The hydrogen atom transfer reactivity of sulfinic acids

Article abstract of DOI:10.1039/C8SC02400F

Sulfinic acids (RSO₂H) have a reputation for being difficult reagents due to their facile autoxidation. Nevertheless, they have recently been employed as key reagents in a variety of useful radical chain reactions. To account for this paradox and enable further development of radical reactions employing sulfinic acids, we have characterized the thermodynamics and kinetics of their H-atom transfer reactions for the first time. The O-H bond dissociation enthalpy (BDE) of sulfinic acids was determined by radical equilibration to be ～78 kcal mol^?1; roughly halfway between the RS-H BDE in thiols (～87 kcal mol^?1) and RSO-H BDE in sulfenic acids (～70 kcal mol^?1). Regardless, RSH, RSOH and RSO₂H have relatively similar inherent H-atom transfer reactivity to alkyl radicals (～10⁶ M^?1 s^?1). Counter-intuitively, the trend in rate constants with more reactive alkoxyl radicals follows the reaction energetics: ～10⁸ M^?1 s^?1 for RSO₂H, midway between thiols (～10⁷ M^?1 s^?1) and sulfenic acids (～10⁹ M^?1 s^?1). Importantly, since sulfinic and sulfenic acids are very strong H-bond donors (αH2 ～ 0.63 and 0.55, respectively), their reactivity is greatly attenuated in H-bond accepting solvents, whereas the reactivity of thiols is largely solvent-independent. Efforts to measure rate constants for the reactions of sulfinic acids with alkylperoxyl radicals were unsuccessful. Computations predict these reactions to be surprisingly slow; ～1000-times slower than for thiols and ～10?000?000-times slower than for sulfenic acids. On the other hand, the reaction of sulfinic acids with sulfonylperoxyl radicals-which propagate sulfinic acid autoxidation-is predicted to be almost diffusion-controlled. In fact, the rate-determining step in sulfinic acid autoxidation, and the reason they can be used for productive chemistry, is the relatively slow reaction of propagating sulfonyl radicals with O₂ (～10⁶ M^?1 s^?1).

Full text of DOI:10.1039/C8SC02400F

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The Hydrogen Atom Transfer Reactivity of Sulfinic Acids
Markus Griesser, Jean-Philippe R. Chauvin & Derek A. Pratt*
Received 00th January 20xx,
Accepted 00th January 20xx
Sulfinic acids (RSO2H) have a reputation for being difficult reagents due to their facile autoxidation. Nevertheless, they
have recently been employed as key reagents in a variety of useful radical chain reactions. To account for this paradox and
enable further development of radical reactions employing sulfinic acids, we have characterized the thermodynamics and
kinetics of their H-atom transfer reactions for the first time. The O-H bond dissociation enthalpy (BDE) of sulfinic acids was
determined by radical equilibration to be ∼78 kcal/mol; roughly halfway between the RS-H BDE in thiols (∼87 kcal/mol)
and RSO-H BDE in sulfenic acids (∼70 kcal/mol). Regardless, RSH, RSOH and RSO2H have relatively similar inherent H-atom
transfer reactivity to alkyl radicals (∼106 M-1 s-1). Counter-intuitively, the trend in rate constants with more reactive alkoxyl
radicals follows the reaction energetics: ∼108 M-1 s-1 for RSO2H, midway between thiols (∼107 M-1 s-1) and sulfenic acids
(∼109 M-1 s-1). Importantly, since sulfinic and sulfenic acids are very strong H-bond donors (αH2 ∼ 0.63 and 0.55,
respectively), their reactivity is greatly attenuated in H-bond accepting solvents, whereas the reactivity of thiols is largely
solvent-independent. Efforts to measure rate constants for the reactions of sulfinic acids with alkylperoxyl radicals were
unsuccessful. Computations predict these reactions to be surprisingly slow; ∼1000-times slower than for thiols and
∼10,000,000-times slower than for sulfenic acids. On the other hand, the reaction of sulfinic acids with sulfonylperoxyl
radicals – which propagate sulfinic acid autoxidation – is predicted to be almost diffusion-controlled. In fact, the rate-
determining step in sulfinic acid autoxidation, and the reason they can be used for productive chemistry, is the relatively
DOI: 10.1039/x0xx00000x
www.rsc.org/
slow
reaction
of
propagating
sulfonyl
radicals
with
O2
(∼106
M-1
s-1).
Introduction
functionalizations (e.g. Figure 1).15 Central to these radical
chain reactions are chain-propagating steps which involve H-
atom transfer (HAT) from a sulfinic acid to a peroxyl radical
(top, Fig. 1), to a peroxyl radical and alkoxyl radical (middle,
Fig. 1) or alkyl radical (bottom, Fig. 1). Rate constants for these
key reactions are unknown;22 data which would greatly enable
further development of reactions utilizing sulfinic acids for
organic synthesis.
Sulfinic acids (RSO2H) are trivalent sulfur oxyacids isoelectronic
with carboxylic acids. Although they are less prominent than
the thiols from which they are derived, and the sulfonic acids
to which they are oxidized, they are useful Brønsted acids and
as precursors to various sulfonate derivatives. One-electron
oxidation of sulfinic acids (or their conjugated bases) yields
2
sulfonyl radicals,1,
important intermediates in industrial
processes (e.g. sulfoxidation to produce surfactants)3 and
synthetic transformations where they often give way to
sulfones via radical additions to double and triple bonds.4-10,11
Sulfonyl radicals are most commonly generated from sulfonyl
halides,5 pseudohalides8 or azides9 by photolysis or
atom/group transfer reactions as part of chain reactions.
