Amine Induced Retardation of the Radical-Mediated Thiol-Ene Reaction via the Formation of Metastable Disulfide Radical Anions

Article abstract of DOI:10.1021/acs.joc.8b00143

The effect of amines on the kinetics and efficacy of radical-mediated thiol-ene coupling (TEC) reactions was investigated. By varying the thiol reactant and amine additive, it was shown that amines retard thiyl radical-mediated reactions when the amine is

Full text of DOI:10.1021/acs.joc.8b00143

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Article
Amine Induced Retardation of the Radical-Mediated Thiol-Ene
Reaction via the Formation of Metastable Disulfide Radical Anions
Dillon Marshall Love, Kangmin Kim, John Taylor Goodrich, Benjamin D. Fairbanks,
Brady T. Worrell, Mark P. Stoykovich, Charles B. Musgrave, and Christopher N. Bowman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00143 • Publication Date (Web): 01 Feb 2018
Downloaded from http://pubs.acs.org on February 2, 2018
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Amine Induced Retardation of the RadicalꢀMediated ThiolꢀEne
Reaction via the Formation of Metastable Disulfide Radical
Anions
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Dillon M. Love,† Kangmin Kim,‡ John T. Goodrich,† Benjamin D. Fairbanks,† Brady T.
Worrell,† Mark P. Stoykovich,|| Charles B. Musgrave,†,‡,§ and Christopher N. Bowman*,†,‡,§
†Department of Chemical and Biological Engineering, ‡Department of Chemistry and Biochemistry, and §Materials
Science and Engineering Program, University of Colorado Boulder, Boulder, Colorado 80309, United States
|| Current Address: The Institute for Molecular Engineering, The University of Chicago, Chicago Illinois, 60637,
United States
*christopher.bowman@colorado.edu
Abstract: The effect of amines on the kinetics and efficacy of radicalꢀmediated thiolꢀene coupling (TEC) reactions was
investigated. By varying the thiol reactant and amine additive, it was shown that amines retard thiyl radicalꢀmediated reactions
when the amine is adequately basic enough to deprotonate the thiol affording the thiolate anion. E.g. when the weakly basic
amine tetramethylethylenediamine was incorporated in the TEC reaction between butyl 2ꢀmercaptoacetate and an allyl ether at 5
mol%, the final conversion was reduced from quantitative to < 40%. Alternatively, no effect is observed when the less acidic
thiol butyl 3ꢀmercaptopropionate is employed. The thiolate anion was established as the retarding species through the
introduction of ammonium and thiolate salt additives into TEC formulations. The formation of a twoꢀsulfur threeꢀelectron bonded
disulfide radical anion (DRA) species by the reaction of a thiyl radical with a thiolate anion was determined as the cause for the
reduction in catalytic radicals and the TEC rate. Thermodynamic and kinetic trends in DRA formations were computed using
density functional theory and by modeling the reaction as an associative electron transfer process. These trends correlate well
with the experimental retardation trends of various thiolate anions in TEC reactions.
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INTRODUCTION
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Thiyl radical chemistry is of exceptional interest in biochemistry1 and synthetic organic chemistry2 owing to the
ubiquity of thiol containing moieties found in nature and the availability of a diverse range of alkyl and aryl thiols with similar
reactive character. Valuable reactions include thiyl radical reactions with thioketones, used in the development of selfꢀhealing,
thiuram disulfide materials,3 and reactions with alkynes, or thiolꢀyne click reaction, which affords two thioether linkages and is a
tool of great use in synthesizing materials with complex/branching architectures and in bioconjugation chemistry.4 Reactions with
alkenes, i.e., radicalꢀmediated thiolꢀene coupling (TEC) reactions, constitute the most popular and robust thiyl radical
transformation, with TEC reactions having become a staple in material fabrication, conjugation chemistry, and to a lesser extent,
small molecule synthesis.5
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Under appropriate implementation conditions, TEC reactions for polymer synthesis and functionalization have been
designated as “click” reactions due to their high chemicalꢀ and regioselectivity, rapid kinetics, ability to be conducted without
solvent, full atom economy, and insensitivity to water and oxygen. The reaction proceeds via the cyclic mechanism shown in
Scheme 1, where the thiyl radical is usually generated using a photoinitiator (P.I.). The thiyl radical then propagates (kP) into the
alkene generating a CꢀS bond and simultaneously forming an intermediate 2° Cꢀradical. The Cꢀradical then chainꢀtransfers (kCT
to a thiol via Hꢀatom abstraction to regenerate the thiyl radical, resulting in a thioether linkage.
