Formose Reaction Controlled by a Copolymer of N,N-Dimethylacrylamide and 4-Vinylphenylboronic Acid

polymers

Article Formose Reaction Controlled by a Copolymer of N,N-Dimethylacrylamide and 4-Vinylphenylboronic Acid

Tomohiro Michitaka, Toru Imai and Akihito Hashidzume * ID Department of Macromolecular Science, Graduate School of Science, Osaka University, Osaka 560-0043, Japan; [email protected] (T.M.); [email protected] (T.I.) * Correspondence: [email protected]; Tel.: +81-6-6850-8174

Received: 8 October 2017; Accepted: 24 October 2017; Published: 25 October 2017

Abstract: The formose reaction is an oligomerization of formaldehyde under basic conditions, which produces a complicated mixture of monosaccharides and sugar alcohols. Selective formation of useful monosaccharides by the formose reaction has been an important challenge. In this study, we have investigated the formose reaction controlled by N,N-dimethylacrylamide/4-vinylphenylboronic acid copolymer (pDMA/VBA) and phenylboronic acid (PBA) because boronic acid compounds form esters with polyols, e.g., monosaccharides and sugar alcohols. We obtained time–conversion data in the presence of these boronic acid compounds, and characterized the products by liquid chromatography-mass spectroscopy and NMR measurements. pDMA/VBA and PBA decelerated the formose reaction because of the formation of boronic acid esters with products. It is noteworthy that the formose reaction in the presence of pDMA/VBA and PBA formed favorably six- and seven-carbon branched monosaccharides and sugar alcohols.

Keywords: formose reaction; boronic acid compounds; N,N-dimethylacrylamide/4-vinylphenyl boronic acid copolymer; phenylboronic acid; monosaccharides; sugar alcohols

1. Introduction Carbohydrates are ubiquitous in our life and very important biological materials [1,2]. Carbohydrates can be divided into three categories based on their molecular weight; (1) low molecular weight saccharides, e.g., monosaccharides and disaccharides, (2) oligosaccharides, and (3) polysaccharides. Low molecular weight saccharides are utilized as energy source for living organisms, and oligosaccharides exhibit a number of physiological activities. Two representative polysaccharides are cellulose and starch; the former is utilized as a structural material in plants whereas the latter is employed as energy storage. Carbohydrates used in biological systems are synthesized by enzymatic reactions [1,2]. Synthesis of carbohydrates in a non-enzymatic way has been an important subject of investigation [3–6]. Especially, synthesis of monosaccharides from starting materials containing one or two carbon atoms is still remaining as a challenging subject because monosaccharides possess a number of chiral centers to be controlled [7,8]. Since monosaccharides, e.g., glyceraldehyde, erythrose, ribose, and glucose have the general formula (CH2O)n, monosaccharides can be formed by oligomerization of formaldehyde. In 1861, Butlerow [9] reported that a sugar-like product called ‘formose’ is obtained from formaldehyde by heating in water under basic conditions. This reaction is called the formose reaction. Detailed studies have revealed that the formose reaction proceeds through three major stages [10–13]. In the ﬁrst stage, two formaldehyde molecules couple to form glycolaldehyde. Since this reaction is the rate-determining step, the formose reaction indicates an induction period. As glycolaldehyde acts as a co-catalyst, a variety of monosaccharides are formed dominantly through aldol reaction and aldose–ketose

Polymers 2017, 9, 549; doi:10.3390/polym9110549 www.mdpi.com/journal/polymers PolymersPolymers 20172017,, 99,, 549549 22 ofof 1111

