Reaction rates and mechanisms for radical, photoinitated addition of thiols to alkynes, and implications for thiol-yne photopolymerizations and click reactions

Article abstract of DOI:10.1021/ma1002968

Because of its utility in network polymerization, dendrimer synthesis, and monomer development, the photoinitiated addition of thiols to alkynes has rapidly become an important tool for polymer scientists. Yet, because this chemistry has only recently been applied to cross-linked polymer development, understanding of the nature of how the yne structure affects the reactions and information on the relative reactivities of alkynes bearing various substituents is unavailable as is the relative addition rate of the thiol to the yne as compared to the vinyl sulfide. Herein, the photoinitiated addition of octanethiol to various alkynes is explored. The most rapid addition of thiols to alkynes is that to cyclooctyne, although the resulting vinyl sulfide does not permit subsequent thiol addition. Furthermore, in the absence of radical initiators and light, thiols add spontaneously to cyclooctynes, suggesting limitations to the orthogonality of the strain-promoted copper-less azide, alkyne cycloadditions. In order of decreasing reaction rates, the consecutive addition of two thiols occurs with the aliphatic 1-octyne > propargyl acetate > methyl propargyl ether > 2-octyne. Ethyl propiolate and methyl propargylamine exhibit very small reaction rates with thiols, and no consecutive addition is observed.

Full text of DOI:10.1021/ma1002968

Macromolecules 2010, 43, 4113–4119 4113
DOI: 10.1021/ma1002968
Reaction Rates and Mechanisms for Radical, Photoinitated Addition of
Thiols to Alkynes, and Implications for Thiol-Yne Photopolymerizations
and Click Reactions
†
†
†,§
Benjamin D. Fairbanks, Evan A. Sims, Kristi S. Anseth, and Christopher N. Bowman*
,†
†
§
Department of Chemical and Biological Engineering and Howard Hughes Medical Institute, University of
Colorado, Boulder, Colorado 80309-0424
Received February 5, 2010; Revised Manuscript Received March 23, 2010
ABSTRACT: Because of its utility in network polymerization, dendrimer synthesis, and monomer deve-
lopment, the photoinitiated addition of thiols to alkynes has rapidly become an important tool for polymer
scientists. Yet, because this chemistry has only recently been applied to cross-linked polymer development,
understanding of the nature of how the yne structure affects the reactions and information on the relative
reactivities of alkynes bearing various substituents is unavailable as is the relative addition rate of the thiol to
the yne as compared to the vinyl sulfide. Herein, the photoinitiated addition of octanethiol to various alkynes
is explored. The most rapid addition of thiols to alkynes is that to cyclooctyne, although the resulting vinyl
sulfide does not permit subsequent thiol addition. Furthermore, in the absence of radical initiators and light,
thiols add spontaneously to cyclooctynes, suggesting limitations to the orthogonality of the strain-promoted
copper-less azide, alkyne cycloadditions. In order of decreasing reaction rates, the consecutive addition of
two thiols occurs with the aliphatic 1-octyne > propargyl acetate > methyl propargyl ether > 2-octyne.
Ethyl propiolate and methyl propargylamine exhibit very small reaction rates with thiols, and no consecutive
addition is observed.
1
6
17
18
Introduction
polyfunctional materials, dendrimers, and polymer brushes
in addition to cross-linked polymers. The general radical-
mediated mechanism is presented in Figure 1. Briefly, a thiyl
radical adds across the alkyne triple bond to form a vinyl sulfide
radical. This radical abstracts a hydrogen from a thiol, regene-
rating the thiyl radical and forming a vinyl sulfide. Subsequently,
a thiyl radical adds across the double bond of the vinyl sulfide
generating a dithioether radical which abstracts a hydrogen atom
from a thiol, thereby regenerating the thiyl radical and forming a
dithioether. This polymerization mechanism is analogous to
that of the thiol-ene photopolymerization, in which alter-
nating propagation and chain transfer reactions lead to a
radical-mediated step-growth polymerization. Because thiols
add consecutively to the alkyne, the thiol-yne polymerization
is also analogous to the epoxy-amine polymerization, in which
The thiol-ene photopolymerization has received significant
attention in recent years. Though the reaction is radically
mediated, the unique mechanism (alternating propagation across
the ene and chain transfer to the thiol) results in a regular step-
1-3
growth network.