Despite the fact that sulfinic acids are widely considered to
be difficult to work with due to their facile autoxidation, the
direct use of sulfinic acids in organic synthesis has recently
gained popularity.12-21 Particularly noteworthy are Lei’s reports
of the use of sulfinic acids for sulfonylation of alkenes12 and
alkynes,13 and Nicewicz’s use of sulfinic acids as catalytic H-
atom donors in photocatalytic anti-Markovnikov alkene
Lei's aerobic sulfinylation of alkenes and alkynes (2013)
HOO
R1
R
O
R1
O
O
O
pyr, CHCl3
45 °C
R
S
R
R
O2
+
+
S
+
+
R2
Ar
HO
R2
R3
O
O
O
pyr, DCE
45 °C
R
S
O2
Ar
S
HO
Nicewicz's photocatalytic anti-Markovnikov alkene hydroacyloxylation (2013)
PhSO2Na
(0.25 eq)
R1
R1
O
H
O
R
+
R
R2
R2
Fukuzumi's acridinium salt
(2.5 mol%)
HO
R3
R3
O
450 nm LEDs
DCE, 23 °C
Figure 1. Examples of recently reported transformations employing sulfinic acids for
group transfer/radical additions.
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Likewise, surprisingly little is known of the stability of Our results provide key information for the development of
sulfonyl radicals relative to other commonly utilized reagents synthetic methodology employing sulfonyl radicals and/or
for addition and/or H-atom transfer in organic synthesis, such sulfinic acids and offer unique insights on the role of secondary
as thiols. The stability of a given radical (e.g. X•) relative to orbital interactions in the reactions of peroxyl radicals, which
another (e.g. Y•) is generally estimated by comparing the X-H are quite significant for sulfenic acids and virtually non-
bond dissociation enthalpy (BDE) to that of Y-H. No definitive existent for sulfinic acids.
sulfinic acid O-H BDE has been reported. To the best of our
knowledge, the first suggestion was made in 1971 (111
kcal/mol),23 but was shortly thereafter revised to be at most
104 kcal/mol.24 Benson later estimated that the phenylsulfonyl
radical should have a similar stability to the benzyl radical (and
therefore a BDE of ca. 90 kcal/mol).25 A subsequent estimate
put the BDE at 73 kcal/mol,26 and a recent calculation
Results
Kinetic and thermochemical experiments were carried out
with phenylsulfinic acid (PhSO2H) (generated from its
commercially-available sodium sulfinate salt) and/or 9-
triptycenesulfinic acid (TrptSO2H), which enables direct
comparison with the analogous 9-triptycenesulfenic acid
suggested 77 kcal/mol.27 Given the central importance of the
•
R• + SO2 equilibrium to the chemistry of sulfonyl
(TrptSOH).28, The 9-triptycenesulfinic acid was prepared as
31
RSO2
ꢀ
•
radicals, knowledge of the inherent stability of RSO2 is highly
desirable.
described in the ESI, in a manner similar to that we recently
described for the synthesis of a fluorinated analog.32
Herein we provide the first experimental determination of
the O-H BDE in sulfinic acids, and report on the kinetics of their
H-atom transfer to alkyl, alkoxyl, and peroxyl radicals. We
compare these results to corresponding data for the
structurally-related sulfenic acids, which have among the
weakest O-H bonds28 and some of the fastest HAT reactions29,
O-H Bond Dissociation Enthalpies of Sulfinic Acids
The radical equilibration EPR (REqEPR) technique33 was
employed to establish a reliable O-H BDE for sulfinic acids. The
approach, depicted in Figure 2A, relies on the equilibration of
persistent radicals – one derived from a precursor whose X-H
BDE is known (the reference compound) and one from the
compound for which the Y-H BDE is desired. The difference in
30
ever reported. We also study the solvent effects on these
reactions, and demonstrate that sulfinic (and sulfenic) acid(s)
engage in strong H-bonding interactions that slow HAT.
Figure 2. (A) The equilibration of the sulfonyl and nitroxyl radicals derived from TrptSO2H/PhSO2H and N-methylbenzhydroxamic acid (NMBHA) enables the derivation
of an O-H BDE for the sulfinic acid. (B) EPR spectrum obtained during the irradiation of a mixture of TrptSO2H and di-tert-butylperoxide in benzene at 298 K. (C) EPR
2 | Chem. Sci., 2018, 00, 1-3
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spectrum of the nitroxide derived from NMBHA. (D) Representative EPR spectrum of the equilibrated radical mixture. (E,F) CBS-QB3-calculated and experimental
BDEs for TrpSO2H and PhSO2H.
the X-H and Y-H BDEs can be estimated directly from the approach employing the 1,2-aryl migration in the
equilibrium constant determined by double integration of the (naphthyl)neophyl radical as the reference reaction (kr = 1.4
EPR signals of the two equilibrated radicals X• and Y•, assuming 104 M-1 s-1 at 25 C).40 The radicals were generated by
×
°
the entropy of the H-atom exchange is negligible.
photolysis of the corresponding Barton ester, and the reduced
Previous EPR studies of sulfonyl radicals24, 34, 35 have been and rearranged products were quantified by GC/MS as a
challenging owing to their rapid disproportionation (e.g. k = 8 function of sulfinic acid concentration to yield the H-atom
108 M-1 s-1 for p-tosylsulfonyl)35 to sulfinyl and sulfonyloxyl transfer rate constant (Figure 3A). Initial experiments in THF
×
radicals. As such, it was hoped that the triptycene substituent yielded kH = (5.2 ± 0.7)
× ×
104 and (8.7 ± 1.8) 104 M-1 s-1 for
in TrptSO2H would impart sufficient persistence to the sulfonyl PhSO2H and TrptSO2H, respectively (Figure 3B) – the order of
radical to enable the REqEPR experiment. Indeed, the room reactivity being consistent with the slightly weaker O-H bond
temperature photolysis of a solution of 9-triptycenesulfinic in TrptSO2H compared to PhSO2H. Given the acidity of the O-H
acid containing t-BuOOt-Bu yielded a broad signal which could bond in sulfinic acids, we anticipated a significant solvent
be ascribed to the 9-triptycenesulfonyl radical (Figure 2B). effect on the H-atom transfer kinetics and therefore sought to
Within seconds, a significantly sharper signal appeared at determine rate constants in a range of H-bond accepting
slightly lower field. Assuming that the latter signal solvents. Unfortunately, the limited solubility of the sulfinic
corresponded to the 9-triptycenesulfinyl radical, which we had acids at the concentrations necessary to afford reliable kinetics
previously characterized to have g = 2.0114,28 the former by the competition method precluded such an endeavor.