)
Scheme 1. TEC Reaction Mechanism
Because TEC reactions do not require toxic metal catalysts and are generally orthogonal to many organic functional
group chemistries, they have become a powerful tool in bioconjugation strategies5a,5e,6 as well as in the formation and
modification of cellꢀencapsulating hydrogels.7 Further, the orthogonality of TEC reactions allows them to be employed
sequentially with thiolate anion (RS–) mediated addition reactions, which include thioester exchange, thiolꢀepoxy, thiolꢀ
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isocyanate, and thiolꢀMichael (base or nucleophile catalyzed) reactions, to synthesize architectures and microstructures of
increasing complexity.5c,8
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Recently, the “click” designation for TEC reactions has been called into question under certain conditions where TEC
reactions do not achieve quantitative conversion without any appreciable sideꢀproduct formation. For example, recent work in our
lab aimed towards synthesizing nucleobase containing, sequenceꢀordered polymers with sequential TEC\thiolꢀMichael reactions
revealed that performing TEC polymerizations in the presence of basic amine functionalities often result in extremely low rates
and poor conversions < 50%, despite the basicity of such groups being too low to induce significant deprotonation of the reactive
thiol groups.8f In other recent work, Colack et al. investigated the factors that affect thiolꢀene kinetics in aqueous environments to
show that thiol conversions drop significantly when the system pH approaches and surpasses the reacting thiol pKa, attributed to
the loss of the thiol group’s ability to react, or when an amine containing buffer is used, for which no mechanism was proposed.9
Such results limit the application of TECs in the fabrication of materials possessing complex combinations of functional group
chemistries (e.g. peptides, proteins, nucleic acids, biomimetic materials) or in applications employing consecutive reactions
involving TEC and a reaction with a basic/amine catalyst (e.g. thiolꢀMichael, thiolꢀepoxy, thiolꢀhalide, thiolꢀisocyanate).
Considering these observations, the phenomena that causes the poor performance of the radicalꢀmediated thiolꢀene reaction needs
to be better understood for this chemistry to be employed to its fullest potential.
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In this work, the mechanism by which amines retard radicalꢀmediated TEC reactions within a manyꢀcomponent organic
system, conditions analogous to typical thiolꢀene photopolymerizations, was investigated. The results presented establish
guidelines for designing TEC systems and other thiyl radicalꢀmediated transformations by furthering the understanding of the
behavior of Sꢀcentered radicals in the context of general synthetic chemistry. Using realꢀtime Fourier transform IR (rtꢀFTIR)
spectroscopy to monitor the kinetics and longꢀrange hybrid DFT calculations to assess the validity of proposed mechanisms from
both a thermodynamic and kinetic stand point, it was concluded that retardation occurs due to the generation of thiolate anions
RS− in situ by amine facilitated deprotonation. Thiolate anions then react to form a twoꢀsulfur threeꢀelectron (2Sꢀ3e) covalent
interaction with thiyl radicals, partitioning the catalytic radical species of the TEC reaction into a metastable disulfide radical
anion species. Strong correlations between the retardation activity of various thiolate species and the calculated σꢀwithdrawing
character of the substituent(s) were observed. Further, when the formation reaction of the disulfide radical anion was modeled as
the reverse of a stepꢀwise dissociate electron transfer (DET) reaction, an inverse correlation emerged between the calculated
magnitude of solvent reorganization required in going from reactants to the transition state and the retardation activity of the
thiolate anion. It was also observed, by selecting TEC systems with rapid kinetics and are not propagation limited (e.g. the
reaction between butyl 3ꢀmercaptopropionate and 5ꢀnorborneneꢀ2ꢀmethanol), that the retardative effects of the thiolate anion may
be mitigated.
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RESULTS and DISCUSSION
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Scheme 2. TEC Reactions in the Presence of Amines
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pKa values for thiols and conjugate acid pKa values for amines shown in parenthesis. Values obtained from references
f
a10, b11, c12, d13, e14, 15.
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
a.
b.
0.05:1 [Amine]:[SH]
No Amine
Aniline
0.05:1 [Amine]:[SH]
No Amine
TMEDA
TMEDA
TEA
TEA
DBU
0
1
2
3
4
5
0
1
2
3
4
5
Time/min
Time/min
Figure 1. Ene conversion versus time for the TEC reaction between (a) MP and E1 (1:1 [SH]:[C=C]), for clarity not all data
points are included, and (b) MA and E1 (1:1 [SH]:[C=C]) in the presence of amines with varying basicity. The reactions were
formulated with MP/MA (3M), E1 (1.5 M), DMPA (0.03 M) with no amine, TMEDA, TEA, or DBU at 5 mol%.
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Amine Effects on the TEC Reaction. Initially, TEC reactions between several thiols (3 M) and a diallyl ether (E1, 1.5
M) (Scheme 2) were conducted in the presence of amines of differing basicity, and their kinetics were monitored via FTIR when
initiated by continuous irradiation with 0.03 M photoinitiator (2,2ꢀdimethoxyꢀ2ꢀphenylacetophenone, DMPA). With 5 mol%
amine, the least acidic thiol, butyl 3ꢀmercaptopropionate (MP) exhibited retarded kinetics with the strongly basic 1ꢀ8ꢀ
diazabicyclo[5.4.0]undecꢀ7ꢀene, DBU, while remaining unaffected by the less basic triethylamine, TEA, and
tetramethylethylenediamine, TMEDA (Figure 1A). The more acidic thiols butyl 2ꢀmercaptoacetate (MA, see Figure 1B) and
thioacetic acid (TA, Figure S2) were retarded in the presence of DBU, TEA, and TMEDA, with the most acid thiol, TA, being
the only thiol retarded by the least basic amine, aniline. In all cases, reactions exhibited reduced rates and conversions only when
the aqueous pKa of the thiol was lower than the conjugate acid pKa of the amine additive, indicating that the thiol must be
deprotonated by the amine for the system to exhibit retardation (i.e. the RS– or ammonium ion must be present).