izations may benefit from the spatial and temporal control that
radical photoinitiation affords it while the resulting materials
Accordingly, thiol-ene network polymer-
4
possess the intrinsic benefits of step-growth polymers (e.g.,
regular network architecture resulting in toughness, delayed gel
point resulting in high conversion of glassy polymers and low
extractables). Additionally, thiol-ene polymerizations are insen-
sitive to oxygen inhibition and generally exhibit very rapid
5
polymerization rates. For the radical thiol-ene photopolymer-
izations various functional groups have been evaluated in regards
to their reaction rates and analysis of which stepsare rate limiting,
including aliphatic alkenes, allyl ethers, vinyl ethers, acrylates,
1
9
two epoxies add to a single primary amine.
Because of the bireactive nature of the alkyne functionality, the
thiol-yne photopolymerization addresses one of the funda-
mental and intrinsic limitations of the thiol-ene reaction.
Because each alkene in a step-growth thiol-ene polymerization
is monofunctional while each alkene in a chain growth radical
6
vinyl silanes, and norbornenes. One general trend that has been
identified is that increasing electron density of the vinyl moiety
1
,6
also increases the reaction rate. A notable exception to this
trend is the norbornene group, which, presumably because of the
ring strain alleviated by the dissolution of the π bonds upon thiol
addition, also exhibits a very high reaction rate.
2
0
polymerization is difunctional as it forms two new bonds,
thiol-ene polymerizations typically result in materials with
relatively low cross-link density, which contributes to low glass
While the radical addition of thiols to alkynes was described as
11
7
-9
transition temperatures and low moduli. Thus, thiol-yne
reactions have the potential to improve these properties while
still retaining other advantageous characteristics of thiol-ene
polymerized materials. However, since the photopolymerization
of thiol-yne networks has only recently been explored, the
relative reactivities of various ynes, which in part determines
monomer utility, have not been adequately addressed.
early as the 1930s,
network polymerizations has only recently been explored.
While much of the previous research examined the monoaddition
the use of this reaction in photoinitiated
1
0-12
1
3-15
of thiols to phenylacetylene,
much of the research of the
past year has focused on the consecutive diaddition of thiols to
akynes, which reaction has been utilized for the synthesis of
In thiol-yne photopolymerizations previous reports have
utilized aliphatic alkynes, propargyl ethers, and propargyl
esters as monomers due to their availability and ease of
*
To whom correspondence should be addressed. E-mail: christopher.
bowman@colorado.edu.
r 2010 American Chemical Society
Published on Web 04/06/2010
pubs.acs.org/Macromolecules

4
114 Macromolecules, Vol. 43, No. 9, 2010
Fairbanks et al.
Figure 2. Materials used: (1) I184, (2) octanethiol, (3) butyl 3-mercap-
topropionate (4) 1-octyne, (5) propargyl acetate, (6) methyl propargyl
ether, (7) ethyl propiolate, (8) methyl propargylamine, (9) 2-octyne, and
Figure 1. Generalized radical thiol-yne polymerization scheme. Cycle
represents the initial addition of a thiol to an alkyne while cycle 2
represents the subsequent addition to the vinyl sulfide product from the
first addition. Because the participation of the vinyl sulfide is dependent
on the identity of the initial alkyne as demonstrated herein, this cycle is
presented in gray to indicate that this reaction may or may not occur,
1
(10) cyclooctyne.
under an argon atmosphere. NMR spectra where recorded on a
Varian INOVA 500 MHz instrument, and chemical shifts are
reported in parts per million (δ) from TMS using the residual
CHCl3 peak as an internal reference (7.26 ppm); coupling
constants (J values) are reported in hertz. Gas chromato-
graphy-mass spectrometry was performed on a Thermo Finni-
gan Polaris Q instrument (electron impact, 70 eV).
depending on the initial yne structure. For terminal alkynes, R
3
= H.
11,16-18,21
synthesis.