signal was centered at g = 2.0053 in good agreement with
previously reported values for sulfonyl radicals.24, 36
Therefore, we also performed direct kinetic experiments by
laser flash photolysis. Cumyl radicals were generated by the
To identify an appropriate reference compound for the photolysis of dicumylketone with the 308 nm emission of a
REqEPR experiment, CBS-QB3 calculations were carried out to nanosecond-pulsed XeCl excimer laser. The rate of decay of
predict the O-H BDEs of each of the phenylsulfinic acid (77.2 the 330 nm absorption of the cumyl radicals was determined
kcal/mol) and 9-triptycenesulfinic acid (76.7 kcal/mol).37 We as a function of sulfinic acid concentration to yield the H-atom
also calculated an O-H BDE of 71.0 kcal/mol for 9- transfer rate constant (Figure 3C). Initial experiments in
triptycenesulfenic acid using the same methodology, which is benzene yielded a rate constant of (1.0 ± 0.2)
×
106 M-1 s-1 for
in excellent agreement with the experimental value of 71.9 PhSO2H (Figure 3D) – consistent with a substantial kinetic
kcal/mol we previously determined using the REqEPR solvent effect when comparing to the data in THF. Additional
technique,28,38 suggesting that oxidation of the sulfur atom has experiments were carried out in isooctane, chlorobenzene,
a relatively modest (∼5 kcal/mol) effect on the O-H BDE. N- and anisole, which revealed a dramatic drop in the HAT rate
Methylbenzohydroxamic acid (NMBHA) was therefore chosen constant with increasing hydrogen bond basicity (Figure 3G).
as the reference compound since its O-H BDE (78 kcal/mol)39 is Plotting the data according to the Ingold-Abraham equation41
similar to the predicted values for the sulfinic acids and the N- that relates H-atom transfer kinetics to solvent H-bond basicity
oxyl radical produced upon H-atom abstraction therefrom is (βH2 ),
persistent (Figure 2C).
Photolysis of a solution of 9-triptycenesulfinic acid and
log kSinh= -8.32αH2 βH2 + log k0inh
NMBHA containing t-BuOOt-Bu yielded spectra consistent with
the superposition of the sulfonyl and N-oxyl radical spectra suggests an H-bond acidity of the sulfinic acid of αH2 = 0.61. The
(Figure 2D). The equilibrium constant was readily determined deviation of the data points obtained by competition kinetics
from these data, but estimation of the sulfinic acid O-H BDE (empty symbols) from the correlation comprised of data points
first required correction of the equilibrium constant for the H- obtained by LFP is consistent with the increased reactivity of
bonding interactions between the sulfinic acid/NMBHA and primary over tertiary alkyl radicals (ca. 10 x).
the t-BuOH used to help solubilize them in benzene (10% v/v)
Corresponding experiments carried out with the sulfenic
– see ESI for the details. The resultant value of 77.6 kcal/mol is acid (in isooctane, chlorobenzene, benzene, and anisole)
in excellent agreement with the CBS-QB3 calculations, and yielded rate constants that were systematically ca. 3-fold
confirms that oxidation of the sulfur atom in a sulfenic acid greater than those of the sulfinic acids (e.g. (2.9 ± 0.4)
×
106 M-
1
raises the O-H BDE by 5 to 6 kcal/mol. Analogous experiments
were carried out with phenylsulfinic acid in benzene, which the Ingold-Abraham equation yields αH2 = 0.57 for the sulfenic
yielded an O-H BDE of 78.3 kcal/mol, again consistent with the acid, in excellent agreement with previous reports (α2H
predictions by CBS-QB3. By comparison, alkylthiols and 0.54).31 The modest difference in the H-atom transfer kinetics
s-1 for TrptSOH in benzene). Plotting these data according to
=
arylthiols have S-H BDEs of 87 and 79 kcal/mol, respectively.
of sulfinic and sulfenic acids is surprising given the ca. 5-6
kcal/mol difference in the experimental O-H BDEs, and may
reflect a more favorable polarization of the H-atom transfer TS
in the case of the sulfinic acid compared to the sulfenic acid,
Reactions with Alkyl Radicals
The kinetics of H-atom transfer from PhSO2H and TrptSO2H to
alkyl radicals were determined using the radical clock
consistent with their pKas (∼
1.9 vs. 12.5, respectively).32
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The HAT transition states (TS) for the reactions of trends. That is, CBS-QB3 predicts a barrier of ∆G‡ = 10.3
representative sulfinic and sulfenic acids are shown in Figure kcal/mol for PhSO2H (corresponding to
3EF. The results are fully consistent with the experimental and
k = 4.1 ×
106 M-1 s-1)
Figure 3. (A) Photolytic generation of the 2-methyl-2-(2-naphthyl)-1-propyl radical and its use as a radical clock to obtain the rate constant for HAT from sulfenic and
sulfinic acids to alkyl radicals. (B) Ratio of reduced (R’H) to rearranged and reduced (R’’H) products as a function of the concentration of TrptSO2H (red) or PhSO2H
(blue) during photocleavage of the radical precursor in THF at 25
first order rate on the concentration of PhSO2H (red) and TrptSOH (black) upon photolysis of dicumylketone in PhCl at 25
radical. (E,F) Calculated (CBS-QB3) transition state structures and associated free energy barriers, estimated rate constants and reaction free energies for HAT
between a model alkyl radical (t-Bu•) and either PhSO2H or
-BuSOH (model for TrptSOH). (G) The HAT rate constants for PhSO2H (red) and TrptSOH (black),
determined via LFP (full symbol) and radical clock (empty symbol) plotted as a function of medium βH2 .
