Understanding Chemoselectivity in Proton-Coupled Electron Transfer: A Kinetic Study of Amide and Thiol Activation

Article abstract of DOI:10.1021/jacs.9b08398

While the mechanistic understanding of proton-coupled electron transfer (PCET) has advanced significantly, few reports have sought to elucidate the factors that control chemoselectivity in these reactions. Here we present a kinetic study that provides a quantitative basis for understanding the chemoselectivity in competitive PCET activations of amides and thiols relevant to catalytic olefin hydroamidation reactions. These results demonstrate how the interplay between PCET rate constants, hydrogen-bonding equilibria, and rate-driving force relationships jointly determine PCET chemoselectivity under a given set of conditions. In turn, these findings predict reactivity trends in a model hydroamidation reaction, rationalize the selective activation of amide N-H bonds in the presence of much weaker thiol S-H bonds, and deliver strategies to improve the efficiencies of PCET reactions employing thiol co-catalysts.

Full text of DOI:10.1021/jacs.9b08398

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Communication
Understanding Chemoselectivity in Proton-Coupled Electron
Transfer: A Kinetic Study of Amide and Thiol Activation
Guanqi Qiu, and Robert R Knowles
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08398 • Publication Date (Web): 01 Oct 2019
Downloaded from pubs.acs.org on October 5, 2019
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Journal of the American Chemical Society
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Understanding Chemoselectivity in Proton-Coupled Electron Trans-
fer: A Kinetic Study of Amide and Thiol Activation
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Guanqi Qiu and Robert R. Knowles*
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
Supporting Information Placeholder
activation under the reaction conditions, and the thiophenol S–H
ABSTRACT: While the mechanistic understanding of proton-
bond (BDFE ~ 79 kcal/mol)5 is significantly weaker than the sub-
coupled electron transfer (PCET) has advanced significantly, few
strate amide N–H bond (BDFE ~ 99 kcal/mol).6 Accordingly, one
reports have sought to elucidate the factors that control chemose-
might expect that the thiophenol would inhibit the desired N–H ox-
idation reaction by sequestering the Ir/phosphate catalysts in a
highly favorable, but unproductive, PCET process. However, com-
petitive luminescence quenching studies in a model system re-
vealed a rate law for deactivation of the Ir excited state that exhib-
ited a first-order concentration dependence on the amide and phos-
phate and a zero-order dependence on the concentration of thiol
(Scheme 1).3a Efficient and selective amide activation in opposition
to such a large thermodynamic bias raises intriguing questions
about the physical origins of MS-PCET selectivity in these sys-
tems.
lectivity in these reactions. Here we present a kinetic study that pro-
vides a quantitative basis for understanding the chemoselectivity in
competitive PCET activations of amides and thiols relevant to cat-
alytic olefin hydroamidation reactions. These results demonstrate
how the interplay between PCET rate constants, H-bonding equi-
libria, and rate-driving force relationships jointly determine PCET
chemoselectivity under a given set of conditions. In turn, these
findings predict reactivity trends in a model hydroamidation reac-
tion, rationalize the selective activation of amide N−H bonds in the
presence of much weaker thiol S−H bonds, and deliver strategies
to improve the efficiencies of PCET reactions employing thiol co-
catalysts.
Scheme 1. MS-PCET chemoselectivity relevant to catalytic
hydroamidation reactions
Useful synthetic methods exhibit reliable selectivities, enabling
users to confidently predict reaction outcomes in complex settings.
To this end, we have recently become interested in trying to under-
stand the features governing chemoselectivity in multi-site proton-
coupled electron transfer (MS-PCET) reactions. Oxidative MS-
PCET reactions are redox processes wherein protons and electrons
are exchanged between a substrate and two independent molecular
acceptors – a Brønsted base and one electron oxidant – in a con-
certed elementary step. Similar to related hydrogen-atom transfer
(HAT) reactions,1 prior kinetic studies have shown that MS-PCET
processes generally exhibit linear rate-driving force relationships,2
suggesting that abstraction selectivity should track with bond
strength differential with weaker bonds to hydrogen reacting pref-
erentially. These quantitative insights reinforce a common intuition
that homolytic activation of very strong bonds (BDFEs ≥ 100
kcal/mol) is generally not practical when much weaker bonds to
hydrogen (BDFEs ≤ 80 kcal/mol) are also present.