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The retardation activity, R0/R, defined here as the ratio of the steadyꢀstate reaction rate for the TEC reaction in the
absence (R0) relative to in the presence of an additive (R), of DBU in the MP/E1 reaction was characterized. With 1, 2.5, 5, and
25 mol% DBU, R0/R values of 1.1, 9.9, 43, and 180 were obtained, respectively. The 1 mol% DBU sample achieved 100%
conversion after 2 min irradiation, while the 2.5 mol% sample reduced the rate by a factor of ~10 and limited the conversion to ~
30%. 25 mol% DBU effectively prevented any reaction (see Figure 2). These results, along with the pKa trend, demonstrate that
retardation is a result of either the ammonium or thiolate ion interacting with a TEC radical.
1.0
0.8
[DBU]/[SH] x 100%
0%
0.6
1%
2.5%
5%
25%
0.4
0.2
0.0
0
1
2
3
4
5
Time/min
Figure 2. Ene conversion versus time for the TEC reaction between MP and E1 (1:1 [SH]:[C=C]) in the presence of 0, 1, 2.5, 5,
and 25 mol% DBU.
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Amine Effects on the ThiolꢀYne Reaction. The same retardation trends established with the E1 TEC reactions were
also observed in the radicalꢀmediated thiolꢀyne reaction (Table 1) between MP or MA with the alkyne 4ꢀoctynylꢀ1ꢀol (Y1) (see
Scheme S1). Thiolꢀyne reactions are similar to TEC reactions; the thiyl radical propagates into the alkyne generating a vinyl
sulfide functionality, followed by a more rapid second thiyl radical addition16 affording a dithioether product. The MP/Y1
reaction (Figure S4) exhibited limited final conversions when 1 mol% DBU was present (66% yne conversion) while TEA and
TMEDA had a minimal effect on the rate and no effect on conversion. The MA/Y1 reaction (Figure S5) was significantly
retarded when DBU, TEA, or TMEDA were present at 1 mol% and relatively unaffected by aniline at 25 mol%, as expected.
These results allow for the rule for amine retardation of TEC reactions (that retardation occurs when the amine is basic enough to
deprotonated the thiol reactant) to be extended to thiyl radical reactions, in general. Interestingly, the retardation activities
increased by at least an order of magnitude for this thiolꢀyne reaction versus the TEC reactions with E1, e.g. R0/R = 1.12 and 16
for MP/E1 and MP/Y1, respectively, with 1 mol% DBU present, and R0/R = 1.8 and 40 for MA/E1 and MA/Y1, respectively,
with 1 mol% TMEDA present. Previous work in the Bowman Lab focusing on thiolꢀyne kinetics had found the alkyne, methyl
propargylamine, to exhibit limited conversions and slow kinetics in lieu of its electron rich character.16b The results presented
here demonstrate that the observed phenomena was a result of the basic character of the alkyne functionality being investigated
rather than the reactive character of the propargyl amine functional group towards thiyl radicals.
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Table 1. Effect of Amines on the ThiolꢀYne Reaction
Alkyne
Conversion
Thiol Additive
Equiv
ꢀꢀ
R0/R a
1
(%) b
MP
MP
MP
MP
MP
MA
MA
MA
MA
MA
MA
ꢀꢀ
quant.
66(±11)
25(±2)
quant.
quant.
quant.
DBU
DBU
TEA
0.01
0.05
0.25
12(±6)
7400(±1200)
1.5(±0.3)
1.6(±0.2)
1
TMEDA 0.25
ꢀꢀ
ꢀꢀ
DBU
TEA
0.01
0.01
13000(±2000) 16(±2)
20(±2)
67(±2)
TMEDA 0.01
TMEDA 0.05
40(±10)
60(±10)
18000(±3000) 12(±2)
1.8(±0.2) quant.
Aniline
0.25
Thiolꢀyne reaction between MP or MA and Y1, 2:1 [SH]:[Yne], formulated with amine additives. a The steadyꢀstate propagation
rate R0= 9.3 and 10.8 M minꢀ1 for MP and MA, respectively, with Y1 when no additive is present. b Conversions determined by
FTIR in situ from the decrease in the C–H peak corresponding to the alkyne functional group at 3330 cmꢀ1. Conversions
correspond to 10 min of irradiation.
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Scheme 3. TEC Reactions in the Presence of Ammonium and Thiolate Salts
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Table 2. Effects of Ammonium and Thiolate Ions on TEC
Additive (0.05 equiv)
Ene
conversion
(%) b
Anion
AcO−
Cation
Amine
DBU
TEA
R0/R a
44(±3)
35(±6)
quant.
quant.
quant.
quant.
quant.
92(±4)
45(±2)
49(±5)
quant.
quant.