°C. (C) Photolytic generation of cumyl radicals from dicumylketone. (D) Dependence of the pseudo-
°C; inset: example decay of the cumyl
t
∆G t-BuSOH (corresponding to k = 6.0 ×
‡ = 8.7 kcal/mol for 107 Representative results of initial measurements of the reactivity
M-1 s-1). Again, the difference in the kinetics (ca. 15-fold) is of PhSO2H with the benzophenone triplet (3BP) are shown in
relatively modest given the significant difference in the driving Figure 4C. Interestingly, the pseudo first order rate constants
force (∆∆G° = 9.1 kcal/mol).
from the decay traces yielded a non-linear relationship with
sulfinic acid concentration. This suggested that self-association
of the sulfinic acid in H-bonded dimers may retard the rate by
precluding access to the labile H-atom. Indeed, the data could
be easily fit to a non-linear equation accounting for the
contribution of the competing equilibrium that defines the
amount of sulfinic acid available for reaction (Figure 4D). Doing
Reactions with Alkoxyl Radicals
The reaction of sulfinic acids with t-butoxyl radicals has been
used to generate sulfonyl radicals for low-temperature EPR
studies24 (as above for our REqEPR experiments), but the
kinetics of this reaction have never been reported.42 To
provide insight to this reactivity, we chose cumyloxyl radicals
as model species since they possess an absorption at 485 nm.
The cumyloxyl radicals were generated from dicumylperoxide
via laser flash photolysis, and their decay monitored as a
function of sulfinic acid concentration to obtain the desired
rate constants. In addition, kinetics for the reactions of the
sulfinic acids with the triplet state of benzophenone
(monitored at 530 nm) were also determined (Figure 4A). The
benzophenone triplet state has a much higher extinction
coefficient than the cumyloxyl radical, greatly improving the
signal quality. The results are comparable to those obtained
with cumyloxyl radicals since the n → π* state of the carbonyl
so for the data in Figure 4C yielded kH = (1.7 ± 0.3)
and Kd = (6.4 ± 2.2)
10-3 M. Corresponding data obtained with
cumyloxyl radicals under otherwise identical conditions was
ca. 2-fold slower, yielding kH = (6.9 ± 1.3)
108 M-1 s-1.
×
109 M-1 s-1
×
×
Given the retardation of the H-atom transfer from PhSO2H
to 3BP and cumyloxyl by self-association and the foregoing
results with alkyl radicals, it was expected that the H-atom
transfer kinetics would again be highly solvent dependent.
Therefore, our investigations were expanded to include more
(CH3CN, EtOAc) and less (PhCl) H-bond accepting solvents, the
results of which are summarized in Figure 4E. Plotting these
data according to the Ingold-Abraham equation yields α2H
=
0.65, in good agreement with the value of 0.61 derived from
has
a similar electronic structure as alkoxyl radicals.
4 | Chem. Sci., 2018, 00, 1-3
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the alkyl radical kinetic data. The rate constant for the reaction 0.1)
ARTICLE
×
108 M-1 s-1, a factor of
∼
3 greater than that measured for
×
107 M-1 s-1, consistent with its slightly
3
of TrptSO2H with BP was also determined for comparison. In PhSO2H (kH = 6.5 ± 0.2)
CH3CN, where self-association does not contribute, kH = (1.8 ±
Figure 4. (A) Excitation of benzophenone to its triplet state and photolytic generation of cumyloxyl radicals from dicumylperoxide. (B) The HAT rate constants for
PhSO2H (red) and TrptSOH (black) with cumyloxyl radicals plotted as a function of medium βH2 . (C) Dependence of the pseudo-first order rate on the concentration of
PhSO2H upon excitation of BP in benzene at 25
°
C and non-linear fit; inset: example decay of 3BP. (D) Contribution of sulfinic acid dimerization to the observed HAT
3
rate constant. (E) The HAT rate constants for PhSO2H (black), TrptSO2H (red) and TrptSOH (blue), with BP, plotted as a function of medium βH2 (F) Calculated (CBS-
QB3) transition state structures and associated free energy barrier, estimated rate constant and reaction free energy for HAT between a model alkoxyl radical (t-
BuO•) and PhSO2H and
t-BuSOH.
lower O-H BDE, and implying that the triptycene moiety energy barriers are very close; ∆G‡ = 6.6 and 4.7 kcal/mol for
imparts little to no steric effect on its fast HAT activity. PhSO2H and -BuSOH, respectively, corresponding to = 2.4
1010 M-1 s-1, respectively. Obviously, the
t
k
×
For comparison, the kinetics of HAT from TrptSOH to 3BP 109 and 5.3
×
and cumyloxyl were also determined. In benzene, kH = (2.3 ± exergonicity of these reactions is so great (∆G0
= −29.2 and
3
0.1)
× −38.3 kcal/mol, respectively) that the kinetics have converged
respectively. Consistent with the foregoing observations with to be essentially diffusion-controlled.