Previous work: PCET competition studies between amides and thiols
O
*IrIII
*IrIII
O
Ph
PhS
H
PhS
Ph
N
H
Me
N
Me
(BuO)2P(O)O
(BuO)2P(O)O
amide PCET
thiol PCET
BDFEN-H ~ 99 kcal/mol
BDFES-H ~ 79 kcal/mol
Experimental rate law for luminescene quenching:
d[*Ir]/dt = [amide]1[phosphate]1[thiol]0
What are the origins of selective amide PCET activation in
opposition to such a large thermodynamic bias?
This work: Kinetic characterization of amide and thiol PCET reactions
hydrogen bonding
equilibria
rate-driving force
relationships
PCET rate
constants
We recently observed a curious exception to this principle in
the development of a catalytic method for alkene hydroami-
dation.3a, 3b In these reactions, which were subsequently studied in
detail by Nocera and coworkers,3c a substrate amide N–H bond en-
gages in a concerted MS-PCET reaction with an excited-state Ir(III)
oxidant and a dialkyl phosphate base to furnish a reactive amidyl
radical. Subsequent addition of the amidyl to a pendant olefin cre-
ates a new C–N bond and a vicinal carbon-centered radical that is
then reduced by HAT from a thiophenol co-catalyst to form the
closed-shell product. A surprising aspect of this reaction relates to
the selectivity of the initial MS-PCET step. Both amides3 and thi-
ols4 were demonstrated to be competent substrates for MS-PCET
• Quantitative basis for understanding PCET chemoselectivity
• Application to predicting performance in catalytic
PCET-based hydroamidation reactions
Here we present a kinetic study of both amide and thiol PCET
activations that sheds light on this surprising selectivity. These ex-
periments demonstrate that both pre-equilibrium hydrogen bonding
and the sensitivity of the rate-driving force relationship for each
substrate class plays a key role in determining PCET selectivity un-
der a given set of conditions. In turn these findings provide insights
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Page 2 of 6
into potential pitfalls associated with PCET-based catalysis with
excited state oxidant. The PCET rate constants and H-bonding
equilibrium constants for both the amide and thiol series are pre-
sented in Table 1 and the corresponding rate-driving force correla-
tions are shown in Figure 2.9
1
2
3
4
thiol H-atom donors, as well as actionable strategies to overcome
them. The details of these investigations and their applications to
predicting reactivity trends in a catalytic hydroamidation reaction
are described herein.
These results provide a compelling explanation for selective amide
activation in the competitive luminescence quenching studies dis-
cussed above, as seen through comparison of the data for PCET
activation of (A1) and (T1) by Ir-1 and the phosphate base. Sur-
prisingly, the rate constants for PCET with both A1 (8.4 x 109 M-
1s-1) and T1 (9.5 x 109 M-1s-1) approached the diffusion limit in
DCE (~1 x 1010 M-1s-1).10 However, the KA values indicated that the
amide forms a more favorable hydrogen-bonded complex (KA =
1050 M-1) with the phosphate base than the thiol does (KA = 200 M-
1), ensuring that the concentration of the reactive amide-phosphate
H-bond complex in solution is significantly higher than that of the
competing thiol-phosphate complex. As both elementary steps oc-
cur with similar rate constants, the thiol reaction is unable to take
advantage of the additional 20 kcal/mol of driving force, and the
resulting selectivity is gated by the relative concentration of the re-
active H-bonded complexes in solution. Based on the KA and kPCET
values obtained, the relative rates for amide and thiol activation at
the concentrations of the synthetic hydroamidation reactions is ~
50:1, consistent with the previously determined rate law for lumi-
nescence quenching.3a
5
6
7
8
Table 1. Kinetic and H-bonding equilibrium data
kPCET
(M-1s-1)
ΔG°'PCET
BDFEN-H/S-H
(kcal/mol)6,8
amide
/thiol
entry
*Ir(III)
KA (M-1)
(kcal/mol)
9
1
2
3
4
5
6
7
8
98.9
98.9
1050
1050
3550
3550
1390
1390
1500
1500
8.4
10.9
11.3
13.8
11.2
13.7
9.7
8.4x109
1.1x109
9.3x108
6.8x107
9.3x108
7.5x107
3.0x109
1.8x108
9.5x109
3.6x109
1.0x1010
7.0x109