21(±5)
16(±8)
1.0(±0.1)
0.82(±0.04)
1.09(±0.06)
1.4(±0.2)
3.4(±0.7)
6(±1)
TEA(H)+
DBU(H)+
Am1+
Na+
−
PF6
MP−
Am1+
Na+
TP−
49(±22)
41(±12)
3.3(±0.4)
2.6(±0.7)
125(±64)
140(±80)
Am1+
Na+
Am1+
Na+
TA–
MA−
Am1+
TEC reaction between MP and E1, 1:1 [SH]:[C=C], formulated with amine or salt additives, 0.05:1 [additive]:[SH]. a R0=5.65 M
minꢀ1 b Conversions determined by FTIR in situ from the decrease in the C–H peak corresponding to the alkene functional group
at 3050 cmꢀ1. Conversions correspond to 10 min of irradiation.
Effect of Ammonium and Thiolate Ions on TEC Reactions. Effects of ammonium cations, quaternary and
protonated tertiary amines, and thiolate anions on the MP/E1 reaction were studied by introducing 5 mol% salt additives
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(Scheme 3). The salts of protonated TEA and DBU with acetate, [TEA(H)+ AcO–] and [DBU(H)+ AcO–], show no effect on the
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ꢀ
reaction rate (Table 2); likewise, similar rates were observed with the quaternary ammonium containing salt [Am1+ PF6 ]. For all
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formulations without thiolate anions present, quantitative conversions by FTIR were achieved in ~ 2 min irradiation, ruling out
the potential of radical chainꢀtransfer to protonated amine or other radical sideꢀreactions with amine additives employed in the
previous section. Figure S6 compares the impact of the anion on MP/E1 while keeping the cations structure constant, i.e., Am1+.
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–
The anion PF6 , exhibits slightly delayed kinetics, with the rates shown in Table 2, but quantitative conversion continues to be
achieved around ~2 min irradiation.
1.0
0.8
0.6
0.05:1 [Salt]:[SH]
No Amine
Am1+ TA-
Am1+ MP-
0.4
Am1+ TP-
Am1+ MA-
0.2
0.0
0
1
2
3
4
5
Time/min
Figure 3. Ene conversion versus time for the TEC reaction between MP and E1 (1:1 [SH]:[C=C]) in the presence of salt
additives. The reaction samples were formulated with with no salt, [Am1+ TAꢁ], [Am1+ MPꢁ], [Am1+ TPꢁ], and [Am1+ MAꢁ].
The MPꢁ anion resulted in significantly suppressed reaction rates, R0/R = 6, and a delayed time to completion, > 5 min
irradiation. Given that for MP/E1 reactions at steadyꢀstate it is expected that R ∝ [C•],17 where [C•] is the concentration of 2° Cꢀ
radicals, the steadyꢀstate reaction rates for MP/E1 with [Am1+ PF6ꢁ] and [Am1+ MPꢁ] correspond to approximately an 18% and
71% reduction in [C•], respectively. Figure 3 compares the results of varying the thiolate anion structure while keeping the
cation structure constant as Am1+, where the thiolate retardation activities follow the trend: MAꢁ > TPꢁ > MPꢁ > TAꢁ, with the
MAꢁ anion effectively preventing any significant reaction from occurring as an average ene conversion of 19% was obtained
with the MA– with two countercations. Retardation activity trends persist independent of the counter ion structure (Na+ or
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Am1+). Considering these results, it was concluded that the thiolate anion directly retards TEC reactions by stabilizing or reacting
with catalytic radicals. Considering these results, it was concluded that the thiolate anion directly retards TEC reactions by
stabilizing or reacting with catalytic radicals. The trials with [TEA(H)+ AcOꢀ] and [DBU(H)+ AcOꢀ] show that the retardive
effects of amines may be overcome by the addition of an acid with a lower pKa than the reacting thiol. This prevents the thiolate
from forming and preserves the rapid reaction rate.
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Scheme 4. TEC Reactions with Different Enes in the Presence of DBU and Thiolate Salts
Table 3. Effect of Alkene Structure on the Retardation Activity of DBU and Thiolate Anions
Ene
Ene
(R0 )a
Conversion
b
kP/kCT
Additive
DBU
Am1+ MPꢀ
Am1+ TPꢀ
DBU
Am1+ MPꢀ
Am1+ TPꢀ
DBU
Am1+ MPꢀ
Am1+ TPꢀ
R0/R c
(%) d
44(±3)
35(±2)
92(±6)
49(±5)
Quant.
Quant.
Quant.
10
5.6(±1.4)
41(±10)
150(±50)
41(±15)
68(±13)
E1
(5.63)
1.0
0.2
E2
(150)
1300(±900) 24(±6)
345(±61) 43(±8)
1500(±700) 18(±2)
E3
(52)
TEC reaction between MP and 3 different alkenes, 1:1 [SH]:[C=C],. a Steadyꢀstate propagation rate with no additive present,
reported in units of M minꢀ1. b kP/kCT values for the MP/E1 and MP/E2 reactions were obtained from reference 53. kP/kCT for the
c
MP/E3 reaction was determined by kinetic modeling (see SI section 6 for modeling details). Ratio of steadyꢀstate rate of
propagation formulated without additive and with amine or salt 0.05:1 [additive]:[SH]. d Conversions determined by FTIR in situ.
Conversions correspond to 10 min of irradiation.
