pyridinyl)ethylamines and Sulfides, Synlett 1 (1999) 41–44. 15. Tanabe Y., Yamamoto H., Yoshida Y., Miyawaki T., Utsumi N. – Practical and Safe Sulfonylation of 2–Alkynyl and 2–Alkenyl Alcohols Using the Combined Bases of a Catalytic Amount of Tertiary Amine and Potassium Carbonate, Bulletin of the Chemical Society of Japan 68 (1995) 297–300. 16. Basko M., Bednarek M., Nguyen L. –T. T., Kubisa P., Du Prez F. – Functionalization of polyurethanes by incorporation of alkyne side–groups to oligodiols and subsequent thiol– yne post–modification, European Polymer Journal 49 (2013) 3573–3581.