Article Cite This: Macromolecules XXXX, XXX, XXX−XXX
pubs.acs.org/Macromolecules
Mechanistic Modeling of the Thiol−Michael Addition Polymerization Kinetics: Structural Effects of the Thiol and Vinyl Monomers Sijia Huang,† Jasmine Sinha,† Maciej Podgoŕ ski,†,‡ Xinpeng Zhang,† Mauro Claudino,† and Christopher N. Bowman*,† †
Downloaded via DREXEL UNIV on July 31, 2018 at 15:50:17 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
Department of Chemical and Biological Engineering, University of Colorado Boulder, 596 UCB, Boulder, Colorado 80309-0596, United States ‡ Department of Polymer Chemistry, Faculty of Chemistry, MCS University, Gliniana St. 33, 20-614 Lublin, Poland S Supporting Information *
ABSTRACT: Kinetic parameters and their influence on the overall rates of base-catalyzed thiol−Michael reactions proceeding via an alternating propagation and chain transfer cycle were evaluated. A kinetic model was developed that enables the determination and accurate prediction of the reaction kinetic paths for the thiol−Michael addition reaction and its accompanying polymerization. Individual kinetic parameters for propagation and chain transfer steps were evaluated for three commonly used thiol and vinyl functional monomers. Chain transfer and propagation kinetic parameters were determined in binary combinations of monomers from analysis of experimental data for the reaction rates. Subsequently, eight ternary thiol− Michael systems composed of thiol−acrylate−vinyl sulfone and thiol 1-thiol 2-vinyl were analyzed based on the binary kinetic model parameters. It was clearly demonstrated that the kinetic parameters determined from the binary reactions enabled an accurate prediction of the relative reactivity and selectivity in the multicomponent systems. Finally, the calculated kinetic parameters were utilized in network-forming polymerizations to validate the suitability of the model to predict network development, particularly in the initial stages prior to any diffusion limitations on the reaction kinetics. These results serve as a useful guide for monomer selection in designing thiol−Michael-based polymers with appropriate kinetic characteristics and material properties.
■
INTRODUCTION As a member of the “click” reaction family, the thiol−Michael reaction exhibits many unique features such as being amenable to benign reaction conditions, having minimal byproduct formation, negligible oxygen inhibition, solvent tolerance, and high reaction yields.1−4 Owing to these advantageous characteristics, the thiol−Michael reaction has been introduced to a wide range of applications including dendrimer synthesis,5 surface modification,6,7 bioconjugation,8−10 particle synthesis,11 and polymer network formation.12 Typically, thiol−Michael reactions proceed through either a base-catalyzed pathway or a nucleophile-initiated pathway. Recently, Nguyen et al. highlighted 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) as a highly efficient base catalyst for base-catalyzed thiol−Michael addition, specifically highlighting the thiol−methacrylate addition.13 Moreover, with recent progress in the development of photocuring methodologies,14−16 spatial and temporal control of base-catalyzed thiol−Michael polymerization reaction have led to improvements in photoreaction efficiency,12,17 visible wavelength sensitivity,1,18 and reaction orthogonality.19,20 A visible-light base generating system based on isopropylthioxanthone/triazabicyclodecene tetraphenylborate (ITX/ TBD·HBPO 4 ) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was reported to efficiently catalyze the thiol− © XXXX American Chemical Society
Michael addition reaction to yield cross-linked materials with stoichiometric consumption of both functional groups and complete conversion.21 Recently, a series of photoinduced amine catalysts were reported which featured excellent amine catalytic activity, resulting in quantitative final conversion within a few minutes for thiol−acrylate Michael addition systems.17 In general, thiol−Michael reactions and polymerizations are anion-mediated additions of a multifunctional thiol to an electron-deficient vinyl group of a multivinyl component. As indicated in Figure 1, the general photoinduced base-catalyzed thiol−Michael polymerization is described in three distinct stages: initiation, propagation, and chain transfer. Initiation typically involves the cleavage of a photoprotecting group to generate a base upon UV light irradiation. Further, the generated base reacts with the thiol to form a strong nucleophile, a thiolate anion. Subsequently, propagation takes place wherein the thiolate anion adds to an electron-deficient β-carbon of the vinyl group and results in the formation of an intermediate carbanion. In the presence of a strong base, the generated carbanion deprotonates the thiol to yield the thioether product Received: June 14, 2018 Revised: July 16, 2018
A
DOI: 10.1021/acs.macromol.8b01264 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
induced base-catalyzed thiol−Michael reaction.30 Modeling equations derived from a molar balance of the species involved indicated that the overall reaction rates followed a pseudo-firstorder kinetic process and were strongly controlled by the ratio of the propagation to chain transfer kinetic parameters. This mathematical framework provided an insight into the reaction mechanism and showed that individual propagation and chain transfer kinetic parameters could be extracted by varying the initial reactive group ratios near equimolarity or performing the reaction under extreme (flooding) conditions. Herein, building on the previous work, we investigated the structural effects of thiol and vinyl functional groups on the kinetics and mechanism of the base-catalyzed thiol−Michael reaction carried out in the absence of solvents. The propagation and chain transfer kinetic parameters were evaluated for each thiol and vinyl binary combination. The extracted kinetic data were further used to probe the component selectivity in multicomponent mixtures as well as cross-linking-capable monomer mixtures.
Figure 1. A general scheme for the photo thiol−Michael reaction mechanism. Initiated with a photobase generator, the thiol−Michael polymerization proceeds through a cyclic step growth mechanism consisting of alternating propagation/chain transfer steps catalyzed by long-term stable anionic intermediates.