4.0x109
1.0x109
8.3x109
2.2x109
A1
A1
A2
A2
A3
A3
A4
A4
Ir-I
Ir-2
Ir-I
Ir-2
Ir-I
Ir-2
Ir-I
Ir-2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
101.1
101.1
101.6
101.6
100.0
100.0
12.2
T1
T1
T2
T2
T3
T3
T4
T4
Ir-I
Ir-2
Ir-I
Ir-2
Ir-I
Ir-2
Ir-I
Ir-2
9
79.1
79.1
76.9
76.9
84.0
84.0
81.3
81.3
200
200
44
44
5600
5600
2150
2150
-12.4
-9.8
-15.6
-13.0
-5.5
-3.0
-8.8
-6.3
10
11
12
13
14
15
16
CN
O
CF3
O
COMe
O
O
Ph
Me
N
H
Me
N
H
Me
N
Me
N
H
H
A4
A3
A1
A2
T2
F
F3C
SH
F
F
SH
SH
SH
F
MeO
CF3
F
T3
T1
T4
F3C
F3C
F
F
t-Bu
N
N
N
N
N
N
F
F
F
F
IrIII
IrIII
N
N
t-Bu
F
F
F3C
F3C
Ir-1
[Ir(dF(CF3)ppy)2(bpy)]PF6
E1/2(Ir*III/II) = +0.94 V vs. Fc+/Fc
Ir-2
[Ir(dF(CF3)ppy)2(dtbpy)]PF6
E1/2(Ir*III/II) = +0.83 V vs. Fc+/Fc
Oxidative MS-PCET reactions typically occur through hydrogen-
bonded complexes between the substrate E–H bond and the
Brønsted base.7 As such, the free energy profiles of these reactions
are determined by both the kinetic barrier for the PCET event and
the favorability of forming the reactive hydrogen-bonding com-
plex, as illustrated in Figure 1. Based on this understanding, we
studied the PCET reactions of four N-aryl amides (A1 – A4) and
four aryl thiols (T1 – T4), mediated by two distinct Ir(III)-based
photooxidants (Ir-1 and Ir-2) and a dibutyl phosphate base
(NBu4OP(O)(OBu)2) in 1,2-dichloroethane (DCE) at room temper-
ature (Table 1). The hydrogen bonding equilibrium constant (KA)
for association with the phosphate base and the PCET rate constant
for oxidation of this H-bonded complex (kPCET) were determined
simultaneously for both the amide and the thiol series via a simple
luminescence quenching method we recently described in a study
of ketone PCET activation.2c This method enabled us to evaluate
the sensitivity of the reaction rates to changes in driving force as-
sociated with varying either the substrate or the potential of the
Figure 1. Free energy surface for the MS-PCET activation of am-
ides and thiols.
Evaluating a series of amide and thiol substrates with less favor-
able driving forces enabled us quantify the rate-driving force rela-
tionship for each substrate class outside of the diffusion-limited re-
gime. Linear rate-driving force correlations were observed for both
reactant classes. The amide series exhibited rate constants compa-
rable to those obtained previously by Nocera,3c and a Brønsted
slope (a) of 0.53, similar to the value expected from Marcus the-
ory.11 However, the thiol series exhibits a much shallower depend-
ence (a = 0.10), indicating a difference in intrinsic barriers for the
two sets of substrates.12,13 This value is similar in magnitude to the
small Brønsted slope observed in our previous study of PCET acti-
vations of ketones that was attributed to non-perfect synchroniza-
tion (NPS),2c wherein factors that serve to stabilize the product are
only partially realized at the transition state.14 Mayer and
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Journal of the American Chemical Society
coworkers recently proposed a similar NPS-based explanation for
The reactions in the upper portion of Table 2 are divided into three
groups. Within each group, a single thiol is employed, while the
identities of the amide and oxidant are varied. Notably, in all cases
the reaction yields were found to trend together with the Q0 values.
The mass balance for reactions that did not reach full conversion
was comprised predominantly of recovered starting material. Fur-
ther evidence that PCET chemoselectivity had a direct impact on
reaction outcomes could be found in entry 9, which reached a reac-
tion endpoint of 60% yield and 30% recovery after 12 hours. How-
ever, adding a second equivalent of starting material after 12 hours
(and thus re-raising the Q value above the critical threshold) re-
sulted in restored hydroamidation reactivity and an additional 36%
yield of product formation. This indicates that while the productive
reaction had stalled, the catalyst system was still active and that the
lack of reactivity was principally a function of a kinetically domi-
nant but non-productive PCET activation of the thiol.