aldose–ketose isomerization in the second stage. This stage is called the sugar-forming period. After isomerizationcompletion of inconversion the second of stage. formaldehyde, This stage isthe called monosaccharides the sugar-forming formed period. are decomposed After completion mainly of conversionthrough retro of formaldehyde,-aldol and Cannizzaro the monosaccharides reactions formed in the are third decomposed stage. This mainly stage through is calledretro-aldol the andsugar Cannizzaro-decomposing reactions period. in theThus, third the stage. formose This stage reaction is called yields the a sugar-decomposing complicated mixture period. of Thus,monosaccharides the formose and reaction sugar yieldsalcohols a complicatedthrough these mixture three stages. of monosaccharides The formose reaction and sugar is considered alcohols throughas the most these promising three stages. pathway The formose to form reactionmonosaccharides is considered under as the prebiotic most promising conditions pathway [14–19]. to form monosaccharidesIf the formose under reaction prebiotic proceeds conditions in a controlled [14–19]. manner, it will provide an important pathway for nonIf the-enzymatic formose reaction synthesis proceeds of monosaccharides. in a controlled manner,Some pioneering it will provide works an on important a selective pathway formose for non-enzymaticreaction were synthesis conducted of frommonosaccharides. the 1970s to Some the pioneering1980s. Shigemasa works on et a al. selective [20–23 formose] devoted reaction their wereremarkable conducted efforts from to the optimize 1970s to the the conditions. 1980s. Shigemasa Consequently, et al. [ 20 they–23 ]first devoted isolated their a remarkable branched effortsseven-carbon to optimize sugar alcohol the conditions. from the reaction Consequently, mixture they of the first formose isolated reaction a branched catalyzed seven-carbon by barium sugarhydroxide alcohol in from methanol the reaction [24,25] mixture. Matsumoto of the formose et reaction al. [26,27] catalyzed successfully by barium synthesized hydroxide in1,3- methanoldihydroxyacetone, [24,25]. a Matsumoto three-carbon et monosaccharide al. [26,27] successfully, using a thiazolium synthesized catalyst 1,3-dihydroxyacetone, in ethanol in the apresen three-carbonce of triethylamine. monosaccharide, After using these a thiazolium pioneering catalyst works, in however, ethanol in there the presence have been of triethylamine. only a few Afterstudies these on pioneeringa selective works, formose however, reaction there [28,29] have and been, onlythus, athe few selectivestudies on formation a selective of formose useful reactionmonosaccharides [28,29] and, by the thus, reaction the selectiveremains under formation-examined. of useful monosaccharides by the reaction remainsWe under-examined. have been working on the formose reaction controlled by molecular recognition of polymersWe have and been molecular working assemblies on the formose [30–32 reaction]. We have controlled reported by molecularthat the reaction recognition is accelerated of polymers in andreverse molecular micelles assemblies of aerosol [30-OT,–32 an]. We anionic have reportedsurfactant, that and the yields reaction ethylene is accelerated glycol as in a reverse major micellesproduct of[31] aerosol-OT,. an anionic surfactant, and yields ethylene glycol as a major product [31]. Recently, we we have have also also utilized utilized boronic boronic acid acid compounds compounds to control to control the formose the formose reaction reactionbecause becauseboronic boronicacid compounds acid compounds form esters form with esters polyols, with polyols, e.g., monosaccharides e.g., monosaccharides or sugar or sugar alcohols. alcohols. This Thisphenomenon phenomenon has hasbeen been utilized utilized as asartificial artificial molecular molecular sensors sensors for for saccharides saccharides [33 [33––3636]] and as as polymericpolymeric materials responsive responsive to to saccharides saccharides [37] [37. When]. When the formose the formose reaction reaction is carried is carried out in outthe inpresence the presence of boronic of boronic acid compounds, acid compounds, boronic boronicacid esters acid may esters be formed may be to formed stabilize to the stabilize products, the products,leading to leadingan enhance to and selectivity. enhanced selectivity.We have, thus We, have,studied thus, the studiedformose the reaction formose in the reaction presence in the of presencesodium of phenylboronate sodium phenylboronate (NaPB) (NaPB) and an and anionic an anionic copolymer copolymer (pNaSS/NaVB) (pNaSS/NaVB) of of sodium sodium 4-styrenesulfonate4-styrenesulfonate (NaSS) and sodium 4-vinylphenylboronate4-vinylphenylboronate (NaVB) [[32]32].. We observedobserved thatthat NaPBNaPB and pNaSS/NaVBpNaSS/NaVB decelerated decelerated the the reaction. reaction. More More importantly, importantly, we exhibited we exhibited that the that formose the formose reaction producedreaction produced three- to three five-carbon- to five monosaccharides-carbon monosaccharides preferably preferably in the presence in the presence of NaPB of and NaPB four- and to eight-carbonfour- to eight sugar-carbon alcohols sugar favorablyalcohols favorably in the presence in the ofpresence pNaSS/NaVB. of pNaSS/NaVB However,. However, we also observed we also thatobserved NaSS that polymer NaSS deceleratedpolymer decelerated the formose the formose reaction. reaction. We have, We thus, have been, thus motivated, been motivated to use to other use boronicother boronic acid polymers. acid polymers. In this In article, this wearticle, describe we describe the formose the formose reaction reactioncarriedout carried in the out presence in the ofpresence a copolymer of a ofcopolymer non-ionic ofN ,N non-dimethylacrylamide-ionic N,N-dimethylacrylamide and 4-vinylphenylboronic and 4-vinylphenylboronic acid (pDMA/VBA, acid Scheme(pDMA/VBA,1). Scheme 1).

SchemeScheme 1.1. ChemicalChemical structuresstructures ofof pDMA/VBApDMA/VBA ( a) and PBA ( b).

2. Materials and Methods

2.1. Materials

4 2 Methanol-Methanol-d4 (>99.8%,(>99.8%, Merck Merck,, Darmstadt, Darmstadt, Germany Germany),), deuterium deuterium oxide oxide (D O, (D99.9atom%D,2O, 99.9atom%D, Sigma 6 6 SigmaAldrich, Aldrich, St. Louis, St. Louis, MO, MO,USA USA),), dimethyl dimethyl sulfoxide sulfoxide--d d(DMSO6 (DMSO--d ,d 6 99.5, 99.5 atm%, atm%, Sigma-Aldrich),Sigma-Aldrich), acetonitrile (>99.8%, (>99.8%, HPLC HPLC grade, grade, Kishida Kishida Chemical Chemical,, Osaka, Osaka, Japan), Japan), and dimethyl and dimethyl solfoxide solfoxide (DMSO, (DMSO,>98.0%, >98.0%, Nacalai Nacalai Tesque Tesque,, Kyoto, Kyoto, Japan) Japan) were were purchased purchased and used and as received. used 4-Vinylbenzylas received. 4-Vinylbenzyltrimethylammonium chloride (VTAC, 99%, Sigma Aldrich), 4,4′-azobis(4-cyanovaleric

Polymers 2017, 9, 549 3 of 11 trimethylammonium chloride (VTAC, 99%, Sigma Aldrich), 4,40-azobis(4-cyanovaleric acid) (ACVA, 98.0+%, Wako, Osaka, Japan), 4-vinylphenylboronic acid (VBA, >97%, TCI, Tokyo, Japan), calcium hydroxide (Ca(OH)2, >95.0%, Sigma Aldrich), phenylboronic acid (PBA, >97.0%, TCI), lithium bromide (>98.0%, Nacalai Tesque), poly(sodium 4-styrenesulfonate) (pNaSS, average Mw~1,000,000, Sigma Aldrich), and Amberlite® IR120 (hydrogen form, Sigma Aldrich) were purchased and used as received. Acetylacetone (99.0+%, Wako), acetic acid (>99.0%, Nacalai Tesque), ammonium acetate (>97.0%, Nacalai Tesque), and ethanol (>99.5%, Shinwa Alcohol) were used for the acetylacetone method as received. N,N-Dimethylformamide (DMF, >99.5%, Kanto Chemical) was puriﬁed using a Glass Contour solvent dispensing system. N,N-Dimethylacrylamide (DMA) (>99.0%, KJ Chemicals, Tokyo, Japan) was used after treatment with a short alumina column. Water was puriﬁed with a Millipore Elix 5 system. Formaldehyde solution (36.0–38.0%, Wako) was diluted with water to adjust 1/12 vol% and used for the formose reaction. Amberlite® IRA410 (chloride form, Sigma Aldrich) was used after treatment with 1 M NaOH, followed by washing with water. Spectra/Por 5 dialysis tubing, 12–14 kD MWCO (Spectrum Laboratories) was used for dialysis. Other reagents were used as received.

