(196e) Amine Effects on Radial-Mediated Thiol-Ene Reactions

Thiyl
radical chemistry is of exceptional interest in biology and organic chemistry
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
reactivities. S-centered radicals undergo efficient, essentially barrierless
compared to alkyl and alkoxy radicals, anti-Markovnikov addition into
unsaturated X=C(R)R’bonds. Of particular interest is the thiyl radical reaction
with alkenes, radical-mediated thiol-ene coupling (TEC), which is one of the
so-called “click” reactions and has become a staple in polymerization and
conjugation chemistry. TEC reactions may be performed under ambient conditions
and without solvent, exhibiting rapid, often quantitative conversions, and an insensitivity
to water and oxygen, and offers the ability for spatio-temporal control. Robustness
of the thiol-ene reaction is amplified when used in concert with thiolate anion-mediated
reactions with electron deficient alkenes (thiol-Michael coupling),
isocyanates, thioesters, or epoxides to generate linear and network polymers
with increasing compositional and topological complexity as these reactions may
be performed orthogonally to thiol-ene reactive alkenes. In our present
efforts, our group’s focus is on fabricating polymers and networks with unique
properties through the synergistic incorporation of thiyl radical and thiolate
chemistries, including: sequence-ordered, DNA-mimetic polymers, covalent
adaptable networks, and low dispersity oligomers and block copolymers.

Despite
being well regarded as insensitive to most chemical functionalities present in
organic and biological systems, we observed significant retardation in TEC
reaction and reduced conversions (<50%) when performed in the presence of
amines, which were incorporated into the formulation either as the polymer
side-group functionality (e.g. nucleobases), buffering system, or catalyst for
thiolate reactions in dual-cure networks. Interested in the mechanism of this
phenomenon, we investigated the impact of amines, and ammonium and thiolate
ions on the reaction kinetics of TEC reactions using real-time Fourier
transform infrared (rt-FTIR) spectroscopy in order to expand the guidelines for
developing thiol-ene systems and to further understand the nature of S-centered
radicals in the context of general synthetic chemistry. We determined that amines
indirectly retard radical-mediated thiol-ene reactions through the generation
of the thiolate anion in situ, which sequesters the catalytic reactivity
of the thiyl radical through a radical—lone pair, two-sulfur three-electron (2S-3e)
interaction, effectively partitioning the radical population into an
intermediate disulfide radical anion (DRA) species. The degree of retardation
increases proportionally with the ratio of thiyl to carbon radicals present
under steady-state reaction conditions, the concentration of thiolate anion,
and depends highly on the structure of the thiolate anion and the resulting
disulfide radical anion.

Solution
phase, density functional theory (DFT) calculations were employed to validate
the mechanism by estimating, and comparing to experimental results, the
retardation activities of various thiolate anions on the TEC kinetics.
Computation revealed that all DRA structures possible in our systems are
metastable with respect to the thiol-ene product and that the electron
withdrawing character of the parent thiol substituent is the main factor in
determining the DRA’s stability. Additionally, kinetic barriers to DRA
formation were determined using parameters from Saveant theory on electron-transfer
(ET) reactions, where the DRA formation was treated as a step-wise, associative
ET reaction. Interestingly, the relatively high viscosity and low polarity/dielectric
character of the reaction medium led to the solvent reorganization energy to be
the more contributive parameter to the kinetic barrier in the formation than
the theory previously assumed; therefore, thiolate anions with a more rigid structure
and lower internal reorganization requirements displayed minimal barriers to
DRA formation, which is in agreement with experimental data.

The
phenomena of amine/thiolate induced retardation discussed in this paper has
important implications for the design of thiol-ene systems when the reaction is
performed under alkaline conditions in aqueous environments or in the presence
of basic moieties in polymer/organic synthesis. Although computations and
experiments showed that the DRAs are, in general, thermodynamically favorable
to form, near quantitative conversions may be obtained by choice of the
reacting thiol and/or alkene substrate, i.e. using a thiol with low acidity or
an alkene, like norbornene or vinyl ether, which have rapid curing kinetics and
are not rate-limited by the thiyl radical propagation step, like allyl ether
and vinyl siloxane. Further, the importance of the solvent reorganization
energy on the rate of ET highlights that conventional ET theories may not
adequately describe ET reactions in solvent environments that polymer chemists
frequently encounter (i.e. organic, weakly polar, and viscous).