1
2
3
4
5
6
7
8
modest Bronsted slopes in the MS-PCET oxidations of C–H bonds,
and we anticipate that similar explanations may be operative here.
15
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Evaluating the results in Table 2 more broadly, we can distinguish
several general reactivity trends. First, amide substrates bearing
electron-withdrawing groups (EWGs) are more favorable H-bond-
ing partners for the anionic phosphate, resulting in an increased
value of KA-amide and a higher equilibrium concentration of the am-
ide phosphate adduct. However, kPCET-amide decreases for the same
substrates as EWGs increase the strength of the N–H bond. Since
the Brønsted a value for amides is comparatively large (~0.53), the
change in driving force dominates and the overall rate of N–H
PCET is suppressed. Accordingly, Q0 also decreases, and the hy-
droamidation reactions of these substrates are less efficient than the
parent compound (e.g. comparing entries 4, 5, 6; 8, 11, 12).
Figure 2. Rate-driving force relationships
Importantly, MS-PCET chemoselectivity between competing sub-
strates is determined by differences in both KA and kPCET. The dif-
fering slopes of the plots in Figure 2 highlights that changes in driv-
ing force effect kPCET-amide and kPCET-thiol with different sensitivities.
Therefore, the selectivity between N–H and S–H activation path-
ways can be modified by changing the overall driving force for the
reaction, which is jointly determined by the identity of the oxidant
and the base catalysts. Similarly, differences in KA values modulate
the concentrations of the reactive H-bonded adducts, whose relative
abundance also factors into the observed chemoselectivity.
Incorporating EWGs into the aryl thiol also increases KA-thiol and
the equilibrium concentration of the thiol-phosphate complex,
while simultaneously diminishing kPCET-thiol as the S–H BDFE in-
creases. However, the Brønsted slope for the thiol is comparatively
small (a =0.10), indicating that changes in the driving force have
comparatively little impact on kPCET-thiol. As such, the increase in
adduct concentration is the dominant factor, and serves to increase
the overall rate of S–H PCET activation. This in turn decreases Q0
and makes the hydroamidation reaction less efficient (e.g. compar-
ing entries 5 ,11, 17; 19, 20).
To demonstrate how the interplay of these factors can influence the
chemoselectivity of the PCET step, we define a selectivity factor
Q, which is taken as —the ratio of the PCET rate constant for oxi-
dation of the amide-phosphate H-bond adduct times its concentra-
tion, to that of the thiol adduct counterpart (equation 1).
Finally, as the reduction potential of the Ir photocatalyst be-
comes more positive the driving force for both PCET reactions be-
comes more favorable. This causes both kPCET-amide and kPCET-thiol to
increase while both KA values remain constant. However, since
kPCET-amide is more sensitive to changes in the driving force than
kPCET-thiol, Q0 increases when a stronger oxidant is employed, result-
ing in a more efficient hydroamidation reaction (e.g. comparing en-
tries 3, 6; 9, 11). These results demonstrate how chemoselectivity
in MS-PCET reactions and their attendant effects on reaction effi-
ciency can be modulated simply by varying the driving force asso-
ciated with the one-electron oxidant. Considered altogether, we
note that every oxidant and thiol can effectively facilitate the hy-
droamidation reaction of at least one amide substrate; moreover,
every amide substrate can be effectively cyclized with at least one
combination of oxidant and thiol. These studies provide quantita-
tive framework for interpreting reactivity trends and suggest gen-
eral strategies for increasing selectivity for amide activation in mar-
ginal reactions. We anticipate that the framework presented here
kPCET amide[amide•phosphate]
(1)
Q =
kPCET thiol[thiol•phosphate]
Q reflects the competition between the two H-bonded adducts to
serve as the electron donor for a limiting concentration of the ex-
cited-state oxidant. As such, we hypothesized that the PCET selec-
tivity reflected in Q may correlate with efficiency in a catalytic hy-
droamidation reaction, and that variation of the factors comprising
Q could provide useful insight into the ways in which reaction out-
comes can be rationally modulated (and complex reactivity trends
understood) through careful choice of reaction conditions. There-
fore, we evaluated a series of hydroamidation reactions where the
value of Q and its component factors were systematically varied
(Table 2). Importantly, during these catalytic reactions the amide
substrate is consumed while the concentration of the thiol catalyst
remains relatively constant.3c This will cause the initial value of Q
(Q0 in Table 2) to decrease as the reaction proceeds, and below a
certain threshold of Q the thiol is expected to compete kinetically
with the amide substrate in the PCET event, effectively halting re-
action progress.
