O-H hydrogen bonding promotes H-atom transfer from α C-H bonds for C-alkylation of alcohols

Article abstract of DOI:10.1126/science.aac8555

The efficiency and selectivity of hydrogen atom transfer from organic molecules are often difficult to control in the presence of multiple potential hydrogen atom donors and acceptors. Here, we describe the mechanistic evaluation of a mode of catalytic activation that accomplishes the highly selective photoredox a-alkylation/lactonization of alcohols with methyl acrylate via a hydrogen atom transfer mechanism. Our studies indicate a particular role of tetra-n-butylammonium phosphate in enhancing the selectivity for α C-H bonds in alcohols in the presence of allylic, benzylic, α-C=O, and α-ether C-H bonds.

Full text of DOI:10.1126/science.aac8555

Reports
gioselectivity of HAT from mul-
tiple C–H groups of similar
strength (10).
O–H Hydrogen bonding promotes H-atom
transfer from α C–H bonds for
C-alkylation of alcohols
We questioned whether the
basic principles of PRC could be
integrated into a catalytic system
for the selective activation of
alcohol α-C–H bonds in the
presence of a wide range of other
C–H bonds (e.g., α-C=O, α-ether,
allylic or benzylic C–H) (11, 12).
Specifically, we postulated that
the selective C-alkylation of al-
cohols could be achieved via a
photoredox-catalyzed, H-bond-
assisted bond activation strategy
Jenna L. Jeffrey,* Jack A. Terrett,* David W. C. MacMillan†
Merck Center for Catalysis, Princeton University, Princeton, NJ 08544, USA.
*
These authors contributed equally to this work.
†
Corresponding author. E-mail: dmacmill@princeton.edu
The efficiency and selectivity of hydrogen atom transfer from organic
molecules is often difficult to control in the presence of multiple potential
hydrogen atom donors and acceptors. Herein, we describe the mechanistic
evaluation of a mode of catalytic activation that accomplishes the highly
selective photoredox α-alkylation/lactonization of alcohols with methyl
acrylate via a hydrogen atom transfer mechanism. Our studies indicate a
unique role of tetra-n-butylammonium phosphate in enhancing the
selectivity for α C–H bonds in alcohols in the presence of allylic, benzylic,
α-C=O, and α-ether C–H bonds.
(Fig. 1) (13–15), wherein the hy-
droxyalkyl C–H bond is selective-
ly polarized and weakened via
O–H hydrogen bonding.
It is well known that the
strength of α C–H bonds of alco-
hols decreases upon deprotona-
tion of the alcohol O–H group.
Complex molecules, such as medicinal agents and natural
products, often possess multiple types of C–H bonds, each
with a different inherent reactivity. This intrinsic reactivity
depends on a multi-faceted interplay of steric effects, induc-
This so-called “oxy anionic substituent effect” (16, 17) leads
to the acceleration of a wide range of organic reactions (e.g.,
oxyanionic [1,3] and [3,3] sigmatropic rearrangements and
HAT from alkoxides (18)). More recently, it has been shown
that intermolecular hydrogen bonding between alcohols and
various acceptor molecules gives rise to a similar polariza-
tion and weakening of the adjacent C–H bond (19), the
tive and conjugative influences, as well as innate strain (1,
3
2
). The intermolecular catalytic functionalization of C(sp )–
H bonds in a selective manner represents a longstanding
challenge that has inspired decades of effort within the syn-
thetic community. Notable early studies by Bergman (3), as
well as recent advances in selective intermolecular transi-
13
strength of which is reflected in the C NMR chemical shift
13
1
1
and the one-bond C– H coupling constant ( JCH) (20, 21). In
particular, it was found that a 1 kJ/mol increase in the en-
3
tion metal catalyzed C(sp )–H activation—including, among
1
thalpy of the H-bond resulted in a 0.2 Hz decrease in JCH for
others, Hartwig’s rhodium-catalyzed borylation of terminal
methyl groups (4), and White’s iron-catalyzed oxidation of
both secondary (2°) and tertiary (3°) aliphatic C–H bonds
hexafluoroisopropanol complexed to various amines (20).
On the basis of these studies, we reasoned that the efficien-
cy and selectivity of alcohol C–H activation could be en-
hanced by catalytic complexation with a suitable hydrogen-
bond acceptor. In particular, interaction of the hydroxyl
group of an alcohol with a hydrogen-bond acceptor catalyst
should increase n–σ* delocalization of the oxygen lone pair,
thereby rendering the α C–H bond more hydridic (i.e., more
polarized) and more susceptible to HAT by an elecrophilic
radical species.
Herein, we demonstrate the selective α-activation of al-
cohol C–H bonds in the presence of allylic, benzylic, α-oxy
and α-acyl C–H groups via a photoredox protocol, which
relies on the cooperation of three distinct catalysts: an iridi-