109 and (1.4 ± 0.2)
×
109 M-1 s-1 for BP and cumyloxyl,
the sulfinic acids, and trends in HAT reactions in general, the
rate constant for HAT to 3BP is slightly greater than for Reactions with Peroxyl Radicals
cumyloxyl. These kinetics were also explored in different
The reactivity of sulfinic acids to peroxyl radicals was explored
via inhibited co-autoxidation of PBD-BODIPY (Figure 5A).44
PBD-BODIPY reports on the reaction progress of the
autoxidation and its consumption is conveniently monitored
by conventional spectrophotometry. Since its reactivity toward
peroxyl radicals has been independently determined (e.g. kPBD-
solvents, revealing a significantly smaller effect than for the
sulfinic acids (see Figures 4E and 4B as well as the ESI) – a
surprising result given the similarity in H-bond acidity of the
sulfenic and sulfinic acids (vide supra). In fact, when the rate
constants for reactions with 3BP and cumyloxyl are plotted
against the solvent H-bond basicity, the Ingold-Abraham
equation predicts αH2 = 0.23 and 0.26, respectively – less than
BODIPY = 3790 M-1 s-1 in 1-hexadecene/chlorobenzene at 37
°C,
see ESI), the inhibition rate constant (kinh) of an added peroxyl
half the value measured directly by IR spectroscopy (α2H
=
radical-trapping antioxidant and the stoichiometry of the
0.54)31 or determined above from the kinetics of reactions
with alkyl radicals (αH2 = 0.57). We surmise that a competing
electron transfer reaction is enabled by the more polar (H-
bond accepting) solvents.43
inhibition reactions (
in Figure 5B.
n) can be easily derived from the data as
Despite extensive experimentation under various conditions
and co-substrates, such as 1-hexadecene and styrene, we were
unable to see any inhibition of autoxidation by the sulfinic
acids, suggesting that they do not efficiently react with the
chain-carrying peroxyl radicals. Representative data are shown
The CBS-QB3-calculated TS structures for HAT from PhSO2H
and t-BuSOH to a model alkoxyl radical (t-butyloxyl) is shown
in Figures 4F. Consistent with experiment, the calculated free
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in Figure 5C, where co-autoxidations carried out in the fast reactions with peroxyl radicals (
presence of PhSO2H and TrptSO2H can be compared to Since sulfonyl radicals are known to readily add to alkenes (e.g.
TrptSOH, which has previously been shown to undergo very for 2-
109 M-1 s-1
k = 3.0 ×
106 M-1 s-1).30
k
=
7×
Figure 5. (A, B) PBD-BODIPY serves as the signal carrier in hydrocarbon autoxidations, enabling determination of rate constants (kinh) and reaction stoichiometries (
for reactions of inhibitors with chain-carrying peroxyl radicals. (C) Co-autoxidations of 1-hexadecene (2.8 M) and PBD-BODIPY (10 M) initiated by AIBN (6 mM) at 37
C (dashed black trace) and inhibited by 10 M of TrptSOH (red), TrpSO2H (blue) PhSO2H (green). (D) The inhibition rate constants for TrptSOH, plotted as a function
n)
ꢀ
°
ꢀ
of medium βH2 . (E-H) Calculated (CBS-QB3) TS structures for HAT between model sulfenic and sulfinic acid and model peroxyl radical (MeOO•) and associated free
energy barriers and rate constants estimated using transition state theory, HOMO visualized. TS structures were confirmed to link H-bonded pre- and post-reaction
complexes by intrinsic reaction coordinate calculations (see Electronic Supporting Information).
vinylnaphthalene),45 which would afford an alkyl radical that than for corresponding sulfenic acids, and as such, consistent
could carry the autoxidation chain, inhibited autoxidations of with our observations that the sulfinic acids are incapable of
substrates lacking a double bond (THF and dioxane) were also inhibiting the co-autoxidations that were carried out.
carried out, but yielded similar results. As expected, the
Insight to the stark contrast in reactivity of the sulfinic and
peroxyl radical-trapping kinetics of the sulfenic acid was highly sulfenic acids is provided upon consideration of the HOMO of
solvent-dependent, yielding αH2 = 0.46 when the data was the transition states which are shown in Figures 5E and F for
plotted according to the Ingold-Abraham relationship (Figure the preferred syn TS and in Figures 5G and H for the anti TS.
5D), consistent with previous reports.31
Although there is clearly overlap between the π* of the
To provide insight on the lack of reactivity of the sulfinic peroxyl radical and the lone pair of the sulfur atom that leads
acids to peroxyl radicals, we calculated the transition state to the preference for the syn TS in the reactions of both the
structures for the reactions of
model peroxyl radical (methylperoxyl). Two structures were sulfinic acid (ꢁꢁG‡ = 2.7 kcal/mol) compared to the sulfenic
identified for each system (Figures 5E-H), one wherein the acid (ꢁꢁ
‡ = 5.1 kcal/mol), presumably due to the lower sulfur
t-BuSO2H and t-BuSOH with a sulfinic and sulfenic acids, this interaction is smaller in the
G
substituents on the oxygen atoms between which the H-atom lone pair energy in the sulfinic acid. Indeed, natural bond
is transferred are oriented anti with respect to one another, orbital analyses indicate that the interaction energy of the
and the other wherein they are syn. The syn TS structures sulfur lone pair and peroxyl radical π* drops from 3 kcal/mol in
were significantly lower in energy in both cases and, consistent the syn TS of the sulfenic acid reaction to 0.4 kcal/mol in the
with the experimental observations, the predicted barriers for syn TS of the sulfinic acid reaction.
the reaction of
t-BuSO2H were much higher than those for
t-
In addition to the foregoing efforts, we performed transient
BuSOH. These results suggest that the inhibition rate constants absorption spectroscopic experiments to directly monitor the
for sulfinic acids are roughly seven orders of magnitude lower reaction of peroxyl radicals with sulfinic acids. The cumyl
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radicals generated from photolysis of dicumylketone (see comparatively poor H-atom donors to thiols in good H-bonding
above) were used to produce cumylperoxyl radicals simply by solvents. Thus, sulfinic acids are expected to be useful as H-
carrying out the photolysis under an atmosphere of O2. atom transfer agents only in non-H-bonding solvents;54
Although cumylperoxyl radicals do not exhibit
a visible otherwise, thiols are likely to be a much better choice. Indeed,
absorption – precluding observation of their decay in the Lei’s TOCO-like reaction and Nicewicz’s use of sulfinic acids as
presence of sulfinic acids – the product sulfonyl radicals absorb catalytic H-atom donors in photocatalytic alkene
at 350 nm. Nevertheless, the data acquired over a wide range functionalizations are optimal in weak H-bond accepting
∼
of concentrations (validated through comparing with the chlorinated hydrocarbons (βH2 0.15).55
equivalent alkyl radicals – see ESI for conditions), suggested no
To complete the sulfur oxyacid series, we used CBS-QB3 to
sulfonyl radical formation on the timescale of the experiment.
predict the O-H BDE in a sulfonic acid. The computed result of
107.4 kcal/mol for
t-BuSO3H underscores why these
compounds are unreactive to any of the radicals we have
investigated here. For ease of reference, a summary of our
results is presented in Figure 6.