In addition to these functional groups, we
herein examine the relative reactivities toward thiols of two other
terminal alkynes (methyl propargylamine and ethyl propiolate)
as well as two internal akynes (2-octyne and the ring-strained
cyclooctyne). Exploring the reaction between thiols and various
alkynes, including cyclooctyne, allows for more informed mono-
mer design for the thiol-yne photopolymerization. Additionally,
this study holds implications for the use of azide-alkyne click
reactions as it both demonstrates limitations to the orthogonality
of such reactions and portends the development of hybrid
copolymerization schemes.
1
-Bromocyclooctene. cis-Cyclooctene (25 mL, 182 mmol) was
added to a round bottom flask containing dry dichloromethane
96 mL) and cooled to -15 °C. Bromine (9.35 mL, 182 mmol)
(
was added in a slow stream over about 20 min, at which point a
characteristic brown color persisted. Excess bromine was evapo-
rated under a rapid stream of air, and then the solution was
further concentrated by rotary evaporation. The crude 1,2-
dibromocyclooctane was redissolved in pyridine (72.8 mL)
and brought to reflux with rapid stirring. After refluxing over-
night, a thick slurry had formed, and the reaction was cooled to
ambient, diluted with toluene, and filtered, rinsing with three
portions of toluene. The solution was concentrated and purified
by flash chromatography (100% hexanes) to yield a clear oil
Catalyzed by copper(I), terminal alkynes add to azides to
2
2
form 1,2,3-triazole rings. Terminal as well as internal alkynes
were recently shown to react to form similar triazole rings when
2
3
catalyzed by ruthenium(II), whereas cyclooctynes have been
24
demonstrated to add to azides spontaneously. This sponta-
neous reaction has been used for in vivo imaging of biological
processes as well as star polymer and hydrogel network synthe-
(18.85 g, 99.7 mmol, 55% over two steps). R = 0.70 (100%
f
1
hexanes, stained with ceric ammonium molybdate). H NMR
25-27
sis.
Additionally, a phototriggered click reaction has been
(500 MHz, CDCl
2.13-2.07 (m, 2H), 1.66-1.60 (m, 2H), 1.58-1.47 (m, 6H). GC-
MS: m/z 191, 190 (M ), 189, 188 (M ), 162, 161, 160, 110, 109,
3
) δ: 6.03 (t, J=8.5, 1H), 2.63-2.59 (m, 2H),
demonstrated by photochemical conversion of a cyclopropanone
to dibenzocyclooctyne for subsequent copper-less click addition
þ
þ
28
8
1, 79, 77, 67 (base), 65, 53, 51, 41.
Cyclooctyne. A 0.2 M solution of lithium diisopropylamide
LDA) was prepared by adding n-BuLi (1.0 equiv) to a 0.22 M
to an azide. The click and copper-less click azide-alkyne
reactions have received particular attention in biological applica-
tions as both azides and alkynes are considered generally
unreactive toward functional groups typically displayed on
(
solution of diisopropylamine (1.1 equiv) in THF at -15 °C,
which was stirred for 30 min and then brought to ambient. To a
solution of 1-bromocyclooctene (12.279 g, 61.7 mmol) in THF
29
biomolecules. However, results presented herein demonstrate
the spontaneous addition of thiols to cyclooctyne in a nonpurged
environment, suggesting that the orthogonality of the strain-
promoted copper-less click reactions may be compromised in
biological media where cysteine and other thiol-containing bio-
molecules are often present.
(
(
62 mL) at -15 °C was added 0.2 M solution of LDA in THF
154.25 mL, 30.85 mmol, 0.5 equiv). Upon completion of LDA
addition, the resultant dark brown solution was stirred for 1 h
and then poured into water (600 mL), extracted with hexanes
(
750 mL in three portions), dried with MgSO , filtered, and
4
concentrated. The crude material was purified by flash chroma-
tography (100% hexanes) to yield a clear, sharp smelling oil (688
mg, 6.4 mmol, 21%). The remaining 1-bromocyclooctene was
Experimental Section
Purchased Materials. Structures of materials used in this
study are shown in Figure 2. Reactants octanethiol, butyl 3-mer-
captopropionate, 1-octyne, propargyl acetate, methyl propargyl
ether, ethyl propiolate, and methyl propargylamine were pur-
chased from Sigma-Aldrich. The internal alkyne, 2-octyne, was
purchased from TCI America. The ultraviolet-active photo-
initiator 1-hydroxycyclohexylphenyl ketone (I184) was obtai-
ned from Ciba Specialty Chemicals. All purchased chemicals
were used as received.