■
and also regenerates the thiolate anion. This step is the chain transfer step. Successive, repetitive propagation and chain transfer steps serve as the basis for the step growth thiol− Michael photopolymerization reaction. A comprehensive assessment and understanding of the propagation and chain transfer kinetic parameters of this sequential two steps process are crucial to effectively utilize thiol−Michael reactions by providing the necessary guidelines for adjustment and control over the rates and final conversions. Previous mechanistic studies have demonstrated that the reaction kinetics are highly dependent on the solvent polarity, the thiol basicity, the base strength, the electron deficiency of the vinyl group, steric hindrance within the backbone of the reactants, etc.22,23 However, several aspects of the thiol−Michael reaction kinetics including the propagation and chain transfer kinetic parameters, reaction orders, and the determination of the reaction rate-limiting steps for commonly used thiols and vinyls have not previously been investigated. To date, mechanistic and kinetic studies of base-catalyzed thiol−Michael reactions have focused mostly on solution-based systems, often in dilute solutions. Both computational and experimental investigations have been performed to evaluate the role of solvents, monomers, and catalysts on the reaction mechanism.5,24−27 Many common solvents,24,28 bases,17,24 thiols,24,29 and electron-deficient vinyls13,29 have been screened under various conditions aiming toward the understanding of thiol−Michael reaction kinetics and enhancement of the selectivity, yield, and rate of the reaction. For example, Chatani et al. studied the differences in selectivity between vinyl sulfones and acrylates in the presence of triethylamine (TEA), and the resultant selectivity was further utilized to control the gelation behavior in cross-linked polymer networks.5 In another example, Frayne et al. reported a thorough fundamental study of the catalyst influence on the reactivity and selectivity between various thiol and vinyl functional monomers.29 The fundamental kinetic studies pointed out that the reaction kinetics are highly dependent on the solvent, catalyst type, and catalyst concentration. However, because of limited quantitative assessments and the lack of bulk conditions, it is difficult to draw conclusions from the solvent-based systems and implement the same kinetic parameters to accurately mimic and/or predict the reaction behavior for bulk thiol−Michael addition reactions or polymerizations, wherein the polarity of monomers and the molecular structure of the thiol and vinyl play an even more crucial role. Recently, Claudino et al. developed a mathematical framework based on the reaction scheme to describe the photo-
EXPERIMENTAL SECTION
Materials. The photobase NPPOC-TMG (PBG) utilized was synthesized as described in the literature previously.12,17 TMG has a pKa value of 13.6, as reported in the literature, and hence satisfies the criterion of our assumption of utilizing a strong base. The pKa value of the thiol functional groups was also obtained from previous literature.31 To minimize the diffusion influence on the kinetic model in the model experiments, all monofunctional monomers were chosen for the study so that only dimers would form and no diffusional limitations will arise to the reactions. Thiol-functionalized monomers were chosen based on the basicity of the thiol group whereas vinyl-functionalized monomers were chosen based on the electron deficiency of the CC bond. Figure 2 shows the structures of monomers and initiators under investigation. Butyl 3-mercaptopropionate (BMP), butyl thiolglycolate
Figure 2. Monomer structure of the photobase NPPOC-TMG, thiol, and vinyl derivatives under investigation. (BTG), 1-hexanethiol (HT), ethyl vinyl sulfone (EVS), 1-butyl acrylate (BA), 1-butyl methacrylate (BMA), pentaerythritol tetrakis(3mercaptopropionate) (PETMP), divinyl sulfone (DVS), and 1,6hexanediol diacrylate (HDDA) were purchased from Sigma-Aldrich. PETMP, HDDA, and DVS were then subjected to comparison by utilizing the kinetic parameters obtained from the binary monofunctional systems. All monomers were used as received. Real-Time Fourier Transform Infrared Spectroscopy (FTIR). Reaction kinetics was analyzed using a FTIR spectrometer (Nicolet 8700) to monitor the real-time functional group conversion in transmission mode. Series spectra were taken at the rate of two scans per second. The FTIR chamber was continuously purged with nitrogen. Samples were prepared in certain initial stoichiometric ratios (r = 0.5, 1, B
DOI: 10.1021/acs.macromol.8b01264 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules and 1.5) of thiol to vinyl based on functional groups. 0.05 mol/L NPPOC-TMG was added into sample based on monomer volume. The sample was kept in an ice bath before characterization and then placed between two salt plates with a spacer of 30 μm. Irradiation was performed using a mercury lamp (Acticure 4000) with a 365 nm bandgap filter. The light intensity was kept at 10 mW/cm2, which was measured by an International Light, Inc., model IL 1400A radiometer. The sample was irradiated until the reaction was complete, which was evident by the disappearance of the absorption band(s) corresponding to the functional group. The conversions of the thiol and vinyl functional groups were then calculated based on the changes in the peak area of the corresponding FTIR stretching frequency. The thiol functional group (−SH) disappearance was monitored using the peak between 2550 and 2600 cm−1, while the acrylate CC peak disappearance was monitored between 780 and 820 cm−1. For the vinyl sulfone, the conversion was monitored by the disappearance of CC peak area between 3000 and 3200 cm−1. Three replicates for each sample were performed. Reaction Description. Figure 1 shows a general scheme for the photoinduced base-catalyzed thiol−Michael reaction mechanism. Initiated by photobase generator, the thiol−Michael reaction proceeds through a cyclic step growth mechanism consisting of alternating propagation and chain transfer steps with persistent anionic intermediates. Four differential equations illustrate the species balances for the reactive moieties including the thiol, vinyl, and both anionic intermediates in the reaction scheme as listed in eqs 1−4. Three major assumptions made for the kinetic studies and material balances include (1) negligible diffusive mass and heat transfer effects so that (2) all kinetic parameters remain constant throughout the reaction and (3) the strong base catalyst leads to a nearly instantaneous deprotonation reaction. d[SH] = − k CT[SH][RC−] dt