Discussion
Thiols, the precursors to both sulfenic and sulfinic acids,32, 46, 47
are eminently useful H-atom transfer agents,48 serving as
In light of the similar inherent reactivity of thiols, sulfinic
acids and sulfenic acids to alkyl and alkoxyl radicals, the
difference in the peroxyl radical reactivity between thiols and
sulfenic acids (> 4 orders of magnitude) is quite significant. In
one sense, this is intuitive given that the reactions are far less
terminal (stoichiometric) reductants in
a
number of
transformations, including the thiol-ene coupling49, 50 and its
aerobic counterpart, the TOCO reaction.51,
We recently
52
showed that the oxidation of a thiol to a sulfenic acid32 renders
it a better H-atom donor – on thermodynamic grounds (i.e.
exergonic (e.g. compare
reactions of sulfenic acids and thiols with peroxyl radicals
versus 34 and 18 kcal/mol for reactions of sulfenic
ꢁG° ∼ −16 and ∼0 kcal/mol for
alkyl sulfenic acid SO-H BDE
∼
70 kcal/mol vs. alkyl thiol S-H
107 M-1 s-1 for
BDE k ∼
∼
87 kcal/mol)31 and kinetic grounds (e.g.
ꢁ
G
°
=
−
−
reactions of alkyl sulfenic acids with peroxyl radicals vs. <103
M-1 s-1 for alkyl thiols).30 However, the greater stability of the
sulfinyl radicals precludes useful chemistry. To the best of our
knowledge, there is no equivalent of the thiol-ene coupling or
TOCO reaction with a sulfenic acid, although these could be
very useful reactions! In the preceding pages we have
expanded our previous studies to show that, despite their
significantly weaker bonds, sulfenic acids are only slightly more
inherently reactive towards alkyl and alkoxyl radicals
compared to thiols. Moreover, because sulfenic acids are such
acids and thiols with primary alkyl or alkoxyl radicals).
However, previous work from our group31, 56, 57 suggests that
there is more to it; specifically, that HAT to peroxyl radicals is
enabled by secondary orbital interactions, wherein filled π or
non-bonding orbitals on the group attached to the atom from
which the H-atom is being transferred interact with the
proximal end of the peroxyl radical π
* MO.73 Upon oxidation of
the electron-rich sulfur atom in the sulfenic acid to a sulfinic
acid, this secondary orbital interaction is expected to be
significantly reduced. Indeed, our calculations predict that the
sulfinic acid is not only less reactive to peroxyl radicals than
the sulfenic acid, but is even less reactive than thiols, despite
significantly more favourable reaction energetics (of ca. 10
kcal/mol). Moreover, both PhSO2H and TrptSO2H were
incapable of inhibiting the autoxidation of styrene and 1-
hexadecene, substrates whose autoxidation is propagated by
peroxyl radicals.58
good H-bond donors (α2H
∼0.55) they react more slowly than
thiols (αH2 0-0.1)53 in good H-bond accepting solvents.
∼
Further oxidation of the sulfenic acid to a sulfinic acid
enables production of the more reactive sulfonyl radical that
can be used for productive chemistry. Indeed, Lei and co-
workers recently demonstrated the sulfinic acid equivalent of a
TOCO reaction,12 in another example that sulfinic acids are
gaining in popularity. The foregoing results enable us to place
the reactivity of sulfinic acids into proper context; the alkyl
At first glance, the poor HAT reactivity of sulfinic acids
toward peroxyl radicals would seem to be the best evidence to
date that secondary orbital interactions contribute to the
reactivity of good peroxyl radical-trapping agents (i.e.
antioxidants). However, it must be acknowledged that there is
another explanation for the lack of inhibition of the
autoxidation: the sulfinic acids themselves autoxidize. This has
sulfinic S(O)O-H BDE ∼78 kcal/mol infers that the stability of
the sulfonyl radical is roughly midway between that of thiyl
and sulfinyl radicals. Nevertheless, sulfinic acids are similarly
inherently reactive to both alkyl and alkoxyl radicals as sulfenic
acids and thiols. Importantly, like sulfenic acids, sulfinic acids
are excellent H-bond donors (αH2 ~0.63), and as such, they are
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Figure 6. Comparison of H-atom transfer thermochemistry and kinetics for thiols and each of the thiol-derived sulfur oxyacids.
The rate constant for the reaction of sulfonyl radicals with O2
been noted to be particularly facile in water,59 where it is likely
has been reported to be 1
×
109 M-1 s-1 in water/MeOH.61 If the
to be initiated and propagated by electron transfer reactions,
eventually producing a sulfonate:
reaction were this fast in organic solvent, reactions involving
sulfonyl radicals would be impossible under aerobic
conditions.12, 13, 17 For example, under the reaction conditions
developed by the Lei group for oxidative functionalization of
alkynes,13 both the addition of sulfonyl radicals and the
•−
RSO2− + O2
RSO2• + O2
ꢀ
ꢀ
RSO2• + O2
RS(O)2OO•
(1)
(2)
(3)
(4)
addition of oxygen would have effective rates of around 1×
107
s-1. Therefore, yields of 80% would be impossible, since the
sulfinic acid (present in excess) would simply autoxidize.