Effect of Alkene Substrate on Retardation. Previous work showed that the rate constant ratio, kP/kCT, for a particular
TEC system is equal to the ratio of Cꢀradicals to thiyl radicals at steadyꢀstate, [C·]/[S·].17,18 Thus, the relative concentration of the
TEC radicals may be manipulated to determine if retardation is the result of thiolate anions interacting with the catalytic Cꢀ or Sꢀ
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radicals. TEC reactions between MP and three alkenes (E1, 5ꢀnorborneneꢀ2ꢀmethanol E2, and 1,3ꢀdivinyltetramethyldisiloxane
E3) were conducted with 5 mol% DBU or RS– salt (Scheme 4). kP/kCT for MP/E1 and MP/E2 was previously determined to be
~10 and ~1,17 respectively, while for the MP/E3 reaction kP/kCT = 0.2 (See SI Section 6). R0/R values and final ene conversions
are in Table 3. R0/R trends correlate with kP/kCT, i.e. the higher ratio of thiyl radicals to Cꢀradicals is, the more retarded the
system is by amine and RS– additives. [Am1+ MP−] reduced the rates for the MP/E1, MP/E2, and MP/E3 systems to 18 %, 2 %,
and 0.3 % of the control rates, respectively, and [Am1+ TP−] reduced the rates to 2 %, 1 %, and 0.07 %, respectively. Comparing
the chainꢀtransfer limited MP/E1 and the propagation limited MP/E3, which should decrease the [C·]/[S·] ratio, the average
R0/R values of the three additives increase by a factor of ~ 30 for DBU and TP− and a factor of ~ 60 for MP−. This correlation
indicates that retardation is the result of a thiolateꢀthiyl radical interaction. Owing to the rapid kinetics of the thiolꢀnorbornene
reactions, MP/E2 systems still reached quantitative conversions in each formulation prior to 10 min irradiation, implying that
thoughtful selection of the alkene functionality at least somewhat mitigates the impact of the thiolate/amine induced retardation
effects on conversion in thiolꢀene systems.
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It should be noted that retardation persisted when the TEC reactions were initiated via direct irradiation without
photoinitiator (SI Section 7), ruling out the potential of a thiolateꢀinitiator interaction as the retardation mechanism.
Computational Investigation of the Thiyl RadicalꢀThiolate Anion Interaction. Formation of a 2Sꢀ3e bonded
metastable disulfide radical anion (DRA) by association of a thiyl radical with a thiolate ion (RS· + R’S– ⬌[RSSR’] ·–) was
hypothesized as the cause of the retardation. DRAs occur as intermediates in biochemical processes, e.g. metabolism and
disulfide bridge exchange,19 primarily studied under physiologically relevant environments.20 Further, hitherto performed DRA
studies on thermodynamic stability, and formation/fragmentation kinetics describe reactions of biochemically relevant thiols
without consideration towards moieties frequently employed in TEC formulations, namely mercaptopropionate, mercaptoacetate,
and thioacetate. Given the deficit in the literature regarding DRA formations in nonꢀphysiological environments, especially in
relatively nonpolar and viscous organic environments, and the limited diversity of published DRA structures, DFT calculations
were performed to explore the thermodynamics and kinetics of DRAs in the context of TEC reactions.
DRA formations from the various parent thiols used in this study were thermodynamically favorable in a modeled
solvent environment due to the enhanced charge delocalization in the DRAs vs. the thiolate anions and a favorable enthalpic
contribution from the SꢀS bond formation.20a,20b The MPMA DRA was found to be the most stable and the MPTA DRA, the
least stable (ꢀ17.9 vs. ꢀ6.4 kcal/mol) while other DRAs have intermediate stabilities (Table 4). The behavior of the
computationally calculated stabilities agrees well with the experimental trends where the MPMA formulation exhibited two
orders of magnitude greater retardation compared to that of MPTA while other DRAs induced intermediate degrees of
retardation. It is expected that the differences in the degrees of retardation between formulations originate from the environment
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of the radical electron density in each DRA. The population analysis of the radical density on the disulfide bond (ρ[ꢀꢁ∗ꢁ])
demonstrates that the ester groups in MA and MP, and to a lesser degree, the phenyl group in TP withdraws electron density
from the antibonding ꢀꢁ∗ꢁ orbital, increasing the stability of the DRAs. In contrast, the acetyl group of TA donates electron
density to the ꢀꢁ∗ꢁ orbital, decreasing the stability of the associated DRA.21 (Table 4) This behavior is due to the mismatch in size
between the 3p atomic orbital (AO) of sulfur and 2p AO of carbon22 that limits the electronic delocalization through the πꢀsystem
and ultimately results in the pronounced effect of the inductive electronꢀwithdrawing character (EWC) in substituents.23
Asymmetric DRAs exhibit EWC averaged over the two substituents. Also important are the results from an analysis of the
difference of the localized electronic densities on each Sꢀnucleus of the DRAs (ρ diff.), which reveals an additional cause for the
instability of TAꢀderived DRAs. (Table 4) When the two sulfur nuclei possess equivalent electronic states or nearly so, an
additional degeneracy is introduced that stabilizes the DRA via resonance between the two sulfur fragments.24 All symmetric
DRAs except for TATA exhibited minimal electron density differences between the anionic and radical Sꢀnuclei whereas the
radical Sꢀnucleus had a more localized density than the anionic Sꢀnucleus in TATA.24a Among asymmetric DRAs, MPTA again
exhibited the largest electron density difference, leading to its thermodynamic instability. This result is accompanied by a highly
correlated linear relationship between ∆G° and ρ diff. (R2 = 0.92), excepting MPMA (Figure 4a). The exceptional stability of
MPMA is attributed to negative hyperconjugation resulting from the synꢀperiplanar position of the πC=O and σ*CꢀS orbitals in the
MA substituent (Figure 4b).25 This additional stabilizing electronic effect results in the lengthening of the C–S and C=O bonds
as electron density from the πC=O bonding orbital transfers to the σ*CꢀS antibonding orbital. The required orbital overlap for
hyperconjugation was not predicted for any other DRAs including MAMA. Therefore, it was concluded that the degree of
inductive EWC and the balance of the electron density distribution between the two Sꢀnuclei are the principal reasons for the
experimental trend.