also recovered. R
= 0.36 (100% hexanes, stained with
) δ: 2.19-2.13
f
1
permanganate). H NMR (500 MHz, CDCl
3
(m, 4H), 1.90-1.81 (m, 4H), 1.65-1.58 (m, 4H). GC-MS: m/z
109, 108 (M ), 107, 105, 93, 92, 91, 81, 80, 79 (base), 78, 77, 67,
65, 63, 52, 51, 50, 41.
þ
Cyclooctyne Dimer. When 1-bromocyclooctene was treated
with 1.0 or more equiv of LDA, all in situ formed cyclooctyne
was converted to a species whose molecular weight is twice that
þ
Synthesis of Cyclooctyne. Cyclooctyne was synthesized by a
modified method of Brandsma and Verkruijsse as detailed
below. All reactions were run in flame- or oven-dried glassware
of cyclooctyne, presumably a dimer. GC-MS: m/z 216 (M ),
ꢀ
3
0
201, 187, 173, 59, 145, 147, 145, 134, 131, 119, 117, 105, 93, 92, 91
(base), 79, 77, 67, 51, 41.

Article
Macromolecules, Vol. 43, No. 9, 2010 4115
Figure 3. Conversion of thiols (a) and alkynes (b) for reaction mixtures including 2 M octanethiol and 1 M alkyne: 1-octyne (9), propargyl acetate (4),
2
and methyl propargyl ether(2). Reactionswereinitiatedwith 10 mW/cm lightfiltered at 365nm. All sampleswereprepared with 1 wt% photoinitiator
I184.
Real-Time Fourier Transform Infrared Spectroscopy (FTIR).
FTIR studies were performed on a Nicolet 750 Magna FTIR
spectrometer with a KBr beam splitter and an MCT/A detector
under dry air. Series scans were recorded at a rate of one scan
every 2 s. Thiol conversions were determined by the depletion of
the S-H absorption peak at 2670 cm- . Alkyne conversion was
determined for the terminal akynes by depletion of the C-H
absorption peak at 3100-3200 cm- while internal alkyne con-
version was determined by depletion of the CtC absorption peak
Table 1. Rates of Thiol Depletion (M/min) for Reactions Performed
with Indicated Alkynes at (a) 2 M Octanethiol and 1 M Alkyne or (b) 2
M Each Octanethiol and Alkyne; Participation of the Vinyl Sufide in
a
Cycle 2 of Figure 1 Is Qualitatively Indicated (c)
initial rates initial rates
2
subsequent
2:2 thiols: addition of thiol
1
a
:1 thiols:
alkyne
b
c
alkyne
-octyne
propargyl acetate
methyl propargyl ether
ethyl propiolate
methyl propargylamine 0.026 ( 0.005
2-octyne
cyclooctyne
alkyne
to vinyl sulfide
1
1
4.5 ( 0.3
2.3 ( 0.2
0.68 ( 0.04 0.68 ( 0.04
0.077 ( 0.01
4.4 ( 0.4
2.1 ( 0.1
>5
>5
>5
∼0
-
1
at 2200 cm . Vinyl sulfide peaks (CdC) were identified for
reactions involving ethyl propiolate, methyl propargylamine,
and cyclooctyne and occupied wavenumbers between 1650 and
∼0
-
1
1
700 cm . Samples were placed in a horizontal transmission
0.24 ( 0.03 0.23 ( 0.03
5.4 ( 0.4 6.6 ( 0.4
>5
∼0
apparatus, between sodium chloride windows, and reaction was
initiated with an EXFO Omnicure light source, 100 W Hg arc
lamp, with a 365 nm filter. All reactions were performed with
a
2
All reactions performed with 1% I184 at 10 mW/cm intensity light
filtered at 365 nm.