2.2. Measurements Size exclusion chromatography (SEC) measurements were performed on a TOSOH HLC-8320GPC EcoSEC equipped with a TOSOH TSK gel α-M column using 1.05 g·L−1 lithium bromide in DMSO as ◦ −1 the eluent at 40 C, with a ﬂow rate of 0.4 mL min . The number of average molecular weights (Mn) and the ratios of the weigtht to the number average molecular weights (Mw/Mn) were calibrated with polyacrylamide standards (American Polymer Standards). UV-VIS spectra were recorded on a HITACHI U-4100 spectrophotometer equipped with a cell holder thermostated at 25 ◦C using a Yamato CF300 circulator for the acetylacetone method. IR spectra were recorded on a JASCO FT/IR-6100 spectrometer equipped with an ATR PRO410-S carrying a diamond prism. Liquid chromatography-mass spectroscopy (LC-MS) measurements were performed on a Bruker Daltonics micrOTOF-QIII compact connected with a Shimadzu Prominence UFLC system. In the LC system, Shimadzu LC-20AD pumps and a Shodex 5NH2P-50 4E column were equipped, and a mixed solvent of water and acetonitrile (25/75, v/v) containing 0.1 vol% formic acid was used as an eluent at a ﬂow rate of 0.6 mL min−1. 13C NMR and distortionless enhancement of polarization transfer with a pulse delay adjusted for 3π/4 (DEPT-135) measurements were performed on a JEOL JNM ECA500 spectrometer using ◦ D2O as a solvent at 25 C. Two-dimensional heteronuclear single-quantum correlation (HSQC) and heteronuclear multiple bond correlation (HMBC) spectra were recorded on a Bruker AVANCE700 ◦ spectrometer using D2O as a solvent at 25 C. Acetonitrile was used as an internal standard, and chemical shifts were referenced to the signal due to the methyl carbon of acetonitrile (δ = 1.47 ppm).

2.3. Preparation of Water Soluble Polymers VTAC (4.23 g, 20.0 mmol) and ACVA (57 mg, 0.21 mmol) were dissolved in a mixed solvent of DMSO and water (9/1, v/v, 10 mL). The solution was deoxygenated by purging with nitrogen gas for 30 min, and then heated with an oil bath thermostated at 60 ◦C with stirring for 7 h. Subsequently, the reaction mixture was treated with 1 M NaOH (100 mL) at room temperature overnight. The polymer obtained was puriﬁed by dialysis against water for 15 days. Yield 3.41 g, 87.0%. DMA (5.1 mL, 50 mmol) and ACVA (140 mg, 0.498 mmol) were dissolved in water (50 mL). The solution was deoxygenated by purging with nitrogen gas for 30 min, and then heated with an oil bath thermostated at 70 ◦C with stirring for 18 h. The polymer obtained was puriﬁed by dialysis against water for six days. Yield 3.96 g, 77.8%. Polymers 2017, 9, 549 4 of 11

2.4. Preparation of N,N-Dimethylacrylamide/4-Vinylphenylboronic Acid Copolymer DMA (4.1 mL, 40 mmol), VBA (59 mg, 0.40 mmol), and ACVA (112 mg, 0.399 mmol) were dissolved in DMF (40 mL). The solution was deoxygenated by purging with argon gas for 1 h, and then heated with an oil bath thermostated at 70 ◦C with stirring for 6 h. The polymer obtained was puriﬁed by dialysisPolymers against2017, 9, 549 water for ﬁve days. Yield 3.01 g, 72.5%. 4 of 11

2.5. Formosethen heated Reaction with inanthe oil Presencebath thermostated of Boronic at Acid 70 °C Compounds with stirring for 6 h. The polymer obtained was purified by dialysis against water for five days. Yield 3.01 g, 72.5%. A typical procedure of the formose reaction is described below. After pDMA/VBA (10 mg) was dissolved2.5. Formose in an aqueous Reaction solutionin the Presence of formaldehyde of Boronic Acid (1 Compounds M, 2 mL), calcium hydroxide (18.8 mg, 0.240 mmol) ◦ was addedA totypical the mixture. procedure The of the reaction formose mixture reaction was is described warmed below. with a After water pDMA/VBA bath thermostated (10 mg) was at 60 C with stirring.dissolved At in predeterminedan aqueous solution reaction of formaldehyde times, aliquots (1 ofM, the2 mL), reaction calcium mixture hydroxide were (18.8 taken mg, to determine0.240 formaldehydemmol) was consumption added to the mixture. by the acetylacetone The reaction mixture method was [38 warmed]. After awith predetermined a water bath time,thermostated the reaction was quenchedat 60 °C with by stirring. adding At 1 predetermined M HCl (0.24 mL).reaction After times, the aliquots reaction of mixturethe reaction was mixture treated were with taken the ion exchengeto determine resins for formaldehyde 30 min, the consumption product was by puriﬁed the acetylacetone by dialysis method against [38]. water After (300 a predetermined mL) for one day. The outertime, aqueousthe reaction solution was quenched was concentrated by adding 1 under M HCl reduced (0.24 mL). pressure. After the After reaction lyophilization mixture was of the solution,treated the with product the ion was exchenge obtained resins aspale for 30 brown min, the solid. product Yield was 28 mg,purified 47%. by dialysis against water (300 mL) for one day. The outer aqueous solution was concentrated under reduced pressure. After 3. Resultslyophilization of the solution, the product was obtained as pale brown solid. Yield 28 mg, 47%.

3.1. Effect3. Results of Water Soluble Polymers on the Formose Reaction

Before3.1. Effect investigationof Water Soluble Polymers on the on formose the Formose reaction Reaction in the presence of polymer-carrying boronic acidBefore moieties, investigation we on started the formose this reaction study in with the presence an examination of polymer- oncarrying the effectboronic ofacid water solublemoieties, polymers. we started We this employed study with anionic an examination poly(sodium on the 4-styrenesulfonate) effect of water soluble (pNaSS), polymers. We cationic poly(4-vinylbenzylammoniumemployed anionic poly(sodium hydroxide) 4-styrenesulfonate) (pVTAOH), (pNaSS), and nonioniccationic poly(4 poly(-vinylbenzylammoniumN,N-dimethylacrylamide) (pDMA)hydroxide) in this (pVTAOH), study. Figure and 1nonionic shows poly( time–conversionN,N-dimethylacrylamide) plots for the (pDMA) formose in this reaction study. Figure carried 1 out usingshows 0.2 M time formaldehyde–conversion plots and for 40 the mM formose calcium reaction hydroxide carried at out 60 using◦C in 0.2 the M absenceformaldehyde and presenceand 40 of thesemM polymers. calcium hydroxide In the absence at 60 °C of in the the polymers, absence and the presence formaldehyde of these polymers. consumption In the absence increased of the up to a quantitativepolymers, one the within formaldehyde 30 min. However, consumption the increased formose reaction up to a wasquantitative decelerated one within signiﬁcantly 30 min. in the However, the formose reaction was decelerated significantly in the presence of 10 g·L−1 pNaSS and presence of 10 g·L−1 pNaSS and pVTAOH, and the formaldehyde consumption became quantitative pVTAOH, and the formaldehyde consumption became quantitative after ca. 40 and 50 min, after ca. 40 and 50 min, respectively. In the presence of 10 g·L−1 pDMA, the formose reaction was respectively. In the presence of 10 g·L−1 pDMA, the formose reaction was slowed down only slightly, slowedi.e., down the formaldehyde only slightly, consumption i.e., the formaldehyde reached a quantitative consumption one within reached 30 a min. quantitative This observation one within 30 min.indicates This observation that pDMA does indicates not considerably that pDMA perturb does notthe formose considerably reaction. perturb the formose reaction.