(1)
d[CC] = − k p[CC][S−] dt
(2)
d[S−] = R i − k p[CC][S−] + k CT[SH][RC−] dt
(3)
d[RC−] = k p[CC][S−] + k CT[SH][RC−] dt
(4)
R rxn =
2.303f ϵ[B]I0λ d[B] = dt NAVhc
k p[CC] + k CT[SH]
[CC][SH] (6)
−
where [B ] is the total anion concentration. In order to examine the reaction order dependence on the ratio of propagation to chain transfer kinetic parameters (kp/kCT), three limiting cases need to be considered based on the analytical equation (eq 6) for 1:1 stoichiometric systems, i.e., where the thiol and vinyl concentrations are approximately equal. For the case where the kp
propagation step is rate-limiting, i.e., k
CT
≪ 1, the overall reaction rate
expression simplifies such that the reaction rate is first-order depending only on the vinyl functional group concentration (eq 7). On the other hand, if chain transfer is the rate-limiting step, where the chain transfer kinetic parameter is much less than the propagation kinetic parameter kp
(k
CT
≫ 1), the overall reaction rate is described by eq 8, predicting
first-order dependence on the thiol functional group concentration. For the last case where kp/kCT ≈ 1, the overall reaction rate is equally dependent on both the thiol and vinyl functional group concentrations as shown in eq 9. A similar relationship between kp/kCT and reaction order, albeit for a radical-mediated process, has also been predicted and observed in the thiol−ene reaction.32,33
R rxn ∝ k p[CC]
for
R rxn ∝ k CT[RSH]
for
kp k CT kp k CT
R rxn ∝ k[RSH]0.5 [CC]0.5
≪1
(7)
≫1
(8)
for k p/k CT ≈ 1
(9)
Kinetic Parameter Determination. To calculate the propagation and chain transfer kinetic parameters, all systems were reacted initially in varying stoichiometric ratios r = 0.5, 1, and 1.5 of thiol:vinyl functional groups. The reaction kinetics were measured with FTIR. The propagation and chain transfer kinetic parameters for each reaction were determined by using the least-squares method to fit the experimental kinetic plots from 10% to 50% conversion, which was used to minimize any effects of inhibition or high conversion changes in the solvent, to differential equations (eqs 1−5) using Matlab. The average reaction rate (Ravg) for each binary system was calculated based on the time that it took the reaction to proceed from 10% to 50% conversion for a 1:1 stoichiometric mixture.
■
Equation 1 describes the consumption of the thiol functional group [SH] via chain transfer from the carbanion to thiol. This equation assumes the consumption of the thiol functional group by initiation is negligible, relative to their consumption by chain transfer. Equation 2 accounts for consumption of the vinyl functional group [CC] during the propagation of the thiolate anion into the vinyl functional group. Equation 3 accounts for generation of the thiolate anion [S−] when initiated by a base catalyst followed by subsequent chain transfer along with its consumption by propagation. Equation 4 describes the consumption and generation of the carbanion species [RC−] through chain transfer and propagation, respectively. The photoinitiation rate, Ri, is calculated using a general photoinitiation rate equation: Ri = −
k pk CT[B−]
RESULTS AND DISCUSSION As previously found, the rates of the thiol−Michael reaction depend on the basicity of the catalyst, the acidity of the thiol, and the electrophilicity of the vinyl.22 In this study, a series of experiments were performed to investigate the effects of the thiol and vinyl functional group chemistry in the presence of a strong base toward the execution of thiol−Michael reactions. The thiol reactants utilized were three monothiols (1-hexanethiol, butyl thioglycolate, and butyl 3-mercaptopropionate) selected based on varied pKa value. Vinyl sulfone, acrylate, and methacrylate double bonds were chosen as Michael acceptors for this kinetic study based on varied electron deficiency. Effect of Thiol Structure. To evaluate the effect of the thiol structure, three thiols of varied pKa’s were examined in a reaction with ethyl vinyl sulfone in the presence of a strong PBG with an initial 1:1 stoichiometric ratio of thiol:vinyl functional groups under bulk conditions. Figure 3 shows a significant difference in reactivity of the selected thiols toward ethyl vinyl sulfone (EVS). Since all the reactions were executed under the same conditions, the differences in reaction rates are primarily a result of the change in the thiol structure. In the presence of a strong base catalyst, where the pKa of the conjugated acid of the base catalyst
(5)
where f is the efficiency assumed to be 1, ϵ is the molar absorptivity of NPPOC-TMG having a value of 240 L/(mol cm) for 365 nm light,17 [B] is the undegraded photobase concentration, I0 is the light intensity, λ is the wavelength, NAV is Avogadro’s number, h is Planck’s constant, and c is the speed of light in a vacuum. Owing to the step growth nature of this anionic cycle, the elementary chain transfer and propagation steps occur at approximately the same rate, i.e., RCT = RP. By also assuming that the total anion concentration is equal to the total amount of base that has disappeared, the overall reaction rate is30 C
DOI: 10.1021/acs.macromol.8b01264 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
conjugate addition is another important factor that dominates thiol−Michael reaction kinetics. Typically, more electrondeficient β-carbon of the vinyl group ensure rapid reaction kinetics. Accordingly, Figure 4 shows the conversion as a
Figure 3. Effect of thiol functional group on thiol−Michael reaction kinetics. Ethyl vinyl sulfone reacting with BMP (○), BTG (□), or HT (△) at an initial stoichiometric ratio of 1:1 of thiol:vinyl functional group concentrations. Samples contain 0.05 mol/L NPPOC-TMG. Each sample was stabilized in the dark for 1 min and then irradiated with 10 mW/cm2 365 nm wavelength at ambient temperature.