2
1 wt % I184 initiator and an intensity of 10 mW/cm , measured
with an International Light Inc. radiometer, model IL1400A.
Results and Discussion
Thiol Addition to Terminal Alkynes. It was previously
demonstrated that the thiol-yne copolymerization of penta-
erithrytol tetrakis(mercaptopropionate) (PETMP) and 1,9-
decadiyne proceeds as portrayed in Figure 1 with two thiols
1
1
adding consecutively to a single alkyne. As might be
anticipated, the reaction between 1-octyne and 2 equiv of
octanethiol occurs similarly (Figure 3) with nearly complete
1
1
consumption of both thiols and alkynes. (The relative rates
of consumption of alkynes and their corresponding vinyl
sulfides are addressed explicitly in a subsequent section.)
Furthermore, propargyl acetate and methyl propargyl ether
exhibited the 2 to 1, thiol-to-alkyne reactivity, although at
diminished rates (Figure 3 and Table 1).
Such behavior is not universal to terminal alkynes, how-
ever. Methyl propargylamine and ethyl propiolate both react
with thiols whereas the consecutive addition is not observed.
Figure 4 shows the thiol and alkyne conversions for a 2:1
stoichiometric reaction. It can be seen here that thiols and
alkynes are consumed on an approximately equimolar basis.
Figure 4. Conversion of thiols (open symbols) and alkynes (closed
symbols) for reaction mixtures including 2 M octanethiol and 1 M
alkyne: ethyl propiolate (circles) and methyl propargylamine (squares).
Reactions were initiated with 10 mW/cm light filtered at 365 nm. All
samples were prepared with 1% photoinitiator I184.
2
Unlike with thiol-ene reactions, explaining the diffe-
rences in relative reactivities among the various alkynes in
terms of electron density is problematic. Thiyl radicals, like
oxygen-centered radicals, have an electrophilic character.
Thus, in thiol-ene reactions, addition to electron-rich vinyl
groups is generally favored. For the thiol-yne photoaddi-
tion, such polar effects could explain the slow addition to
ethyl propiolate as the electron-withdrawing carbonyl de-
creases the electron density of the π bonds as has been
(Since the concentration of thiols is twice that of alkynes, this
equimolar consumption is represented with a thiol conver-
sion of approximately half that of alkynes.) No consumption
of the intermediate vinyl sulfide species was observed, indi-
cating failure of both the thiol-ene reaction or the homo-
mpolymerization of the vinyl sulfide intermediate, which, for
the reaction with propiolate, shares a similar structure to
acrylates. Moreover, the rates of reaction were compara-
tively low for photoinitiated addition of thiols to these
terminal alkynes.
1
3
hypothesized previously. Such reasoning, however, fails
to explain why methyl propargylamine, with its electron-rich
amine, reacts even more slowly than does the ethyl propio-
late. It was considered that the basic secondary amine could

4
116 Macromolecules, Vol. 43, No. 9, 2010
Fairbanks et al.
Figure 5. Functional group conversion, (a) thiols and (b) alkynes as a function of time for reaction of octanethiol with 2-octyne (0) and cyclooctyne
2
(
b). Reactant concentrations were 2 M octanethiol and 1 M alkyne. Reactions were initiated with 10 mW/cm light filtered at 365 nm. All samples were
prepared with 1% photoinitiator I184.
potentially deprotonate a fraction of the thiols present and
thus decrease the reaction rate. This hypothesis was dis-
counted by examining IR spectra of defined concentrations
of thiols in the presence and absence of methyl propargyla-
mine (thiols and methyl propargylamin at 2 M each). With a
uniform pathlength, the thiol peak area, corresponding to
the S-H stretch, was not diminished for those samples in the
presence of the amine. Unfortunately, an adequate hypo-
thesis of the factors determining the kinetic effects of polar
substituents remains elusive.
Regardless of the cause for the relative reactivities of
various alkynes toward octanethiol, conclusions can be
made regarding the potential for application in polymer
synthesis. The utility of the thiol-yne reaction is largely
the bireactive character of the alkyne. Since methyl propar-
gylamine and ethyl propiolate lack this feature and the
reactions are relatively slow, the utility of these functional
groups in monomer design is limited, at least under the
experimental conditions examined herein. It is probable that
the use of higher light intensities and more effective initiators
could produce sufficient radicals to drive these less rapid
reactions to forward. However, the respective trends des-
cribed herein would likely persist.