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Table 4. Computational Data on the Formulation of Disulfide Radical Anions
DRA
∆G°
K
ρ[ꢂ∗ꢃꢃ
ꢀ0.94
ꢀ1.21
ꢀ0.66
ꢀ0.90
ꢀ0.95
ꢀ1.07
ꢀ0.90
]
BDEa
59.4
55.4
59.5
60.7
58.3
57.4
63.9
λtotal
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5.6
3.6
3.1
1.5
3.3
2.7
∆G‡
9.0
TPTP
ꢀ14.0
ꢀ11.2
ꢀ13.7
ꢀ15.0
ꢀ8.8
1.8E+10
1.8E+08
1.0E+10
1.0E+11
2.8E+06
4.7E+04
1.3E+13
TATA
MAMA
MPMP
MPTP
MPTA
MPMA
10.1
9.7
9.3
10.9
12.2
8.9
ꢀ6.4
ꢀ17.9
a Bond dissociation energies of corresponding neutral disulfide molecules. Values for ∆G°, BDE, λtotal, and ∆G‡ are in kcal molꢀ1
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a.
MPTA
-6
-8
b.
MPTP
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-10
-12
-14
-16
-18
TATA
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MAMA
TPTP
MPMP
MPMA
0.4
0.0
0.2
0.6
0.8
1.0
1.2
p diff.
Figure 4. (a) Correlation of DRA stability ∆G° with the difference of the localized electronic densities on each Sꢀnucleus of the
DRAs (ρ diff.). The MPMA DRA is an anomaly due to its unique electronic configuration. (b) Comparison of the πC=O and σ*
CꢀS
orbitals in the (upper) MPMA and (lower) MAMA radical anions. The unique synꢀperiplanar positioning of these orbitals in
MPMA results in a stabilizing orbital overlap.
Saveant’s model of dissociative electron transfer (DET) was applied to study the kinetics of DRA formations and specifically,
how ∆G°, BDE, and λtotal contribute to the activation free energy (∆G‡)26 for the ET reaction. This DET theory models an ET
reaction that is concomitant with a bond dissociation, in this case through a radical anion intermediate. The reverse reaction ꢀꢀꢀ
associative ET ꢀꢀꢀ is analogous to the hypothesized mechanism for DRA formation. Again, the calculations demonstrated that
MPMA has the smallest activation barrier and MPTA, the largest (8.9 vs. 12.2 kcal/mol) with other DRA formations possessing
intermediate barriers, further corroborating the agreement between the computational and experimental results. However, neither
the stability nor the barrier studies explain why MPTP display a higher retardation rate than MPMP. Kinetic calculations affirm
that MPTP’s anomalous retardation activity results from the unusual behavior of the reorganization energy in low polar and
viscous resin environments. The rigidity of aromatic structures, such as in TP, reduces the required changes in structure that
occur during the ET reaction, leading to a low internal reorganization energy (λi).27 MA in the MPMA DRA may also experience
a similar rigidity effect due to the partial double bond character that arises from hyperconjugation. In contrast, TA undergoes
significant changes in its bond lengths, bond angles and dihedral angle torsions upon ET, requiring a large λi. (See SI Section 9
for a comparison of the geometric relaxations of TP and TA upon ET) In low polarity environments, low λi as in TP and MP
likely leads to low solvent reorganization energies (λs) because molecular translation for solvent cavity formation becomes the
dominant mode for λs rather than a change in dipole orientation resulting from electrostatic interactions of reacting species in
conventional polar environments.28 Furthermore, high viscosity is correlated with longer solvent response times which reduces
the population of reacting species in the transition state, effectively rendering the low λs requirement more crucial in overcoming
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the activation barrier.29 Considering the two factors of low solvent polarity and high solvent viscosity, it is proposed that in the
system under consideration and other similar systems that both reorganization energies contribute more to the barrier for the
associative ET reaction of DRA formation than in standard Saveant DET models where low λi leads to low λs due to low polarity
solvent and the effect of low λs is accentuated by high viscosity solvent. This assumption provides the explanation of the greater
retardation activity of the TP thiolate anion over the MP anion in the MP/E1 TEC formulation (λtotal = 1.5 vs. 3.1 kcal/mol).