Figure 4. Effect of vinyl functional group on reaction kinetics. BMP reacting with BMA (○), EVS (□), or BA (△) at an initial stoichiometric ratio of 1:1 of thiol:vinyl functional group concentrations. Samples contain 0.05 mol/L NPPOC-TMG. Each sample was stabilized in the dark for 1 min and then irradiated with 10 mW/cm2 365 nm wavelength at ambient temperature.
is much higher than that of the thiol, TMG released from the decomposition of the photoprotecting group will rapidly deprotonate the thiol, resulting in the thiolate anion. Moreover, the thiolate anion is mainly generated by the chain transfer step with the stronger basic intermediate carbanion. As such, any effects of the pKa difference of the thiols on the initiation are negligible. The overall reaction rate should instead depend mostly on the reactivity of the generated thiol/thiolate anion in the propagation and chain transfer steps. Here, the higher pKa value of the thiol results in faster overall reaction rates in the presence of the same strong base catalyst (TMG). However, with a weaker base catalyst, the trend is expected to reverse as the deprotonation process involved in the initiation step would be of more importance as previously observed.26 Figure 3 confirms this trend for the selected thiols. As shown, BTG, which has the lowest pKa value of 7.9 and correspondingly exhibits the slowest reaction kinetics, whereas HT (with the highest pKa ∼ 11) shows the fastest reaction kinetics with EVS. This trend is also further evidenced by the kinetic parameters determined from the kinetics and presented in Table 1. It is clear from Figure 3 that even with all else equal, the structure of the thiol plays a significant role in controlling the reaction rate with average rates differing by a factor of 3 from HT to BTG. Effect of Vinyl Structure. In addition to the structure of the thiol, the inherent propensity of an activated vinyl to undergo
function of time for three different vinyl groups reacting with BMP at a stoichiometric ratio of 1:1 of thiol:vinyl functional group concentrations. EVS exhibits the fastest reaction rate which is attributed to its highly electron-deficient vinyl group. Further, with a less electron-deficient vinyl group, BA exhibits a slower reaction kinetic but still reaches ∼90% conversion within 2.5 min of irradiation. Contrarily, the methacrylate-based vinyl group of BMA, with a much less electron-deficient CC bond, shows less than 10% conversion after 2.5 min of irradiation. This reduction in the reactivity is attributed to the positive inductive effect associated with the methyl group on the β-carbon that helps in stabilizing the electrophilic character of the carbon atom, resulting in a reduction of its reactivity. Kinetic Parameters Determination. Experimental and model-fitted predictions for three representative binary systems are shown in Figures 5−7 as a function of a variable stoichiometric ratio of thiol:vinyl functional group concentrations. The experimental and predicted kinetic plots for all of the other systems were found to be similar and are included in the Supporting Information (Figures S1−S4). All kinetic
Table 1. Propagation and Chain Transfer Kinetic Parameters, Ratio of Propagation to Chain Transfer Kinetic Parameters, Average Reaction Rate, and Reaction Rate Scaling with Thiol Functional Group Concentration for the Varied Thiol and Vinyl Functional Monomers under Investigation vinyl group
thiol group
kp (L/(mol s))
EVS
BTG BMP HT BTG BMP HT BMP
4.7 14 85 5.8 6.4 14 0.03
BA
BMA
kCT (L/(mol s))
kp/kCT
6.1 12 30 55 10 4.5 2.9 Rrxn ∝ [RSH]α[CC]1−α
Ravg (mol/(L s))a
α
0.03 0.05 0.1 0.03 0.02 0.02 0.002
0.5 0.6 0.9 0 0.3 1 0
0.73 1.2 2.8 0.11 0.64 3.1 0.01
a
Values for the average reaction rate, Ravg, are only valid for equimolar ratios of thiol to vinyl functional groups. D
DOI: 10.1021/acs.macromol.8b01264 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
Figure 5. Model predictions and experimental data for functional group conversion vs time for the 1-butyl thioglycolate and ethyl vinyl sulfone reaction: (a) thiol conversion for initial stoichiometric ratios r = 0.5 (○, ---), r = 1 (□, ···), and r = 1.5 (△, ) of thiol:vinyl functional group concentrations; (b) vinyl conversion for r = 0.5, 1, and 1.5. Samples contain 0.05 mol/L NPPOC-TMG. Each sample was stabilized in the dark for 1 min and then irradiated with 10 mW/cm2 365 nm wavelength at ambient temperature.
Figure 6. Model predictions and experimental data for functional group conversion vs time for the 1-butyl thioglycolate and 1-butyl acrylate reaction: (a) thiol conversion for initial stoichiometric ratios r = 0.5 (○, ---), r = 1 (□, ···), and r = 1.5 (△, ) of thiol:vinyl functional group concentrations; (b) vinyl conversion for r = 0.5, 1, and 1.5. Samples contain 0.05 mol/L NPPOC-TMG. Each sample was stabilized in the dark for 1 min and then irradiated with 10 mW/cm2 365 nm wavelength at ambient temperature.
Figure 7. Model predictions and experimental data for functional group conversion vs time for the 1-hexanethiol and ethyl vinyl sulfone reaction: (a) thiol conversion for initial stoichiometric ratios r = 0.5 (○, ---), r = 1 (□, ···), r = 1.5 (△, ) of thiol:vinyl functional group concentrations; (b) vinyl conversion for r = 0.5, 1, and 1.5. Samples contain 0.05 mol/L NPPOC-TMG. Each sample was stabilized in the dark for 1 min and then irradiated with 10 mW/cm2 365 nm wavelength at ambient temperature.
parameters, ratios of propagation to chain transfer kinetic parameters, and average rates as well as the overall reaction orders based on thiol concentration are summarized in Table 1. For all of the systems, an equal consumption rate of thiol and vinyl functional groups indicates that no homoreaction of vinyl and thiol groups occurs as side reactions in any of these systems
(e.g., compare the blue curves in Figures 5−7). Kinetic features exhibited by the binary thiol−Michael systems are all accurately predicted by fitting the propagation and chain transfer kinetic parameters. A small discrepancy arises between the predicted and experimental data at higher conversion which could be accounted for due to the increase in viscosity and temperature E
DOI: 10.1021/acs.macromol.8b01264 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
Figure 8. (a) Model predictions and experimental plots for selectivity study of BMP (□) reacting with BA (○) and EVS (△) at an initial stoichiometric ratio of 1:0.5:0.5 of BMP:BA:EVS functional group concentrations. (b) Model predictions and experimental plots for selectivity study of BMP (□) reacting with BA (○) and EVS (△) at an initial stoichiometric ratio of 1:1:1 of BMP:BA:EVS functional group concentrations. Samples contain 0.05 mol/L NPPOC-TMG. Each sample was stabilized in the dark for 1 min and then irradiated with 10 mW/cm2 365 nm wavelength at ambient temperature.