Figure 6. Concentration of cyclooctene sulfide product with respect to
time during exposure of reaction mixture at 2 M octanethiol and 1 M
2
cyclooctyne. Reaction initiated with 1% I184 at 10 mW/cm 365 nm
light.
unsubstituted terminal carbon. For the initial addition to the
cyclooctyne, steric interactions are overcome by the enthal-
pic energy released by the π bond dissolution when the ring-
strained cycloalkyne is converted to a vinyl sulfide. Because a
cyclooctene is not under significant ring strain, such ener-
getic advantages do not aid in the consecutive reaction.
Nevertheless, it is interesting that no reaction is observed
for the cyclooctene sulfide while it is observed for the vinyl
sulfide product of the 2-octyne, thiol addition. The reason
for this behavior, again, may be steric interactions. Follow-
ing the addition of a thiol to the cyclooctyne, the cyclooctene
sulfide is conformationally liberated, which may result in
hindering of the approach of the potentially attacking thiyl
radical by the bulky alkyl cycle.
Thiol Addition to 2-Octyne and Cyclooctyne. The thiol-
yne addition also occurs between thiols and internal alkynes.
Reactions involving internal alkynes differ from the other
terminal alkynes explored herein in terms of both reaction
rates and functionality of the alkyne groups. Thiols add to
2
-octyne much more slowly than to 1-octyne. Unlike the
other less reactive propargylamine and propiolate, however,
the 2-octyne does permit the consecutive additions as
demonstrated by the consumption of two thiols for every
alkyne (Figure 5).
Reaction Orders with Respect to Thiol and Alkyne Con-
centrations. At low conversions, the polymerization rate in a
thiol-yne polymerization is equivalent to the rate of thiol
consumption, which scales to the concentrations of reactants
according to
Conversely, while the addition of a single thiol to a
cyclooctyne is relatively rapid, the subsequent addition does
not measurably occur (Figure 5). It is noted that even
following complete conversion of the cyclooctyne, the thiol
consumption continues to increase, though only marginally
and over extended times. This outcome may be due, in part,
to thiyl radical combination. The vinyl sulfide peak remained
static following complete consumption of the cyclooctyne,
indicating constant concentration and no participation in
additional reactions (Figure 6). The absence of any
d½SHꢀ
R
β
Rp ¼ -
∼½C t Cꢀ ½SHꢀ
ð1Þ
dt
where R and β represent the reaction orders relative to alkyne
and thiol concentrations. Using ethylene glycol diacetate as
an inert diluent, concentrations of octanethiol and the
corresponding alkynes were varied independently to observe
the effect of varying the concentration of a single reactant on
thiol consumption. Regressing a linear fit to the log values of
both the initial reaction rate and the initial reactant concen-
trations provided the values presented in Table 2. It was
1
dithioether was confirmed with H NMR spectroscopy.
The differences in reactivity between 2-octyne and cyclo-
octyne are interesting and merit further investigation. Pre-
sumably, the slow reaction of thiols with 2-octyne and its
corresponding vinyl sulfide is caused by steric interactions.
A single thiol, adding to 1-octyne, adds exclusively to the

Article
Macromolecules, Vol. 43, No. 9, 2010 4117
observed that the reaction was first order with respect to
thiols for the reaction with 1-octyne. This result agrees with
previous experiments on similar reactants. The same rela-
tionship holds for terminal alkynes including propargyl ether
and propargyl acetate which may be the result of vinyl
radical stabilization by the sulfide substituent which would
Here, k is the reaction rate constant for the addition of a thiol
to an alkyne and r is the ratio of the reaction rate constant for
the subsequent thiol-vinyl sulfide addition to the initial
addition. Parameters R, β, γ, and δ are reaction rate orders
for alkynes and thiols participating in the first addition and
vinyl sulfides and thiols participating in the subsequent
addition. Both the sum of R with β and that of γ with δ must
equal one.