Figure 1. Time–conversion plots for the formose reaction carried out using 0.2 M formaldehyde and Figure 1. Time–conversion plots for the formose reaction carried out using 0.2 M formaldehyde and 40 mM calcium hydroxide at 60 °C in the absence (black circle, dotted line) and presence of 10 g·L−1 40 mM calcium hydroxide at 60 ◦C in the absence (black circle, dotted line) and presence of 10 g·L−1 pNaSS (blue triangle), pVTAOH (green square), and pDMA (red circle). The curves are drawn as a pNaSSguide (blue for triangle), the eye. pVTAOH (green square), and pDMA (red circle). The curves are drawn as a guide for the eye. 3.2. Preparation of N,N-Dimethylacrylamide/4-Vinylphenylboronic Acid Copolymer On the basis of the observations described above, we have chosen a copolymer of DMA and VBA (pDMA/VBA) to study the effect of polymer-carrying boronic acid moieties on formose

Polymers 2017, 9, 549 5 of 11

3.2. Preparation of N,N-Dimethylacrylamide/4-Vinylphenylboronic Acid Copolymer Polymers 2017, 9, 549 5 of 11 On the basis of the observations described above, we have chosen a copolymer of DMA and VBA (pDMA/VBA)reaction in this tostudy. study The the copolymer effect of polymer-carrying was prepared by boronic radical acidcopolymerization moieties on formose of DMA reaction and VBA in thisin DMF study. using The ACVA copolymer as initiator. was prepared The pDMA/VBA by radical copolymerizationcopolymer was purified of DMA by and dialysis VBA inagainst DMF water using ACVAfor five as days. initiator. The VBA The pDMA/VBAcontent in the copolymer copolymer was was purified determined by dialysis to be ca. against 2 mol% water by 1 forH NMR. five days. The 5 1 TheMn and VBA M contentw/Mn values in the were copolymer evaluated was determinedto be 3.58 × to10 be and ca. 21.58, mol% respectively, by H NMR. by The SEC.M nThus,and M a wsingle/Mn valueschain carries were evaluated ca. 70 boronic to be acid 3.58 moieties× 105 and in 1.58,average. respectively, It is likely by that SEC. the Thus, distribution a single of chain VBA carries units ca.on 70the boronic polymer acid chain moieties is practically in average. random. It is likely that the distribution of VBA units on the polymer chain is practically random. 3.3. Effect of the N,N-Dimethylacrylamide/4-Vinylphenylboronic Acid Copolymer 3.3. Effect of the N,N-Dimethylacrylamide/4-Vinylphenylboronic Acid Copolymer Since the formose reaction did not proceed in the presence of NaPB or pNaSS/NaVB under the reactionSince conditions the formose in reaction our previous did not study, proceed a in co the-catalyst, presence i.e., of fructoseNaPB or pNaSS/NaVB or glyceraldehyde, under was the reactionnecessary conditions for conversion in our of previous formaldehyde. study, a In co-catalyst, this study, i.e., we fructose have used or glyceraldehyde, the reaction conditions was necessary under forwhich conversion the reaction of formaldehyde. proceeded without In this any study, co-catalyst. we have We used carried the reactionout the formose conditions reaction under using which 1 theM formaldehyde reaction proceeded and 120 without mM calcium any co-catalyst. hydroxide. WeFigure carried 2a indicates out the formosethe time– reactionconversion using plots 1 Min formaldehydethe absence and and presence 120 mM of calciumvarying concentrations hydroxide. Figure of pDMA/VBA.2a indicates In the the time–conversion absence of pDMA/VBA, plots in thethe absence formaldehyde and presence consumption of varying increased concentrations rapidly upof pDMA/VBA. to a quantitative In the one absence within of 20 pDMA/VBA, min. In the thepresence formaldehyde of 1 g·L consumption−1 pDMA/VBA, increased the time rapidly–conversi upon to a plots quantitative were the one same within as 20 those min. for In the the presenceconventional of 1 g · formoseL−1 pDMA/VBA, reaction. theIn thetime–conversion presence of plots 5 g·L were−1 pDMA/VBA, the same as those slight for retardation the conventional of the formosereaction was reaction. observed, In thebut presencethe formaldehyde of 5 g·L consumption−1 pDMA/VBA, became slight quantitative retardation after of 40 the min. reaction At 10 wasg·L−1observed, pDMA/VBA, but the significan formaldehydet retardation consumption was not becameobserved, quantitative but the formaldehyde after 40 min. consumptionAt 10 g·L−1 pDMA/VBA,leveled off at ca. significant 80% after retardation 60 min. These was notobservations observed, indicate but the formaldehydethat polymer-carrying consumption boronic leveled acid offmoieties at ca. 80%retard after the 60formose min. These reaction observations because DMA indicate units that have polymer-carrying almost no effect. boronic Similarly, acid in moieties the case retardof 0.2 mM the formose PBA, the reaction formose because reaction DMA was units slightly have decelerated, almost no effect. and the Similarly, formaldehyde in the case consumption of 0.2 mM PBA,increased the formose up to a reactionquantitative was slightlyone after decelerated, 40 min. In andthe thepresence formaldehyde of 0.5 mM consumption PBA, the formaldehyde increased up toconsumption a quantitative leveled one after off 40 at min. ca. 80 In% the after presence 60 min. of 0.5 At mM 1 andPBA, 2 the mM formaldehyde PBA, the formaldehyde consumption leveledconsumption off at ca. was 80% saturated after 60 min.at ca. At 40 1%. and These 2 mM observations PBA, the formaldehyde confirm that consumption PBA retards was the saturated formose atreaction. ca. 40%. A Thesesolution observations of 5 g·L−1 confirmpDMA/VBA that PBAcontains retards ca. the1 mM formose boronic reaction. acid moieties.A solution It ofshould 5 g·L −be1 pDMA/VBAnoted here that contains 1 mM ca. PB 1A mM exhibits boronic a stronger acid moieties. effect Itof should retardation be noted than here does that 5 1g mM·L−1 pDMA/VBA. PBA exhibits aThis stronger observation effect ofindicates retardation that thanlow molecular does 5 g·L weight−1 pDMA/VBA. boronic acid This moieties observation have a indicates stronger thateffect low of molecularretardation weight than do boronic polymer acid-carrying moieties ones have presumably a stronger effect because of retardation of a lower thaneffective do polymer-carrying concentration of onespolymer presumably-carrying because moieties. of a lower effective concentration of polymer-carrying moieties.