Surprisingly, there is no data for the reaction of sulfonyl
radicals with O2 in the non-aqueous solvents in which synthetic
organic transformations are generally carried out. Moreover,
RS(O)2OO• + RSO2− ꢀ RS(O)2OO− + RSO2
•
RS(O)2OO− + RSO2− ꢀ 2 RSO3
−
There is also precedence for sulfinic acid autoxidation in non-
polar organic solvents,60 which presumably propagates via H-
atom transfer in lieu of electron transfer (In• is an arbitrary
initiating radical):
•
there are no data on the position of the RSO2 /O2 equilibrium
and the H-atom abstraction from
sulfonylperoxyl radical.
a sulfinic acid by a
To provide some insight on the rate and equilibrium
•
position of RSO2 /O2 in organic solvents, we carried out
•
In• + RSO2H
RSO2• + O2
RS(O)2OO• + RSO2H
RS(O)2OOH + RSO2H
ꢀ
RSO2
(5)
(6)
(7)
(8)
additional CBS-QB3 calculations. The addition of oxygen to
•
•
MeSO2 and PhSO2 is predicted to be exergonic by 2.9
kcal/mol, with barriers of ∆G‡ = 11.0 and 10.0 kcal/mol,
ꢀ
RS(O)2OO•
RS(O)2OOH + RSO2
2 RSO3H
corresponding to rate constants of
k = 2.8 × ×
106 and 1.4 107
•
ꢀ
M-1 s-1, respectively, at 37 °C.62 These results suggest that
water and/or protic solvents accelerate the reaction and
increase the driving force – perhaps due to stronger H-bonding
interactions in the product sulfonylperoxyl than the starting
sulfonyl.
ꢀ
Presented in this way, sulfinic acid autoxidation is analogous to
aldehyde autoxidation, which eventually yields carboxylic acid
via Baeyer-Villiger oxidation of aldehyde with the autoxidation
product peracid.
Interestingly, if the sulfonylperoxyl radical forms, it is
predicted to be extremely reactive; the calculated barrier for
H-atom abstraction from MeSO2H by MeS(O)2OO• is predicted
be ∆G‡ = 7.0 kcal/mol, corresponding to a rate constant of 1.9
The increasing popularity of sulfinic acids (and/or their
corresponding sulfinate salts) to carry out sulfonylations of
multiple bonds or serve as a terminal reducing agent is
surprising in light of their purported facile autoxidation. The
autoxidation depends on the rate and equilibrium position of
eq 6 as well as the follow-up H-atom transfer reaction (eq 7).
×
109 M-1 s-1. This would lead to very fast consumption of
sulfinic acid.63 Recall, the predicted barrier for H-atom
abstraction from MeSO2H by MeOO• is nine orders of
magnitude slower!
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To corroborate these predictions, we photolyzed
toluenesulfonyl iodide in benzene and monitored the decay of indicated otherwise. High-resolution mass spectra were
the -toluenesulfonyl radical at 350 nm in the presence and obtained on a Kratos Concept Tandem mass spectrometer (EI)
absence of O2. Under an atmosphere of N2, the tosyl radicals and Micromass Q-TOF (ESI). TrptSO2H, PhSO2H and
decayed with = (7.3 ± 0.5)
108 M-1 s-1, consistent with the dicumylketone were synthesized as described in the ESI.
p-
spectrometer at 400 MHz and 101 MHz, respectively, unless
p
k
×
kinetics of their disproportionation to sulfinyl and sulfonyloxyl TrptSOH,28 PBD-BODIPY,31 STY-BODIPY,44 NMBHA,67 tosyl
radicals obtained by EPR.35 The tosyl radicals decayed at a iodide,68 as well as the GC standards for the alkyl radical clock
greater rate when analogous experiments were carried out kinetics69 were synthesized following previously reported
under an air atmosphere, yielding an apparent rate constant of procedures. Chlorobenzene was dried over 3 Å molecular
k
= (1.0 ± 0.2)
superposition of the disproportionation and O2 addition anhydrous or HPLC quality. UV-visible spectra were measured
reactions, a rate constant for the latter can be estimated to be with Cary 100 spectrophotometer equipped with
= (9 ± 4)
105 M-1 s-1, in remarkably good agreement with thermostatted 6 x 6 multi-cell holder.
×
109 M-1 s-1. Assuming this rate constant is the sieves before use. Solvents for kinetics experiments were of
a
a
k
×
the value predicted by CBS-QB3, and most importantly, >1000-
fold slower than in aqueous solution.64 With a rate constant in Radical Equilibration EPR (REqEPR)
this range, typical propagating reactions of sulfonyl radicals
Electron paramagnetic resonance (EPR) spectra were recorded
on a Bruker EMXplus (X-band) spectrometer equipped with an
ER 4119HS cavity. The (composite) spectra were fitted and the
radical concentration was determined using the quantitative
EPR package of the Bruker Xenon software. The full procedure
to determine thermodynamic data can be found in the ESI. To
generate the radicals 5% (v/v) di-tert-butyl peroxide was
(e.g. addition to double and triple bonds,
1 45 can compete effectively with oxygen addition, which under
k
= 107 – 109 M-1 s-
)
typical synthetic conditions65 translates to a difference of 3 –
3.5 orders of magnitude in reaction rates.66 An indication that
optimized synthetic procedures depend strongly on these
kinetics is highlighted by the significant drop in yield (>50%)
that is observed upon switching from an air atmosphere to
exclusively O2.13
added to the solutions in benzene (with or without 10% v/v t-
BuOH) under nitrogen and the EPR cavity irradiated with a
Hamamatsu LC5 Hg−Xe lamp (150 W) via a 5 mm light guide.
REqEPR experiments with sulfonyl radicals were performed
under continuous irradiation.