For cases in which the initial thiol-alkyne addition is
thiol controlled and the coefficient r is sufficiently greater
than one, the consumption rates of thiols and alkynes
can be expressed as in eqs 5 and 6. Here, at all times,
vinyl sulfide concentration is sufficiently low relative to
thiols that the reaction order γ in eq 2 can be assumed to
be one.
3
1
decrease the rate of chain transfer to another thiol. Such an
explanation does not account, however, for the scaling of the
reaction rate with respect to concentrations of thiols and
cyclooctynes. In this latter case, the reaction rate is 0.4 with
respect to the cyclooctyne and 0.6 with respect to thiol.
Determination of Relative Reaction Rates of Thiol-Yne
and Thiol-Vinyl Sulfide Additions. At any time point, no
observable accumulation of the intermediate vinyl sulfide
occurs for stoichiometric reactions (2:1 thiol:alkyne) bet-
ween 1-octyne and octanethiol, suggesting that the sub-
sequent addition of a thiol to the vinyl sulfide intermediate
is significantly faster than the initial addition of a thiol to the
alkyne (Figure 3). This result confirms previous studies that
quantitatively demonstrated the second addition to occur ∼3
d½SHꢀ
¼
- k½SHꢀ - rk½CdCꢀ
ð5Þ
dt
1
1
times more rapidly than the first. Similarly, no accumula-
tion of vinyl sulfide was observed during the consecutive
additions of two thiols to propargyl acetate, methyl propar-
gyl ether (Figure 3), or 2-octyne (Figure 5), demonstrating
that the increased rate of the second addition is not unique to
radical thiol-yne reactions with terminal, aliphatic alkynes.
For reactions in which the initial concentration of thiol is
twice that of alkyne and proceeds according to the mecha-
nism described in Figure 1, the rates of consumption of
reactants can be described by the following equations:
d½C t Cꢀ
dt
¼
- k½SHꢀ
ð6Þ
As demonstrated in Figure 8a,b, such a model fits the data
obtained for reactions involving 1-octyne, propargyl acetate,
methyl propargyl ether, and 2-octyne. In each of these cases,
the ratio “r” was determined to be greater than 5 by fitting
the model to the experimental data. No improvement of fit
was observed between r=5 and r . 5, establishing a lower
limit for the ratio of reactivities and necessitating that for
each of these ynes the vinyl sulfide consumption is at least 5
times faster than the yne consumption. Previous experiments
in the polymerization of decadiyne and PETMP found the
d½SHꢀ
R
β
γ
δ
¼
- k½C t Cꢀ ½SHꢀ - rk½C ¼ Cꢀ ½SHꢀ
ð2Þ
dt
11
value for the ratio r to be slightly greater than three. The
higher values for r determined here may be explained by the
fact that reaction products here do not form high molecular
weight polymers or networks, perhaps increasing the reac-
tivity of the vinyl sulfide species relative to reactions in which
cross-linked polymers are generated.
d½C t Cꢀ
dt
R
β
¼
- k½C t Cꢀ ½SHꢀ
ð3Þ
ð4Þ
½C ¼ Cꢀ ¼ ½SHꢀ - 2½C t Cꢀ
Table 2. Reaction Rate Orders for the Initial Addition of Thiols to
Alkynes As Determined by Initial Rates Where R = [CtC] [SH]
While it may seem counterintuitive that the addition of a
thiol to the more sterically hindered vinyl sulfide is faster
than the addition of a thiol to a terminal alkyne, this reaction
behavior is consistent with the trends observed for thiol-ene
reactions in which increasing electron density of the alkene
also increases the reaction rate. The sulfide substituent
serves to increase the electron density of the vinyl group. This
characteristic may also be attributable to the higher barrier
r
β
p
alkyne
-octyne
propargyl acetate
R (order in [CtC])
β (order in [SH])
1
0
0
1
1
5,6
methyl propargyl ether
2-octyne
cyclooctyne
0
0
0.4
1
1
0.6
Figure 7. Diaddition of thiol to 2-octyne (a) with vinyl sulfide intermediate and failure of second addition to cyclooctene sulfide (b).