to chain transfer kinetic parameters increases with a more stable thiolate anion. As for the vinyl groups, a more electron-deficient CC bond leads to a higher propagation kinetic parameter, whereas if a more stable carbanion is generated, a reduction in the value of the chain transfer kinetic parameter is observed. Hence, the ratio of propagation to chain transfer kinetic parameters generally increases with an increase in the electron deficiency of the CC bond. Thiol−Vinyl Ternary System. As the measured kinetic parameters indicate considerable variations in the reactivity of the different functional groups, selectivity studies in ternary systems were performed and compared with predictions based on the previously extracted kp and kCT values from the binary experiments (Table 1). To assess the vinyl selectivity, BMP was chosen to react with EVS and BA with an initial stoichiometric ratio of 1:0.5:0.5 and 1:1:1 in the presence of 0.05 mol/L NPPOC-TMG. The conversions of the three functional groups were assessed based on the peak area change of each functional group’s corresponding IR peaks. The final conversions were further confirmed by 1H NMR for these dimerization reactions. The conversion vs time plots for all three functional groups are shown in Figure 8. It is evident from the plots that the kinetic parameters allow accurate predictions of the reaction kinetics for ternary systems. In Figure 8a, BMP:EVS:BA = 1:0.5:0.5, all compounds reached nearly 100% conversion. Equal consumption of the thiol and vinyl groups is again now in the ternary system, indicative of no vinyl homoreaction or cross-reaction within the ternary system. With the coexistence of the two vinyl groups, the competition between vinyl sulfone and acrylate occurs in the propagation step. As such, the relative consumption rates and the final conversions of the vinyl sulfone and acrylate primary depend on the difference in the propagation kinetic parameter for the accounted two vinyl functional groups. From Table 1, the propagation kinetic parameters obtained for vinyl sulfone and acrylate reacting with BMP are 14 and 6.4 L/(mol s), respectively. Consequently, in this ternary system, the initial consumption rate of vinyl sulfone is approximately 2 times higher than the acrylate group. Similarly, in Figure 8b, the initial stoichiometric ratio of BMP:EVS:BA is 1:1:1; the limiting reagent, BMP, reaches 100% conversion within 100 s. The final conversions of the acrylate and vinyl sulfone are 35% and 65%, respectively. The final conversion of vinyl sulfone is also found to be approximately 2 times higher than the acrylate group, which is
during the addition reaction as the kinetic parameters are assumed to be independent of these effects. In Figure 5, the reaction rate is observed to equivalently increase for both r = 0.5 and 1.5. The calculated values for kinetic parameters of propagation and chain transfer are 4.7 and 6.1 L/ (mol s), respectively. The ratio of propagation to chain transfer kinetic parameters was found to be 0.73, close to unity. As a result, the reaction rates are nearly equally dependent on both the thiol and vinyl functional group concentrations which is consistent with eq 9. For the BTG/BA system, the reaction rate is observed to increase only for the r = 0.5 system, and the ratio of the kinetic parameters was determined to be 0.11, where the propagation step is rate-limiting. In this case, the reaction rate is first-order in the acrylate concentration in a manner consistent with eq 7. For the HT/EVS system, the kinetic plots are observed to exhibit yet different trends when compared with the previous two systems. The reaction rate is observed to increase only with the increasing thiol concentration, as seen in Figure 7. The calculated ratio of the kinetic parameters obtained was much greater than unity (kp/kCT = 2.8). Hence, the reaction rate scales approximately with the first order of the thiol functional group concentration, which is consistent with eq 8. In this case, chain transfer was found to be rate-limiting. As summarized in Table 1, the kinetic parameters and subsequent reaction orders vary significantly with the choice of the thiol and vinyl functional group chemistry. The ratio of the propagation to chain transfer kinetic parameters depends on both the stability of the anion species and the electron deficiency of the CC double bond. With higher basicity of the thiol functional group, the less stable thiolate anion leads to a larger propagation kinetic parameter whereas lower acidity of the thiol results in a lower value of the chain transfer kinetic parameter. It is worth noting that HT has at least 2 times higher propagation kinetic parameter when compared with BMP and BTG in a reaction with the same vinyl functional group. This significant increase in the propagation kinetic parameter may arise in part due to the less polar nature of 1-hexanethiol, leading to less stabilization of the highly charged thiolate anion, and consequently the thiolate anion becomes more reactive. As indicated in other reports, the calculated free energy barriers of the propagation and chain transfer steps in the thiol−maleimide reaction are 2 times smaller in nonpolar solvents such as chloroform as compared with those in highly polar solvents such as dimethylformamide.23,24 Therefore, the ratio of propagation F
DOI: 10.1021/acs.macromol.8b01264 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