Conclusions
Sulfinic acids are very good H-atom donors leading to highly
reactive sulfonyl radicals which have a wide range of synthetic
applications. This activity is quite similar to sulfenic acids
Laser Flash Photolysis
Nanosecond transient absorption experiments were
performed on an LFP-112 spectrometer (Luzchem, Canada).
Irradiation source was an EX10 (GAM Laser, USA) XeCl Excimer
laser (308 nm, ca. 10 mJ/pulse, ca. 12 ns pulse width). The
transient absorption data were recorded in a quartz cuvette (1
cm x 1 cm) equipped with a septum. Sample concentrations
were adjusted to yield an absorbance of 0.2-0.3 at 308 nm and
the solutions were bubbled with nitrogen for 10 minutes
before measurement. The rate constants for hydrogen
abstraction (kH) were determined in pseudo-first-order
although because of their increased BDE of
kcal/mol they are typically slightly slower at 2
alkyl and 5
108 M-1 s-1 vs. alkoxyl radicals. A surprising
∼
78 (vs. 70)
×
106 M-1 s-1 vs.
×
property is the slow reaction of sulfinic acids with peroxyl
radicals, which could not be measured but calculated at < 103
M-1 s-1, displaying the effect a change in orbital electronics can
have on reactions that are enhanced via secondary orbital
interactions. An additional disadvantage of sulfinic acids is
their tendency to autoxidize, facilitate via the addition of
oxygen to sulfonyl radicals. Although this has not deterred
recent synthetic endeavours as the reaction seems to be
greatly enhanced in water (polar solvents) and thus is slow
according to the following equation kobs
= k0 + kH[H-Donor].
Competition Kinetics
enough in organic solvents (at ∼1 ×
106 M-1 s-1) to enable these
Alkyl radical clock kinetics was determined using a previously
reported procedure by Valgimigli and co-workers.40 The PTOC
ester synthesis is described in the ESI and the standards were
synthesized as described previously.69 Briefly, vials were
loaded with the appropriate amount of sulfinic acid (150-400
mM) and capped with a septum. THF (950 µL) was added
followed by 1 eq of methanesulfonic acid and the vials were
wrapped in aluminum foil before adding the PTOC ester clock
(20 mM). The vials were purged with nitrogen and the
aluminum foil was removed before the vials were exposed to a
sodium lamp (400 W) at a distance of 40 cm for 1 h at room
temperature (ca. 25°C). Aliquots of 50 μL were taken from
each vial and added to a GC vial containing hexylbenzene
standard solution (50 µL, 40 mM). The solution was diluted by
reactions to proceed. Similar to sulfenic acids, the more
oxidized sulfinic acids also show high H-bond acidity and
therefore a very large modulation of their HAT activity in
different solvents. This should be taken into account when
employing them in catalytic and/or chain reactions.
Experimental Section
General
Reagents were obtained from commercial suppliers and used
as is, unless indicated otherwise. Column chromatography was
1
carried out with 40-63 μm, 230-400 mesh silica gel. H and 13C
NMR spectra were recorded on
a
Bruker AVANCE
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Chemical Science
adding 900 μL of acetonitrile for a total volume of 1 mL per
vial. The samples (4 μL splitless injections) were analyzed by a
GC−MS equipped with an Agilent HP-5 ms column (30 m × 0.25
mm × 0.25 μm) with a constant He flow of 1.1 mL min−1 using
the following temperature profile (inlet temperature was set
at 150 °C): 90 °C, hold 1 min, 2 °C min−1 to 120 °C, hold 1 min, 5
°C min-1 to 165 °C, hold 1 min, 20 °C min-1 to 300, hold 5 min.
The method yielded retention times of 10.9, 22.9, 23.4, and
25.4 min for hexylbenzene, 2-tert-butylnaphthalene, 2-
isobutylnaphthalene, 2-(2-methylallyl)naphthalene and 2-(2-
methylprop-1-en-1-yl)naphthalene, respectively.
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M
=
Calculations
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basis set method71 as implemented in the Gaussian 16 suite of
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Conflicts of interest
21.
22.
There are no conflicts to declare.
Such as was the case for the O-H BDE, only an estimate
exists for the rate constant for the H-atom transfer from
sulfinic acid to alkyl radicals. Gilbert and co-workers had
Acknowledgements
estimated
k ∼
106 M-1 s-1 for the reaction of
This work was supported by grants from the Natural Sciences
and Engineering Research Council of Canada and the Canada
Foundation for Innovation and through generous access to the
computational resources of the Centre for Advanced
Computing (cac.queensu.ca). JPC acknowledges the support of
the Ontario Graduate Scholarships program.
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sulfinic and sulfenic acids: the phenylthiyl radical - for
further details see the ESI.
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s−1).36
ET reactions are more facile in more polar solvents, and
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atom at the other bridgehead position such that the
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65.
Chemical Science
[Substrate (alkene or alkyne)] = 50 mM and [oxygen] = 2-7
mM
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It is very difficult to definitively tease out whether these
types of reactions should be described as a HAT or
proton-coupled electron transfer (PCET). However, simply
considering the TS geometries in Figure 5, the authors are
inclined to describe them as HAT-like. Since both the
sulfinyl/sulfonyl and peroxyl radicals are π radicals, a HAT
TS would feature the H-atom moving along a coordinate
that is orthogonal to the planes made up by the carbon,
sulfur and oxygen of the sulfinyl/sulfonyl radical and the
carbon, oxygen and oxygen of the peroxyl radical. In
contrast, in a purely PCET process, the proton and
electron are, by definition, transferred between different
pairs of (nominally orthogonal) orbitals; the proton
between the lone pairs on the terminal oxygen atoms of
the sulfinyl/sulfonyl and peroxyl radicals and the unpaired
electron is delocalized across both π* orbitals. The
predicted structures are more consistent with the former
description than the latter. This is perhaps easiest to see
in the SOMOs, where there is a node on the H-atom (see
Supporting Information).
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