Figure 2. Cont.

Polymers 2017, 9, 549 6 of 11 Polymers 2017, 9, 549 6 of 11

Polymers 2017, 9, 549 6 of 11

FigureFigure 2. Time–conversion2. Time–conversion plotsplots for the the formose formose reaction reaction carried carried out using out using1 M formaldehyde 1 M formaldehyde and 120 mM calcium hydroxide at 60 °C in the presence of 0 (black circle), 0.2 (blue triangle), 0.5 (green and 120 mM calcium hydroxide at 60 ◦C in the presence of 0 (black circle), 0.2 (blue triangle), inverted triangle), 1 (orange diamond), and 2 mM (red square) PBA (a) and 0 (black circle), 1 (blue 0.5 (green inverted triangle), 1 (orange diamond), and 2 mM (red square) PBA (a) and 0 (black circle), triangle), 5 (orange diamond), and 10 g·L−1 (red square) pDMA/VBA (b). The same colors indicate the 1 (blue triangle), 5 (orange diamond), and 10 g·L−1 (red square) pDMA/VBA (b). The same colors same concentrations of boronic acid moieties. The curves are drawn as a guide for the eye. indicate the same concentrations of boronic acid moieties. The curves are drawn as a guide for the eye. 3.4. ConfirmationFigure 2. of Time the –Formationconversion plotsof Boronic for the Acidformose Esters reaction in Formose carried out Reaction using 1 MixturesM formaldehyde and 3.4. Conﬁrmation120 ofmM the calcium Formation hydroxide of at Boronic 60 °C in Acidthe presence Esters of in 0 (black Formose circle), Reaction 0.2 (blue triangle), Mixtures 0.5 (green It is likelyinverted that triangle), the retardation 1 (orange diamond), effect andof boronic 2 mM (red acid square) moieties PBA (a )in and formose 0 (black reactioncircle), 1 (blue is caused by −1 Itthe is formation likelytriangle), that of boronic the 5 (orange retardation acid diamond), esters. and effect To 10 confirmg· ofL (red boronic square)the formation acid pDMA/VBA moieties of (boronicb). The in same formose acid colors esters, indicate reaction IR spectrathe is caused were by same concentrations of boronic acid moieties. The curves are drawn as a guide for the eye. the formationrecorded for of boronicmixtures acidbefore esters. and after To conﬁrm the reaction the (Figure formation 3). Figure of boronic 3a,b contain acid esters, absorption IR spectra bands were ascribable to calcium hydroxide at 668, 710, 750, and 872 cm−1 (see Figure S1 in Supplementary recorded for3.4. mixturesConfirmation before of the Formation and after of Boronic the reaction Acid Esters (Figure in Formose3). Reaction Figure Mixtures3a,b contain absorption bands Materials). In Figure 3a, absorption bands at 1055, 1357, and 1379 cm−1 are assignable to the B–O–H ascribable to calcium hydroxide at 668, 710, 750, and 872 cm−1 (see Figure S1 in Supplementary deformation,It is Blikely–O stretching, that the retardation and B–O effect and ofB –boronicC stretching acid moieties vibrations, in formose respectively reaction [39,40]is caused. Figure by 3a the formation of boronic acid esters. To confirm the formation of boronic acid−1 esters, IR spectra were Materials).also exhibits In Figure an absorption3a, absorption band bandsdue to the at 1055, aromati 1357,c C– andH deformation 1379 cm vibrationare assignable at 789 cm to−1 the and B–O–H a recorded for mixtures before and after the reaction (Figure 3). Figure 3a,b contain absorption bands deformation,board absorption B–O stretching, band assignable and B–O to and formaldehyde B–C stretching in the vibrations, region of respectively1000–1200 cm [39−1. ,In40 ]. the Figure IR 3a ascribable to calcium hydroxide at 668, 710, 750, and 872 cm−1 (see Figure S1 in Supplementary − −1 1 also exhibitsspectrumMaterials). an for absorption the In Figure reaction 3a, band mixtureabsorption due (Figure to bands the aromaticat 3b), 1055, absorption 1357, C–H and deformation1379 bands cm − at1 are 787, assignable vibration 1353, and to the at 13 B 78979–O cm– cmH areand a −1 boardassignable absorptiondeformation, to the band arom B– assignableO stretching,atic C–H todeformation,and formaldehyde B–O and B B––CO stretching stretching, in the region vibrations, and of B– 1000–1200 Orespectively and B–C cm stretching[39,40].. InFigure the vibrations, IR3a spectrum for therespectively. reactionalso exhibits mixture It is an noteworthy absorption (Figure3 bandthatb), absorption Figuredue to the 3b aromatidoes bands notc C at–exhibitH 787, deformation 1353,any absorption and vibration 1379 atband cm 789− cm1dueare−1 andto assignable B a– O–H to −1 the aromaticdeformationboard C–H absorption at deformation,ca. 1055 band cm− 1assignable whereas B–O stretching, it to contains formaldehyde and a absorption B–O in the and regionband B–C due of stretching 10 to00 the–1200 B– vibrations,O cm–H. inIn quaternized the respectively. IR −1 boronicspectrum acid esters for the at 993 reaction cm− 1 mixture [41] and (Figure a broad 3b), absorption absorption band bands due at 787,to the 1353, C– andO stretching 1379 cm v areibration It is noteworthyassignable that to the Figure arom3aticb doesC–H deformation, not exhibit B– anyO stretching, absorption and B– bandO and dueB–C stretching to B–O–H vibrations, deformation at in the region−1 of 950–1100 cm−1. These observations indicate that as the formose reaction proceeds in ca. 1055 cmrespectively.whereas It is it noteworthy contains athat absorption Figure 3b does band not due exhibit to theany B–O–Habsorption in band quaternized due to B–O boronic–H acid the presence of PBA, the free boronic acid is consumed to form esters. esters at 993deformation cm−1 [41 at] ca. and 1055 a broadcm−1 whereas absorption it contains band a absorption due to theband C–O due to stretching the B–O–Hvibration in quaternized in the region −1 of 950–1100boronic cm− 1acid. These esters observations at 993 cm [41] indicateand a broad that absorption as the formoseband due reactionto the C–O proceeds stretching v inibration the presence of in the region of 950–1100 cm−1. These observations indicate that as the formose reaction proceeds in PBA, the freethe presence boronic of acid PBA,is the consumed free boronicto acid form is consumed esters. to form esters.