FTIR, the final conversions of thiol functional groups were determined by 1H NMR. It is evident from Figure 9 that the kinetics of all the components within the ternary systems are predicted successfully utilizing kinetic parameters determined in the binary systems. Further, the same method was used in vinyl sulfone−thiol 1− thiol 2 ternary systems. However, because the strong electronwithdrawing character of the sulfone group leads to a more stable carbanion intermediate, the chain transfer kinetics parameters would depend on both intermediate stability and basicity of the thiol functional group. Therefore, in this case, it is assumed that the chain transfer kinetic parameters scale with the inverse trend of the propagation kinetic parameters, which indicate the stability of the thiolate anion. This assumption is expressed as kCT3/kCT1 = kP1/kP2 and kCT2/kCT4 = kP2/kP1. All kinetic parameters used for the simulation are summarized in Table 2. Figure 10 presents the model predictions and experimentally measured reaction kinetics for initial 1:1:1 stoichiometric ratios of EVS-BMP-BTG, EVS-BTG-HT, and EVS-BMP-HT systems, respectively. As observed in the systems, the model successfully predicts the kinetic behavior for the ternary systems, while exhibiting discrepancy in the final conversion for the EVS-BMP-BTG system. This discrepancy could come from underestimated chain transfer kinetic parameters of kCT2 and kCT3 from the calculated kinetic parameters. The difference in the reactivity of the thiol monomers in chain transfer might be greater than that of the thiolate anion in propagation. However, in general, the tabulated kinetic parameters well predicted the reaction rate and final conversion for the ternary systems. Therefore, the tabulated kinetic parameters provide a simple approach to estimate the selectivity and reactivity of different functional groups in ternary systems. This unique behavior of structurally distinct functional groups to react at different rates can be used to modulate and design polymeric materials and thus tailor them for specific applications. Multifunctional Monomer Polymerization Systems. To test further the validation of the kinetic parameters, the model predictions were utilized toward simulating polymerization reaction rates within a cross-linking system as is often used in thiol−Michael photopolymerizations. Namely, two distinct multifunctional monomer combinations were used and compared with simulation based on the kinetic parameters
also consistent with the difference in the propagation kinetic parameter. To predict the reaction kinetics of a vinyl and two thiol groups, a model approach was developed based on the binary system reaction model (see Scheme 1). The major difference in Scheme 1
the new model is to incorporate two propagation steps (propagations 1 and 2) and four chain transfer steps (chain transfers 1−4), where propagation 1 and propagation 2 account for the propagation steps for thiol 1 and thiol 2, respectively. Chain transfer 1 accounts for the chain transfer step of carbanion intermediate 1 to thiol 1, and chain transfer 4 represents for chain transfer step of carbanion intermediate 2 to thiol 2. Chain transfers 2 and 3 account for cross-reaction of carbanion intermediates reacting with thiol 1 and thiol 2, respectively. For the ternary acrylate−thiol 1−thiol 2 system, the propagation and chain transfer kinetic parameters for acrylate and different thiol functional groups were all experimentally determined except for two cross-reaction chain transfer 2 and chain transfer 3. For this system, due to the highly reactive nature of the carbanion intermediate, the chain transfer kinetic parameter mainly depends on the thiol acidity and is expected to be independent of the intermediate stability. Therefore, it is assumed kCT2 = kCT1 and kCT3 = kCT4. Utilization of those kinetic parameters enables us to predict the kinetics in ternary acrylate− thiol 1−thiol 2 systems. Experimental reaction kinetics along with model predictions of BA reacting with BTG, BMP, and HT with initial stoichiometric ratio of 1:1:1 of acrylate:thiol 1:thiol 2 functional groups are presented in Figure 9. The acrylate functional group conversion was assessed based on the peak area change of its corresponding IR peak. However, due to the difficulty in distinguishing the different thiol peaks based on
Figure 9. (a) Model predictions and experimental plots for selectivity study of BA (○) reacting with BMP and BTG at an initial stoichiometric ratio of 1:1:1 of BA:BMP:BTG functional group concentrations. (b) Model predictions and experimental plots for selectivity study of BA (○) reacting with HT and BTG at an initial stoichiometric ratio of 1:1:1 of BA:HT:BTG functional group concentrations. (c) Model predictions and experimental plots for selectivity study of BA (○) reacting with BMP and HT at an initial stoichiometric ratio of 1:1:1 of BA:BMP:HT functional group concentrations. The stars represent the final conversion of the thiol functional group as measured by 1H NMR. All samples contain 0.05 mol/L NPPOC-TMG. Each sample was stabilized in the dark for 1 min and then irradiated with 10 mW/cm2 365 nm wavelength at ambient temperature. G
DOI: 10.1021/acs.macromol.8b01264 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
Table 2. Propagation and Chain Transfer Kinetic Parameters Used for Ternary Thiol−Vinyl System Kinetic Predictions resin system
propagation
chain transfer
vinyl
thiol 1/thiol 2
kP1 (L/(mol s))
kP2 (L/(mol s))
kCT1 (L/(mol s))
kCT2 (L/(mol s))
kCT3 (L/(mol s))
kCT4 (L/(mol s))
BA
BMP/BTG BTG/HT BMP/HT BMP/BTG BTG/HT BMP/HT
6.4 5.8 6.4 14 4.7 14
5.8 14 14 4.7 85 85
10 55 10 12 6.1 12
10 55 10 2.0 540 180
55 4.5 4.5 36 0.33 2.0
55 4.5 4.5 6.1 30 30
EVS
Figure 10. (a) Model predictions and experimental plots for selectivity study of EVS (○) reacting with BMP and BTG at an initial stoichiometric ratio of 1:1:1 of EVS:BMP:BTG functional group concentrations. (b) Model predictions and experimental plots for selectivity study of EVS (○) reacting with HT and BTG at an initial stoichiometric ratio of 1:1:1 of EVS:HT:BTG functional group concentrations. (c) Model predictions and experimental plots for selectivity study of EVS (○) reacting with BMP and HT at an initial stoichiometric ratio of 1:1:1 of EVS:BMP:HT functional group concentrations. The stars represent the final conversion of the thiol functional group as measured by 1H NMR. All samples contain 0.05 mol/L NPPOC-TMG. Each sample was stabilized in the dark for 1 min and then irradiated with 10 mW/cm2 365 nm wavelength at ambient temperature.
Figure 11. (a) Monomer structure of multifunctionalized monomers used for networking forming thiol−Michael photopolymerizations. Comparisons of simulations with cross-linking systems in the thiol−Michael reactions. Thiol functional group conversion vs time for the (b) tetrathiol PETMP and diacrylate HDDA (△); (c) tetrathiol PETMP and divinyl sulfone DVS (△) at initial stoichiometric ratio of 1:1 of thiol:vinyl functional group concentrations. All samples contain 0.05 mol/L NPPOC-TMG. Each sample was stabilized in the dark for 1 min and then irradiated with 10 mW/cm2 365 nm wavelength at ambient temperature.