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Table 2. Correlation of Selectivity Factor Q0 with Catalytic Reaction Outcomes
1
2
3
Ir(III) photocatalyst (0.002 M)
X
X
O
NBu4OP(O)(OBu)2 (0.02 M)
Me
O
kPCET amide[amide•phosphate]0
kPCET thiol[thiol•phosphate]0
4
5
6
7
N
Q0
=
SH
Me
N
H
Me
(0.02 M)
Y
Me
(0.1 M)
DCE, blue LED, rt, 12 h
8
9
kPCET amide(M-1s-1) KA amide(M-1) kPCET thiol(M-1s-1) KA thiol(M-1)
% yieldb % recoveryb
Q0
entry
*Ir(III)
Ir-1
thiol
amide X=
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9.5x109
9.5x109
9.5x109
3.6x109
3.6x109
3.6x109
0
0
1
2
3
4
8.4x109
1050
1500
200
200
200
200
96 : 4
91 : 9
100
100
100
H
COMe
CN
PhSH
Ir-1
Ir-1
Ir-2
Ir-2
Ir-2
3.0x109
9.3x108
1.1x109
1.8x108
6.8x107
PhSH
PhSH
PhSH
PhSH
PhSH
0
87 : 13
86 : 12
62 : 38
57 : 43
3550
1050
1500
3550
0
H
100
80
8
9
5
6
200
200
COMe
CN
85
8.4x109
1.1x109
8.3x109
2.2x109
95
85
H
H
3,5-(CF3)2C6H3SH
3,5-(CF3)2C6H3SH
3,5-(CF3)2C6H3SH
3,5-(CF3)2C6H3SH
3,5-(CF3)2C6H3SH
3,5-(CF3)2C6H3SH
1050
1050
2100
2100
78 : 22
64 : 36
7
8
0
Ir-1
Ir-2
Ir-1
Ir-1
Ir-2
Ir-2
0
3.0x109
9.3x108
1.8x108
6.8x107
8.3x109
30
62
47
84
1500
3550
1500
3550
2100
2100
2100
2100
60
COMe
CN
9
56 : 44
47 : 53
23 : 77
18 : 82
8.3x109
2.2x109
2.2x109
10
11
12
13
10
0
COMe
CN
8.4x109
1.1x109
3.0x109
9.3x108
1.8x108
4.0x109
1.0x109
4.0x109
4.0x109
1.0x109
1.0x109
13
14
1050
1050
1500
5600
5600
0
H
H
Ir-1
75 : 25
61 : 39
91
61
C6F5SH
C6F5SH
C6F5SH
C6F5SH
C6F5SH
C6F5SH
Ir-2
Ir-1
Ir-1
Ir-2
Ir-2
23
70
54
54
88
15
16
17
COMe
CN
17
3
5600
5600
5600
56 : 44
3550
1500
44 : 56
24 : 76
trace
0
COMe
CN
18 : 82
18
6.8x107
3550
5600
In the following two entries, [thiol] = 0.04 M, [base] = 0.005 M
3.6x109
1.0x109
200
5600
1.1x109
1.1x109
81 : 19
35 : 65
100
15
0
PhSH
H
H
1050
1050
Ir-2
Ir-2
19
20
50
C6F5SH
a Reactions performed on 0.05 mmol scale. b Yield and recovery assessed after 12h by 1H-NMR relative to an internal standard.
will provides a road map for studying chemoselectivity in other
PCET reactions, where the interplay of hydrogen bonding affini-
ties, differential PCET kinetics, and the sensitivities of the rate
driving force relationships can be rationally exploited to improve
the selectivity of a given process.
ACKNOWLEDGMENT
Financial support was provided by the NIH (R01 GM113105).
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, luminescence quenching data, and
characterization data (PDF)
References
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Activation/ Functionalization. Chem. Rev. 2017, 117, 8622.