Figure 3. IR spectra for the reaction mixture containing 1 M formaldehyde, 120 mM calcium hydroxide, and 2 mM PBA before (a) and after heating at 60 °C for 60 min (b). The measurements Figure 3. IR spectra for the reaction mixture containing 1 M formaldehyde, 120 mM calcium Figurewere 3. carried out after evaporation of the solvent by air blowing on a diamond prism loaded in the IRhydroxide, spectra and for 2 the mM reaction PBA before mixture (a) and containing after heating 1 at M 60 formaldehyde, °C for 60 min (b 120). The mM measurements calcium hydroxide, ◦ and 2ATR mM were attachment. PBA carried before outSymbols after (a) evaporation and (cross after and o heatingf the circle) solvent denote at by 60 air theC blowing for absorption 60 on mina diamond bands (b). prism The assignable measurementsloaded toin the calcium were carriedhydroxide outATR after attachment.and evaporation formaldehyde, Symbols of respectively. (crossthe solvent and circle) by denoteair blowing the absorption on a diamond bands assignable prism loadedto calcium in the ATR attachment. hydroxide Symbols and (cross formaldehyde, and circle) respectively. denote the absorption bands assignable to calcium hydroxide

and formaldehyde, respectively. Polymers 2017, 9, 549 7 of 11

3.5. Characterization of Formose Reaction Products

The formosePolymers 2017 reaction, 9, 549 products were characterized by LC-MS. The products were7 of 11 puriﬁed by treatment of the reaction mixtures with the ion-exchange resins followed by dialysis against pure water. Figure3.5. Characterization4a,b display of mass Formose chromatograms Reaction Products for the products of the formose reaction carried out in the presenceThe of form pDMA/VBAose reaction products and PBA, were respectively.characterized by For LC-MS. reference, The products the masswere purified chromatogram by for the producttreatment without of the any reaction boronic mixtures acid with compound the ion-exchange is indicated resins followed in Figure by 4dialysisc. This against ﬁgure pure indicates a water. Figure 4a,b display mass chromatograms for the products of the formose reaction carried out number ofin signals the presence in the of pDMA/VBA elution time and region PBA, respectively. of 7–14 min, For indicativereference, the of mass the chromatogram formation of for a the complicated mixture inproduct the conventional without any boronic formose acid reaction. compound Onis indicated the other in Figure hand, 4c. as This can figure be seen indicates in Figure a 4a,b, the mass chromatogramsnumber of signals in forthe elution the products time region of of formose 7–14 min, reactionindicative inof the the formation presence of a of complicated pDMA/VBA and PBA exhibitmixture four in major the conventional signals at formose 7.7, 8.7, reaction. 9.3, and On 9.6the min.other hand, These as chromatogramscan be seen in Figure do 4a not,b, the contain any mass chromatograms for the products of formose reaction in the presence of pDMA/VBA and PBA signals in theexhibi elutiont four major time signals region at of 7.7, 10–14 8.7, 9.3, min, and indicating 9.6 min. These that chromatograms the selectivity do of not the contain formose any reaction is somehowsignals enhanced. in the elution time region of 10–14 min, indicating that the selectivity of the formose reaction is somehow enhanced.

Figure 4. Mass chromatograms for the products of the formose reaction carried out using 1 M Figure 4. Mass chromatograms for the products of the formose reaction carried out using 1 M formaldehyde and 120 mM calcium hydroxide at 60 °C in the presence of 10 g·L−1 pDMA/VBA (a) ◦ −1 formaldehydeand 0.5 and mM 120PBA mM(b), and calcium in their absence hydroxide (c). The at reaction 60 C time in thewas presence180 (a,b) or of20 min 10 g(c·).L The pDMA/VBAm/z (a) and 0.5range mM of PBA 60–250 (b), was and detected. in their absence (c). The reaction time was 180 (a,b) or 20 min (c). The m/z range of 60–250 was detected. Figure 5 compares the mass spectra for the four major signals in Figure 4a,b. As a eference, the mass spectrum for the product of the conventional formose reaction is shown in Figure S3 in the FigureSupplementary5 compares Materials. the mass The spectra spectrum for indicates the four a number major of signals signals at m in/z = Figure 145.06, 4153.09,a,b. As175.07, aeference, the mass spectrum183.10, 203.10, for 213.12, the product and 232.08 of assignable the conventional to four- to formoseseven-carbon reaction sugar alcohols is shown, as well in Figure as S3 in six-carbon monosaccharides (for assignments see Figure S3 in Supplementary Materials). These the Supplementary Materials. The spectrum indicates a number of signals at m/z = 145.06, 153.09, signals are indicative of the formation of a complicated mixture. Figure 5a,b show the mass spectra 175.07, 183.10,at the 203.10,maxima 213.12,of four major and signals 232.08 in assignable Figure 4a,b for to the four- products to seven-carbon of the formose sugar reaction alcohols, in the as well as six-carbonpresence monosaccharides of pDMA/VBA and (for PBA, assignments respectively. Fi seegureFigure 5a,b indicate S3 in that Supplementary the formose reaction Materials). yields, These signals areselectively indicative, six of- theand formation seven-carbon of monosaccharidesa complicated mixture. and sugar Figure alcohols5a,b inshow the presence the mass of spectra at pDMA/VBA and PBA. the maxima of four major signals in Figure4a,b for the products of the formose reaction in the presence of pDMA/VBA and PBA, respectively. Figure5a,b indicate that the formose reaction yields, selectively, six- and seven-carbon monosaccharides and sugar alcohols in the presence of pDMA/VBA and PBA. The structure of products was also characterized by NMR spectroscopy. As an example, Figure6 shows 13C NMR and DEPT-135 spectra for the product of formose reaction in the presence of pDMA/VBA. The 13C NMR spectrum shows a number of signals, indicating that the product contains some isomers. The DEPT-135 spectrum contains positive and negative signals ascribed to methine and methylene carbons, respectively. It is noteworthy that there are signiﬁcant signals ascribable to quaternary carbons in the region of 70–90 ppm in the 13C NMR spectrum, which are not observed in the DEPT-135 spectrum. This observation indicates that the products contain branched monosaccharides and sugar alcohols. The formation of branched products was conﬁrmed by HSQC and HMBC spectra (Figures S4 and S5 in Supplementary Materials). Polymers 2017, 9, 549 8 of 11