determined from the monofunctional thiol−Michael reaction under the same reaction conditions. As the thiol reactant, a tetrafunctional thiol, PETMP, having the same thiol functional group as BMP, was used. As the vinyl reactants, a diacrylate, HDDA, and divinyl sulfone, DVS were selected, corresponding
to BA and EVS functional vinyl groups, respectively. The monomer structures and kinetic comparisons are depicted in Figure 11. The simulation well predicted the initial rate in the cross-linking reaction system. However, the cross-linking system begins to slow down and deviate from the prediction at ∼50% H
DOI: 10.1021/acs.macromol.8b01264 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
(2) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem., Int. Ed. 2001, 40 (11), 2004−2021. (3) Li, Y.; Su, H.; Feng, X.; Wang, Z.; Guo, K.; Wesdemiotis, C.; Fu, Q.; Cheng, S. Z. D.; Zhang, W.-B. Thiol-Michael “click” Chemistry: Another Efficient Tool for Head Functionalization of Giant Surfactants. Polym. Chem. 2014, 5 (21), 6151−6162. (4) Chan, J. W.; Hoyle, C. E.; Lowe, A. B.; Bowman, M. NucleophileInitiated Thiol-Michael Reactions: Effect of Organocatalyst, Thiol, and Ene. Macromolecules 2010, 43 (15), 6381−6388. (5) Chatani, S.; Podgórski, M.; Wang, C.; Bowman, C. N. Facile and Efficient Synthesis of Dendrimers and One-Pot Preparation of Dendritic-Linear Polymer Conjugates via a Single Chemistry: Utilization of Kinetically Selective Thiol-Michael Addition Reactions. Macromolecules 2014, 47 (15), 4894−4900. (6) Tedja, R.; Soeriyadi, A. H.; Whittaker, M. R.; Lim, M.; Marquis, C.; Boyer, C.; Davis, T. P.; Amal, R. Effect of TiO2 Nanoparticle Surface Functionalization on Protein Adsorption, Cellular Uptake and Cytotoxicity: The Attachment of PEG Comb Polymers Using Catalytic Chain Transfer and Thiol−ene Chemistry. Polym. Chem. 2012, 3 (10), 2743. (7) Khire, V. S.; Lee, T. Y.; Bowman, C. N. Surface Modification Using Thiol-Acrylate Conjugate Addition Reactions. Macromolecules 2007, 40 (16), 5669−5677. (8) Liu, Z.; Lin, Q.; Sun, Y.; Liu, T.; Bao, C.; Li, F.; Zhu, L. Spatiotemporally Controllable and Cytocompatible Approach Builds 3D Cell Culture Matrix by Photo-Uncaged-Thiol Michael Addition Reaction. Adv. Mater. 2014, 26 (23), 3912−3917. (9) Phelps, E. A.; Enemchukwu, N. O.; Fiore, V. F.; Sy, J. C.; Murthy, N.; Sulchek, T. A.; Barker, T. H.; García, A. J. Maleimide Cross-Linked Bioactive PEG Hydrogel Exhibits Improved Reaction Kinetics and Cross-Linking for Cell Encapsulation and in Situ Delivery. Adv. Mater. 2012, 24 (1), 64−70. (10) Darling, N. J.; Hung, Y. S.; Sharma, S.; Segura, T. Controlling the Kinetics of Thiol-Maleimide Michael-Type Addition Gelation Kinetics for the Generation of Homogenous Poly(ethylene Glycol) Hydrogels. Biomaterials 2016, 101, 199−206. (11) Wang, C.; Zhang, X.; Podgórski, M.; Xi, W.; Shah, P.; Stansbury, J.; Bowman, C. N. Monodispersity/Narrow Polydispersity CrossLinked Microparticles Prepared by Step-Growth Thiol-Michael Addition Dispersion Polymerizations. Macromolecules 2015, 48 (23), 8461−8470. (12) Zhang, X.; Xi, W.; Huang, S.; Long, K.; Bowman, C. N. Wavelength-Selective Sequential Polymer Network Formation Controlled with a Two-Color Responsive Initiation System. Macromolecules 2017, 50 (15), 5652−5660. (13) Nguyen, L.-T. T.; Gokmen, M. T.; Du Prez, F. E. Kinetic Comparison of 13 Homogeneous thiol−X Reactions. Polym. Chem. 2013, 4 (22), 5527. (14) San Miguel, V.; Bochet, C. G.; del Campo, A. WavelengthSelective Caged Surfaces: How Many Functional Levels Are Possible? J. Am. Chem. Soc. 2011, 133, 5380−5388. (15) Matuszczak, S.; Cameron, J. F.; Fréchet, J. M. J.; Wilson, C. G. Photogenerated Amines and Their Use in the Design of a Positive-Tone Resist Material Based on Electrophilic Aromatic Substitution. J. Mater. Chem. 1991, 1 (6), 1045−1050. (16) Hayes, C. O.; Bell, W. K.; Cassidy, B. R.; Willson, C. G. Synthesis and Characterization of a Two Stage, Nonlinear Photobase Generator. J. Org. Chem. 2015, 80 (15), 7530−7535. (17) Xi, W.; Peng, H.; Aguirre-Soto, A.; Kloxin, C. J.; Stansbury, J. W.; Bowman, C. N. Spatial and Temporal Control of Thiol-Michael Addition via Photocaged Superbase in Photopatterning and Two-Stage Polymer Networks Formation. Macromolecules 2014, 47 (18), 6159− 6165. (18) Zhang, X.; Xi, W.; Wang, C.; Podgórski, M.; Bowman, C. N. Visible-Light-Initiated Thiol-Michael Addition Polymerizations with Coumarin-Based Photobase Generators: Another Photoclick Reaction Strategy. ACS Macro Lett. 2016, 5 (2), 229−233.
conversion due to viscosity increases and eventual gelation and vitrification, all of which impact the species mobility and eventually limit the polymerization rate. These systems encounter mobility restriction and diffusional limitations at higher conversion, and the diffusion control has a significant effect on the kinetic parameters. The model is less useful in describing the reaction kinetics at these advanced reaction stages; however, it accurately predicts the initial reaction rate even for cross-linking polymerizations.