4
118 Macromolecules, Vol. 43, No. 9, 2010
Fairbanks et al.
Figure 8. Concentrations of thiol (O) and alkyne (0) for reactions with 1-octyne (a), 2-octyne (b), and cyclooctyne (c). Solid lines represent the fit of eqs
2-4 with r = 5 for reactions with 1-octyne and 2-octyne and r = 0 for cyclooctyne.
Table 3. Initial Rates of Thiol Consumption with Octanethiol and
Butyl 3-Mercaptopropionate under Similar Exposure Conditions
2
1 wt % I184, 10 mW/cm , 365 nm)
(
initial rate with
butyl 3-mercapto-
propionate
initial rate
with 1-octyne
alkyne
-octyne
propargyl acetate
methyl propargyl ether
methyl propargylamine
1
4.5 ( 0.3
2.3 ( 0.2
0.68 ( 0.04
0.026 ( 0.005
4.6 ( 0.3
2.3 ( 0.1
0.66 ( 0.05
0.029 ( 0.003
energy for isomerization of the vinyl radical relative to the
alkyl radical.
3
2
In contrast to the above situation in which the vinyl sulfide
is more reactive, for cases in which the yne is much more
reactive than the vinyl sulfide (r is much less than one), the
final term of eq 2 becomes zero. Such a model fits the data
obtained for reactions involving cyclooctyne (Figure 8c),
methyl propargylamine, and ethyl propiolate, suggesting
that r, for reactions involving these alkynes, is near zero.
Each of these alkynes support the addition of only a single
thiol (Figures 4 and 5).
Figure 9. Spontaneous addition ofthiols to cyclooctynein an unpurged
environment. Initial concentrations of both octanethiol and cyclo-
octyne were 2 M. No initiator was present. No light exposure was
performed.
spontaneously in the absence of light or a photoinitiator in
an unpurged atmosphere (Figure 9). Similar instabilities
have been observed in thiol-ene monomer mixtures, and
while the precise mechanism of dark initiation is unknown,
presumably, it is the result of reactive oxygen species,
introduced by the diffusion of molecular oxygen into the
reaction mixture. This result suggests that copperless click
reactions performed in biological environments where thiols
may be present are not likely to be completely orthogonal,
but may experience at least some degree of nonspecific
reaction.
Influence of Thiol on Reaction Rate. For these model
studies, a simple aliphatic thiol was chosen for the sake of
simplicity. However, it is noted that increased polymeriza-
tion rates have been observed for thiol-ene photopolymer-
izations performed with mercaptopropionates relative to
5
,6
mercaptoacetates and simple aliphatic thiols.
To examine whether rates could be improved by thiol
selection, experiments were repeated for reactions of
Conclusions
1
-octyne, propargyl acetate, methyl propargyl ether, and
propargylamine with butyl 3-mercaptopropionate replacing
the octanethiol. As shown in Table 3, no statistical difference
in initial reaction rates was observed.
Spontaneous Reaction of Cyclooctyne with Octanethiol. It
was also observed that cyclooctyne and octanethiol reacted
The relatively rapid reaction rates coupled with the bireactivity
of aliphatic terminal alkynes and terminal propargyl esters make
these moieties more advantageous generally for thiol-yne photo-
polymerizations than the other alkynes explored herein. The
reactions of methyl propargyl ether with octanethiol suggest that

Article
Macromolecules, Vol. 43, No. 9, 2010 4119
propargyl ethers share the difunctional characteristics of terminal
aliphatic alkynes, but the utility of such alkyne monomers may be
limited by the slow initial addition of a thiol to the alkyne.
Additionally, the internal alkyne, 2-octyne, is radically reactive
toward thiols, but the rate is substantially slower than that to
terminal aliphatic alkynes, propargyl acetate, and propargyl
ether. While the initial reaction between cyclooctyne and octa-
nethiol is relatively fast, the failure of the consecutive addition
suggests that cyclooctyne by itself is not suitable as a thiol-yne
monomer. Should cyclooctyne monomers prove desirable, how-
ever, cyclooctynes with reactive handles, cyclooctynols, and
cyclooctyneacids havebeensynthesized and would allow dicyclo-
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