Polymers 2017, 9, 549 8 of 11 Polymers 2017, 9, 549 8 of 11

Figure 5. Mass spectra obtained in the LC-MS measurements for the products of the formose reaction carried out using 1 M formaldehyde and 120 mM calcium hydroxide at 60 °C for 180 min in the presence of 10 g·L−1 pDMA/VBA (a) and 0.5 mM PBA (b). Spectra A–H were recorded at the maxima of signals A–H in Figure 4. Spectra X and Y are the total mass spectra recorded in the region of 7–14 min in Figure 4a,b, respectively. Cn and CnA denote n-carbon monosaccharide and sugar alcohol, respectively.

The structure of products was also characterized by NMR spectroscopy. As an example, Figure 6 shows 13C NMR and DEPT-135 spectra for the product of formose reaction in the presence of pDMA/VBA. The 13C NMR spectrum shows a number of signals, indicating that the product Figure 5. Mass spectra obtained in the LC-MS measurements for the products of the formose reaction Figurecontains 5. Mass some spectra isomers. obtained The DEPT in the-135 LC-MS spectrum measurements contains positive for the and products negative ofsignals the formose ascribed reactionto ◦ carriedmethine out out using using and 1 methylene M1 M formaldehyde formaldehyde carbons, and respectively. and 120 120mM mM calcium It is calcium noteworthy hydroxide hydroxide that at 60 there atC forare 60 180 °Csignificant for min 180 in the signals min presence in the ofpresence 10 gascribable·L− of1 pDMA/VBA10 gto·L quatern−1 pDMA/VBAary (a) carbons and 0.5(a )in mMand the PBA0.5region mM (b of). PBA70 Spectra–90 ( bppm). A–H Spectra in the were 13 AC recorded–NMRH were spectrum, recorded at the which maxima at arethe of notmaxima signals A–Hof signals inobserved Figure A–H in4 in. the SpectraFigure DEPT 4.- X135 Spectra and spectrum. Y areX and theThis Y total observation are massthe total spectra indicates mass recorded sp thatectra the recordedproducts in the region contain in the of regionbranched 7–14 minof 7– in14 monosaccharides and sugar alcohols. The formation of branched products was confirmed by HSQC Figuremin in4 a,b,Figure respectively. 4a,b, respectively. C n and C CnAn denoteand CnnA-carbon denote monosaccharide n-carbon monosaccharide and sugar alcohol, and sugar respectively. alcohol, and HMBC spectra (Figures S4 and S5 in Supplementary Materials). respectively.

Figure 6. 13C NMR (lower) and DEPT-135 spectra (upper) for the product of the formose reaction 13 Figure 6. carriedC NMR out using (lower 1 M) and formaldehyde DEPT-135 and spectra 120 mM ( calciumupper ) hydroxide for the product at 60 °C for of 60 the min formose in the reaction ◦ carried outpresence using 1of M 5 g formaldehyde·L−1 pDMA/VBA. and 120 mM calcium hydroxide at 60 C for 60 min in the presence of 5 g·L−1 pDMA/VBA. 4. Discussion 4. DiscussionHere we discuss why boronic acid compounds somehow enhance the selectivity of formose reaction products. As described in the introduction part, formose reaction proceeds via some Here we discuss why boronic acid compounds somehow enhance the selectivity of formose reaction products. As described in the introduction part, formose reaction proceeds via some elemental steps, including acyloin condensation, aldol and retro-aldol reactions, aldose–ketose isomerization, and the Cannizzaro reaction. Thus, it is known that formose reaction provides favorably branched monosaccharides and sugar alcohols [24,25,42]. On the other hand, boronic acid compounds form esters with the formose reaction products. Since added boronic acid compounds significantly retard the formose reaction, the formation of boronic acid esters protect the products against further reactions. The stability of boronic acid esters depends on the relative orientation of two hydroxy groups, Figure 6. 13C NMR (lower) and DEPT-135 spectra (upper) for the product of the formose reaction i.e., thecarried species out of using monosaccharides 1 M formaldehyde and and sugar 120 alcohols.mM calcium It hydroxide is also known at 60 that°C for boronic 60 min acid in the esters of apresence five- or six-memberedof 5 g·L−1 pDMA/VBA. ring are rather stable [43]. It is, thus, likely that formose reaction in the boronic acid compounds produces favorably six- and seven-carbon monosaccharides and the corresponding4. Discussion sugar alcohols, which can form rather stable esters of a five- or six-membered ring (Figure7). Here we discuss why boronic acid compounds somehow enhance the selectivity of formose reaction products. As described in the introduction part, formose reaction proceeds via some

Polymers 2017, 9, 549 9 of 11 elemental steps, including acyloin condensation, aldol and retro-aldol reactions, aldose–ketose isomerization, and the Cannizzaro reaction. Thus, it is known that formose reaction provides favorably branched monosaccharides and sugar alcohols [24,25,42]. On the other hand, boronic acid compounds form esters with the formose reaction products. Since added boronic acid compounds significantly retard the formose reaction, the formation of boronic acid esters protect the products against further reactions. The stability of boronic acid esters depends on the relative orientation of two hydroxy groups, i.e., the species of monosaccharides and sugar alcohols. It is also known that boronic acid esters of a five- or six-membered ring are rather stable [43]. It is, thus, likely that formose reaction in the boronic acid compounds produces favorably six- and seven-carbon

Polymersmonosaccharides2017, 9, 549 and the corresponding sugar alcohols, which can form rather stable esters9 of 11 a five- or six-membered ring (Figure 7).