■
CONCLUSION Photoinduced base-catalyzed thiol−Michael reaction kinetics and rate-limiting steps were successfully modeled and experimentally characterized for a variety of thiol and vinyl functional monomers. Based on the species molar balances, the propagation and chain transfer kinetic parameters were evaluated for seven binary thiol−Michael reaction systems. The ratio of propagation to chain transfer kinetic parameters was found to be highly dependent on the structure of both the thiol and vinyl functional groups. A less stable thiolate anion results in a higher ratio of the kinetic parameters. As for the vinyl group, the ratio of kinetic parameters increased with the increase in the electron deficiency of the CC double bond of the vinyl group. This study also demonstrates the dependency of reaction order on the rate-limiting step, which is further attributed to the structure of the thiol and vinyl functional groups. Further, the tabulated kinetic parameters can be used to predict the selectivity and reactivity of different vinyl groups and thiol groups in the ternary thiol−Michael compositions. A comparison between simulation and cross-linking network systems demonstrates the validation of the kinetic parameters for simulation of the initial reaction stage of network forming photopolymerizations. Overall, this study gives a comprehensive picture and predictions for the utilization of the thiol−Michael reaction and its implementation.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b01264. Experimental kinetic data and 1H NMR spectra for selectivity studies (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] (C.N.B.). ORCID
Christopher N. Bowman: 0000-0001-8458-7723 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS The authors acknowledge the financial support from the National Institutes of Health for this research (NIH: 1U01DE023777-01).
■
REFERENCES
(1) Chatani, S.; Sheridan, R. J.; Podgórski, M.; Nair, D. P.; Bowman, C. N. Temporal Control of Thiol-Click Chemistry. Chem. Mater. 2013, 25 (19), 3897−3901. I
DOI: 10.1021/acs.macromol.8b01264 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules (19) Chatani, S.; Kloxin, C. J.; Bowman, C. N. The Power of Light in Polymer Science: Photochemical Processes to Manipulate Polymer Formation, Structure, and Properties. Polym. Chem. 2014, 5 (7), 2187− 2201. (20) Suyama, K.; Shirai, M. Photobase Generators: Recent Progress and Application Trend in Polymer Systems. Prog. Polym. Sci. 2009, 34 (2), 194−209. (21) Chatani, S.; Gong, T.; Earle, B. A.; Podgorski, M.; Bowman, C. N. Visible-Light Initiated Thiol-Michael Addition Photopolymerization Reactions. ACS Macro Lett. 2014, 3 (4), 315−318. (22) Nair, D. P.; Podgórski, M.; Chatani, S.; Gong, T.; Xi, W.; Fenoli, C. R.; Bowman, C. N. The Thiol-Michael Addition Click Reaction: A Powerful and Widely Used Tool in Materials Chemistry. Chem. Mater. 2014, 26 (1), 724−744. (23) Mather, B. D.; Viswanathan, K.; Miller, K. M.; Long, T. E. Michael Addition Reactions in Macromolecular Design for Emerging Technologies. Prog. Polym. Sci. 2006, 31 (5), 487−531. (24) Northrop, B. H.; Frayne, S. H.; Choudhary, U. Thiol−maleimide “click” Chemistry: Evaluating the Influence of Solvent, Initiator, and Thiol on the Reaction Mechanism, Kinetics, and Selectivity. Polym. Chem. 2015, 6 (18), 3415−3430. (25) Li, G.-Z.; Randev, R. K.; Soeriyadi, A. H.; Rees, G.; Boyer, C.; Tong, Z.; Davis, T. P.; Becer, C. R.; Haddleton, D. M. Investigation into Thiol-(Meth)acrylate Michael Addition Reactions Using Amine and Phosphine Catalysts. Polym. Chem. 2010, 1 (8), 1196. (26) Chatani, S.; Nair, D. P.; Bowman, C. N. Relative Reactivity and Selectivity of Vinyl Sulfones and Acrylates towards the thiol−Michael Addition Reaction and Polymerization. Polym. Chem. 2013, 4 (4), 1048−1055. (27) Chen, J.; Jiang, X.; Carroll, S. L.; Huang, J.; Wang, J. Theoretical and Experimental Investigation of Thermodynamics and Kinetics of Thiol-Michael Addition Reactions: A Case Study of Reversible Fluorescent Probes for Glutathione Imaging in Single Cells. Org. Lett. 2015, 17 (24), 5978−5981. (28) Desmet, G. B.; Sabbe, M. K.; D’hooge, D. R.; Espeel, P.; Celasun, S.; Marin, G. B.; Du Prez, F. E.; Reyniers, M.-F. Thiol-Michael Addition in Polar Aprotic Solvents: Nucleophilic Initiation or Base Catalysis? Polym. Chem. 2017, 8 (8), 1341−1352. (29) Frayne, S. H.; Murthy, R. R.; Northrop, B. H. Investigation and Demonstration of Catalyst/Initiator-Driven Selectivity in ThiolMichael Reactions. J. Org. Chem. 2017, 82 (15), 7946−7956. (30) Claudino, M.; Zhang, X.; Alim, M. D.; Podgórski, M.; Bowman, C. N. Mechanistic Kinetic Modeling of Thiol-Michael Addition Photopolymerizations via Photocaged “superbase” Generators: An Analytical Approach. Macromolecules 2016, 49 (21), 8061−8074. (31) Kreevoy, M. M; Harper, E. T.; Duvall, R. E.; Wilgus, H. S.; Ditsch, L. T. Inductive Effects on the Acid Dissociation Constants of Mercaptans. J. Am. Chem. Soc. 1960, 82, 4899. (32) Cramer, N. B.; Davies, T.; O’Brien, A. K.; Bowman, C. N. Mechanism and Modeling of a Thiol-Ene Photopolymerization. Macromolecules 2003, 36 (12), 4631−4636. (33) Cramer, N. B.; Reddy, S. K.; O’Brien, A. K.; Bowman, C. N. Thiol - Ene Photopolymerization Mechanism and Rate Limiting Step Changes for Various Vinyl Functional Group Chemistries. Macromolecules 2003, 36 (21), 7964−7969.
J
DOI: 10.1021/acs.macromol.8b01264 Macromolecules XXXX, XXX, XXX−XXX