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CONCLUSION
In this work, it was determined that amines indirectly retard radicalꢀmediated TEC reactions through the in situ
generation of the thiolate anion that sequesters the catalytic radical population into a metastable DRA species. The degree of
retardation increases with the ratio of thiyl to carbon radicals present, thiolate anion concentration, and the stability of the
resulting DRA. DFT calculations showed that DRAs comprised of parent thiol fragments investigated in the experimental
kinetics studies are all thermodynamically favorable to form. As the reaction is highly reversible, the thermodynamics is a
governing parameter to predict the degree of retardation and fits well with the observed retardation activities of the thiolate
anions on MP thiolꢀene systems, except for the MPTP DRA as the TP anion exhibited exceptional activity. The energetic barriers
to DRA formation were investigated using parameters from the Savaeant model for DET reactions, treating the formation as an
associative ET reaction. It is expected that, due to the relatively high viscosity and low polarity/dielectric character of the reaction
medium, the solvent reorganization is a more significant parameter to the kinetic barrier than is assumed in standard DET
Saveant models. Accordingly, TP anions were determined to have reduced activation barriers toward DRA formation owing to
the rigidity of the aromatic substituent, explaining their high retardation activity and highlighting that conventional ET theories
may not optimally describe ET reactions in a solvent environment that polymer chemists frequently encounter (e.g. relatively
nonpolar and viscous).
These results have important implications for the design of TEC systems, and thiyl radical reactions in general, when it
is desired to perform these reactions under alkaline conditions or in the presence of basic moieties. Although, computations and
experiments showed that the DRAs are in general thermodynamically favorable to form when the thiolate anion is present,
quantitative conversions may still be obtained by appropriate selection of the reacting thiol and alkene substrate, i.e. using a thiol
with low acidity or an alkene, like norbornene or vinyl ether, which has rapid curing kinetics under controlled conditions that are
not propagation limited (e.g. divinyl siloxane), or by incorporation of acids in the reaction mixture. Additionally, amines or
thiolateꢀcontaining salts could be used as formulation stabilizers, or used to control formulation curing rates.
EXPERIMENTAL SECTION
General Experimental Methods. Thiolꢀene reaction rate studies were performed on thiolꢀene mixtures in the mid IR
(Nicolet MagnaꢀIR 750 series II FTIR spectrometer). Samples were deposited between two sodium chloride plates separated by a
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0.051 mm plastic spacer. Thiol (2570 cmꢀ1, S–H stretch) and alkene (3050 cmꢀ1, C=C–H stretch) conversions were monitored in
realꢀtime at a collection rate of ~1 scan per second and a resolution of 1 cmꢀ1. Samples were irradiated until the reaction was
complete, as indicated by the functional group absorption peak no longer decreasing, with UVꢀlight from an Acticure 4000 light
source with a 365ꢀnm filter at an intensity of 2.5 mW cmꢀ2. Irradiation intensities were measured with a NIST Traceable
Radiometer Photometer, model IL1400A.
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1
All starting materials were obtained commercially without further purification. H NMR spectra were recorded on Bruker
AvanceꢀIII 400 spectrometers.
Computational Methods. Quantum calculations describing the disulfide radical anion formation were performed at the LCꢀ
wPBE/augꢀccꢀPVTZ//LCꢀwPBE/6ꢀ31+G** level of DFT,30 solvated by the ethyl acetate CPCM31 continuum solvent model with
the GAUSSIAN09 software package.32 Frequency calculations were performed at the LCꢀwPBE/6ꢀ31+G** level of theory to
confirm optimized geometries and for thermochemical analysis. Overestimated entropies for the solutionꢀphase reaction were
corrected by subtracting the translational entropy contribution (−ꢄ∆S°ꢅꢆꢇꢈꢉ) from the free energies of reactants and products in
solution.33 The atomic polar tensor population (ATP) analysis34 was used to analyze electron density distributions of disulfide
radical anions and reorganization energies (λ) were calculated as described by Cossi and Barone.35 The B3P86 /6ꢀ31G* level of
theory36 was used to calculate the bond dissociation energies (BDE) of disulfides.37 See SI Section 9 for additional computational
details.
Synthesis of protonated tertiary amine/acetate salts. [AcOꢀ TEA(H)+] and [DBU(H)+ AcOꢀ] were
prepared using a modified literature procedure.38,39 Glacial acetic acid (0.1 mL, 1.75 mmol) was added dropwise into a
scintillation flask charged with the appropriate amine (1.66 mmol). The reaction was stirred for 6 h at room temperature. Excess
acetic acid and amine was removed under vacuum and the resulting product was left under high vacuum and while being heated
(50 °C) for 48 h.
Synthesis of sodium thiolate salts. General Procedure: Mono functional thiol (10 mmol) was added dropwise, under a
nitrogen environment, into a scintillation flask charged with sodium hydroxide (390 mg, 9.8 mmol) dissolved in 1 mL of
deionized water. The reaction was stirred for 30 minutes at room temperature. Water and excess thiol was removed under
vacuum and the solids were triturated with cyclohexane (3x 5 mL), ethyl acetate (2 x 5 mL) and ice cold water (1x 5 mL) to
afford the desired salts. The salts were left under vacuum until use to prevent the formation of disulfides.