Figure 7.7. Conceptual illustration of formose reaction in the presence of a boronic acid polymer, in which thethe polymerpolymer stabilizesstabilizes thethe productproduct viavia esterester formation,formation, leadingleading toto anan enhancedenhanced selectivity.selectivity.

It has been reported that two boronic acid moieties of a specific relative location form ester with It has been reported that two boronic acid moieties of a speciﬁc relative location form ester with monosaccharides showing an enhanced selectivity [36]. Thus, molecularly imprinted polymers monosaccharides showing an enhanced selectivity [36]. Thus, molecularly imprinted polymers [44,45] [44,45] or cross-linked dendrimers [46], in which two boronic acid moieties are located or cross-linked dendrimers [46], in which two boronic acid moieties are located appropriately, appropriately, are promising to give a higher selectivity of the formose reaction product. are promising to give a higher selectivity of the formose reaction product.

Supplementary Materials: TThehe following following are are available available online online at www.mdpi.com/2073 at www.mdpi.com/2073-4360/9/11/549/s1-4360/9/11/549/s1. Figure. FigureS1. IR spectra S1. IR for spectra the standard for the standardsamples and samples the reaction and the mixtures: reaction A mixtures: mixture of A 1 mixture M formaldehyde of 1 M formaldehyde and 120 mM andcalcium 120 mMhydroxide calcium in hydroxide water (a), ina watermixture (a), of a 120 mixture mM ofcalcium 120 mM hydroxid calciume hydroxideand 2 mM and PBA 2 mMin water PBA (b), in water PBA (b),(c), PBAthe mixtures (c), the mixtures containing containing 1 M formaldehyde, 1 M formaldehyde, 120 mM 120 calcium mM calcium hydroxide, hydroxide, and 2 mM and 2PBA mM before PBA before (d) and (d) after and after formose reaction at 60 ◦C for 60 min (e). The measurements were carried out after evaporation of the solvent formose reaction at 60 °C for 60 min (e). The measurements were carried out after evaporation of the solvent by by air blowing on a diamond prism loaded in the ATR attachment; Figure S2. IR spectrum computationally calculatedair blowing for on the a ester diamond of quaternized prism loaded diphenylboronic in the ATR acid attachment with fructose; Figure using S2. a IR Gaussian spectrum 09W computationally software with thecalculated following for settings:the ester of calculation quaternized type, diphenylboronic frequency; calculation acid with method, fructose RHF; using basis a Gaussian set, 3–21 09W G (uppersoftware panel), with andthe following a snapshot settings: of the three-dimensional calculation type, frequenc vibrationaly; calculation structure responsible method, RHF; for the basis absorption set, 3–21 band G (upper at 974 panel nm−)1, (lowerand a snapshot panel); Figure of the S3.three The-dimensional mass spectrum vibrational recorded structure in LC-MS responsible measurements for the forabsorption the region band of 7–14at 974 min nm in−1 Figure(lower4 panelc, corresponding); Figure S3. toThe the mass products spectrum of formose recorded reaction in LC carried-MS measurements out using 1 M for formaldehyde the region of and 7–14 120 min mM in calcium hydroxide at 60 ◦C for 20 min in the absence of the boronic acid compounds; Figure S4. HSQC spectrum forFigure the 4 productc, corresponding of formose to reactionthe products carried of formose out using reaction 1 M formaldehyde carried out using and 1 120 M formaldehyde mM calcium hydroxideand 120 mM at 60calcium◦C for hydroxide 60 min in theat 60 presence °C for 20 of min 5 g ·inL− the1 pDMA/VBA; absence of the Figure boronic S5. acid HMBC compounds spectrum; Figure for the S4. product HSQC of spectrum formose reactionfor the product carried outof formose using 1 reaction M formaldehyde carried out and using 120 mM 1 Mcalcium formaldehyde hydroxide and at 120 60 mM◦C for calcium 60 min hydroxide in the presence at 60 of°C 5for g· L60−1 minpDMA/VBA; in the presence Video of S1. 5 Theg·L−1 three-dimensional pDMA/VBA; Figure vibrational S5. HMBC structure spectrum responsible for the product for the absorptionof formose bandreaction at 974carried nm− out1 in using the calculated 1 M formaldehyde spectrum (Figureand 120 S2).mM calcium hydroxide at 60 °C for 60 min in the presence of 5 g·L−1 pDMA/VBA; Video S1. The three-dimensional vibrational structure responsible for the absorption Acknowledgments: This study was financially supported in part by the Sasakawa Scientific Research Grant from −1 theband Japan at 974 Science nm in Society the calculated and JSPS spectrum Kakenhi Grant(Figure Numbers S2). JP23550137, JP26288061. AuthorAcknowledgments: Contributions: ThisTomohiro study was Michitaka financially and Akihitosupported Hashidzume in part by conceivedthe Sasakawa and designedScientific theResearch experiments; Grant Tomohirofrom the Japan Michitaka Science and Society Toru Imaiand JSPS performed Kakenhi the Grant experiments; Numbers Tomohiro JP23550137, Michitaka JP26288061. and Akihito Hashidzume analyzed the data; Tomohiro Michitaka and Akihito Hashidzume wrote the paper. Author Contributions: Tomohiro Michitaka and Akihito Hashidzume conceived and designed the Conflicts of Interest: The authors declare no conflict of interest. experiments; Tomohiro Michitaka and Toru Imai performed the experiments; Tomohiro Michitaka and Akihito Hashidzume analyzed the data; Tomohiro Michitaka and Akihito Hashidzume wrote the paper. References and Notes Conflicts of Interest: The authors declare no conflict of interest. 1. Voet, D.; Voet, J.G. Biochemistry, 4th ed.; Wiley & Sons: New York, NY, USA, 2010.

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