AUTHOR INFORMATION
Corresponding Author
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Soc. 2019, 141, 2721. (d) Nomrowski, J.; Wenger, O. S. Photoinduced
PCET in ruthenium–phenol systems: thermodynamic equivalence of Uni-
and bidirectional reactions. Inorg. Chem. 2015, 54, 3680. (e) Rhile, I. J.;
Mayer, J. M. One-electron oxidation of a hydrogen-bonded phenol occurs
by concerted proton-coupled electron transfer. J. Am. Chem. Soc. 2004,
*rknowles@princeton.edu
ORCID
Guanqi Qiu: 0000-0003-3818-3896
Robert R. Knowles: 0000-0003-1044-4900
Notes
No competing financial interests have been declared.
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126, 12718. (f) Markle, T. F.; Rhile, I. J.; DiPasquale, A. G.; Mayer, J.
M. Probing concerted proton–electron transfer in phenol–imidazoles.
Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 8185. (g) Markle, T. F.; Tronic,
T. A.; DiPasquale, A. G.; Kaminsky, W.; Mayer, J. M. Effect of Basic
Site Substituents on Concerted Proton–Electron Transfer in Hydrogen-
Bonded Pyridyl–Phenols. J. Phys. Chem. A. 2012, 116, 12249.
(3) (a) Miller, D. C.; Choi, G. J.; Orbe, H. S.; Knowles, R. R. Cata-
lytic Olefin Hydroamidation Enabled by Proton-Coupled Electron Trans-
fer. J. Am. Chem. Soc. 2015, 137, 13492. (b) Nguyen, S.T; Zhu, Q;
Knowles, R.R. PCET-Enabled Olefin Hydroamidation Reactions with N-
Alkyl Amides. ACS Catal. 2019, 9, 4502. (c) Ruccolo, S.; Qin, Y.;
Schnedermann, C.; Nocera, D. G. General Strategy for Improving the
Quantum Efficiency of Photoredox Hydroamidation Catalysis. J. Am.
Chem. Soc. 2018, 140, 14926
(4) (a) Kuss-Petermann, M.; Wenger, O. S. Mechanistic Diversity in
Proton-Coupled Electron Transfer between Thiophenols and Photoex-
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Medina-Ramos, J.; Oyesanya, O.; Alvarez, J. C. Buffer Effects in the Ki-
netics of Concerted Proton-Coupled Electron Transfer: The Electrochem-
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K a and Concentration. J. Phys. Chem. C. 2013, 117, 902. (c) Gagliardi,
C. J.; Murphy, C. F.; Binstead, R. A.; Thorp, H. H.; Meyer, T. J. Con-
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Bernardino, R.; Guedes, R.C. Substituent effects on O–H and S–H bond
dissociation enthalpies of disubstituted phenols and thiophenols. Interna-
tional Journal of Quantum Chemistry. 2008, 108, 754. See SI for calibra-
tion of S–H bond energies among different studies.
(9) As in previous studies, we are unable to quantify the favorability
of any potential post-PCET H-bonding. Thus, the reported driving force,
ΔG°’PCET, is taken to be the free energy change from the H-bonded reac-
tant state to the unbound product state, which is expected to be more en-
dergonic than the actual MS-PCET driving force.
(10) Romero, N.; Nicewicz, D. A. Mechanistic Insight into the Photo-
redox Catalysis of Anti-Markovnikov Alkene Hydrofunctionalization Re-
actions. J. Am. Chem. Soc. 2014, 136, 17024
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ment of Ambident Reactivity. Angew. Chem., Int. Ed. 2011, 50, 6470.
(13) The correlation in the thiol series also suggests that any impact
of varying the position of the substituents on aryl ring is accurately cap-
tured by the variance in the BDFEs of the thiol S-H bonds and in their
ability to serve as H-bond donors as reflected in the measured KA values.
(14) (a) Bernasconi, C.F. The principle of imperfect synchronization:
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of non-perfect synchronization. Adv. Phys. Org. Chem. 1992, 27, 119. (e)
Bernasconi, C.F. The principle of nonperfect synchronization: recent de-
velopments. Adv. Phys. Org. Chem. 2010, 44, 223.
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metry in C–H Bond Cleavage by Proton-Coupled Electron Transfer. J.
Am. Chem. Soc. 2019, 141, 10777.
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O
*IrIII
*IrIII
O
1
2
3
Ar
ArS
H
ArS
Ar
N
H
Me
N
Me
(BuO)2P(O)O
(BuO)2P(O)O
amide PCET
thiol PCET
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5
hydrogen bonding
equilibria
rate-driving force
relationships
PCET rate
constants
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• Quantitative basis for understanding PCET chemoselectivity•
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