Sodium/butyl 3ꢀmercaptopropionate thiolate [Na+ MP-]. Salt was obtained as a white solid (1.46 g, 81 % yield). 1H
NMR (400 MHZ, Methanolꢀd4) δ 4.13 (td, 2H), 2.75 (m, 2H), 2.66 (m, 2H), 1.64 (m, 2H), 1.42 (m, 2H), 0.97 (t, 3H); 13C NMR
(101 MHZ, Methanolꢀd4) 172.1, 64.1, 38.2, 30.5, 19.0, 18.8, 12.7.
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Sodium/thiophenolate [Na+ TP-]. Salt was obtained as a white solid (1.10 g, 85 % yield). H NMR (400 MHZ,
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Methanolꢀd4) δ 7.38 (m, 2H), 6.92 (m, 2H), 6.77 (m, 1H); 13C NMR (101 MHZ, Methanolꢀd4) 147.3, 132.9 (2C), 126.9 (2C),
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Sodium/thioacetate [Na+ TA-]. Salt was obtained as a white/yellow solid (700 mg, 73 % yield). 1H NMR (400 MHZ,
Methanolꢀd4) δ 2.43 (s, 3H); 13C NMR (101 MHZ, Methanolꢀd4) 219.1, 37.1.
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Sodium/butyl 3ꢀmercaptoacetate thiolate [Na+ MA-]. Salt was obtained as a white solid (1.02 g, 61 % yield). 1H NMR
(400 MHZ, Methanolꢀd4) δ 4.15 (td, 2H), 3.29 (s, 2H), 1.66 (m, 2H), 1.44 (m, 2H), 0.97 (t, 3H); 13C NMR ( 101 MHZ,
Methanolꢀd4) 171.6, 65.0, 30.4, 25.4, 18.7, 12.8.
Synthesis of tetraethylammonium/thiolate salts [Am1+ RS-]. General Procedure: Mono functional thiol (1.75 mmol)
was added dropwise, under a nitrogen environment, into a scintillation flask charged with tetraethylammonium hydroxide (0.927
mL, 1.66 mmol) in methanol. The reaction was stirred for 30 minutes at room temperature. Solvent and excess thiol were
removed under vacuum and the solids were triturated with cyclohexane (3x 5 mL), ethyl acetate (2x 5 mL) and ice cold water (1x
5 mL) to obtain the desired thiolate salt. The salts were then placed under vacuum until use to prevent disulfide formation.
Tetraethylammonium/butyl 3ꢀmercaptopropionate thiolate [Am1+ MP-]. Salt was obtained as a yellow grease. (250 mg,
52 % yield). 1H NMR (400 MHZ, Methanolꢀd4) δ 4.13 (t, 2H), 3.33 (m, 8H), 2.74 (m, 2H), 2.65 (td, 2H), 1.65 (p, 2H), 1.43 (h,
2H), 1.32 (tt, 12H), 0.97, (t, 3H); 13C NMR ( 101 MHZ, Methanolꢀd4) 172.2, 64.1, 51.9 (4C), 38.1, 30.4, 18.9, 18.8, 12.6, 6.2
(4C).
Tetraethylammonium/thiophenolate [Am1+TP-]. Salt was obtained as a yellow grease. (270 mg, 68 % yield). 1H NMR
(400 MHZ, Methanolꢀd4) δ 7.25(m, 4H), 7.13 (m, 1H), 3.31 (m, 8H), 1.30 (tt, 12H); 13C NMR ( 101 MHZ, Methanolꢀd4) δ
131.7, 128.7 (2C), 128.4 (2C), 124.7, 51.8 (4C), 6.1 (4C).
Tetraethylammonium/thioacetate [Am1+TA-]. Salt was obtained as a yellow grease. (220 mg, 65 % yield). 1H NMR
(400 MHZ, Methanolꢀd4) δ 3.30 (q, 8H), 2.44 (s, 3H), 1.31 (tt, 12H); 13C NMR ( 101 MHZ, Methanolꢀd4) δ 218.7, 51.9 (4C),
37.1, 6.2 (4C).
Tetraethylammonium/butyl 2ꢀmercaptoacetate thiolate [Am1+ MA-]. Salt was obtained as light red grease. (210 mg, 45
1
% yield). H NMR (400 MHZ, Methanolꢀd4) δ 4.15 (t, 2H), 3.32 (q, 8H), 1.66 (m, 2H), 1.44 (m, 2H), 1.32 (tt, 12H), 0.97 (t,
3H); 13C NMR (101 MHZ, Methanolꢀd4) δ 171.5, 65.0, 52.1 (4C), 30.4, 25.5, 18.8, 12.8, 6.6 (4C).
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
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Supplementary figures, kinetic modeling of the MP/E3 TEC reaction, detailed computational methods,
coordinates for optimized molecular structures (PDF)
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AUTHOR INFORMATION
Corresponding Author
* Christopher.bowman@colorado.edu
Notes
The authors declare no competing financial interests.
AKNOWLEDGMENTS
We gratefully acknowledge financial support from NSFꢀMRSEC (DMR 1420736), DoEd GAANN program and NSF CHEꢀ
1214131. We also gratefully acknowledge use of XSEDE supercomputing resources (NSF ACIꢀ1053575).
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