um-based photoredox catalyst; an HAT catalyst; and tetra-n-
butylammonium phosphate (or TBAP), a hydrogen-bonding
catalyst. On the basis of kinetic analyses, NMR structural
data, and kinetic isotope effects (KIEs), we demonstrate the
role of TBAP in facilitating the highly selective α hydrogen
atom abstraction from alcohols.
(
5)—highlight the importance of catalyst structure on site
selectivity.
Catalyst structure has also proven critical to the selectivi-
3
ty of C(sp )–H functionalization via hydrogen atom transfer
HAT) catalysis. HAT—the effective movement of a hydro-
(
gen atom between two molecular sites—represents a ubiqui-
tous elementary reaction step in organic chemistry (6–8).
The rate of hydrogen abstraction from a C–H bond depends
not only on the C–H bond dissociation enthalpy (BDE), but
also on polar effects in the transition state. In 1987, Roberts
noted that certain electrophilic radicals (e.g., t-butoxyl)
preferentially abstract hydrogen from electron-rich C–H
bonds, while nucleophilic radicals (e.g., amine-boryl) selec-
tively cleave electron-deficient C–H bonds (9). The generali-
ty of this concept was subsequently delineated through the
broad application of polarity reversal catalysis (PRC), which
takes advantage of favorable polar effects to control the re-
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The past several years have witnessed a dramatic in- range of hydrogen-bond acceptor catalysts, including the
crease in the application of photoredox catalysis—the use of tetra-n-butylammonium salts of phosphate, trifluoroacetate,
visible light-activated organic dyes or metal complexes to and diphenyl phosphate (Fig. 2B). Superior levels of product
facilitate single electron transfer events—to the develop- formation were achieved with catalytic TBAP (25 mol%),
ment of organic transformations (22). By combining photo- which provided the desired lactone in 84% yield. Initial rate
redox activation with organocatalysis (23, 24) and nickel kinetic analysis of the alkylation/lactonization of 11 revealed
catalysis (25), we have recently highlighted the unique po- rate enhancements in the presence of each hydrogen-
tential of photoredox catalysis to achieve bond construc- bonding catalyst examined, with the largest initial rate ac-
tions that are not possible with more traditional methods.
We became interested in the selectivity and efficiency of and 2.5, respectively).
C–H bond activation in the context of our ongoing cam- We next demonstrated that a wide range of 1° and 2° al-
celeration using Bu
4
NCO
2
CF
3
or Bu
4
N(PhO)
2
PO (rrel = 2.6
2
paign to merge visible light photoredox catalysis with HAT cohols undergo selective α-hydroxy alkylation with methyl
catalysis (26–29). We have previously demonstrated the util- acrylate in good to excellent yields using TBAP catalysis
ity of thiols (S–H BDE = 87 kcal/mol) as HAT catalysts in (Fig. 2C). As outlined in Fig. 3, these conditions clearly ena-
the photoredox coupling of benzylic ethers (C–H BDE = 86 ble the selective activation of alcohol C–H bonds in the
kcal/mol) with arenes (26) and imines (27). We recognized presence of various α-oxy C–H groups, including cyclic and
that the ability to catalytically activate stronger C–H bonds, acyclic alkyl ethers (21, 24 and 25, 85%, 71% and 77% yield,
such as those present in aliphatic alcohols and ethers (α C– respectively); silyl ethers (23, 73% yield); and esters (22,
H BDE > 90 kcal/mol), would hinge on the identification of 81% yield). Moreover, excellent selectivity was achieved in
a catalyst that satisfies two critical requirements: (i) homo- the presence of both allylic and benzylic hydrogens (e.g.,
lytic cleavage of a strong substrate C–H bond must be coun- 26–29, 70–75% yield). The selectivity of this H-bond-
terbalanced by formation of a stronger H–[catalyst] bond, assisted C–H activation platform was further demonstrated
and (ii) selective activation of hydridic C–H bonds (i.e., via the C–H alkylation/lactonization of bifunctional steroid
bonds that are significantly polarized due to oxygen lone derivatives, which provided the corresponding lactone
pair donation) must be realized. With these criteria in mind, products in good levels of efficiency (25 and 26, 77% and
we questioned whether it might be possible to transiently 70%, respectively). It should be noted that electron-deficient
generate a hydridophilic amine radical cation from quinu- α-benzoyloxy and α-acyl C–H bonds (22 and 26) are ex-
clidine (3, Fig. 2A), which would be uniquely suited to ab- pected to be inherently deactivated toward HAT with re-
straction of relatively strong, hydridic C–H bonds, while spect to electrophilic radical HAT systems (10), such as
resisting α-deprotonation due to poor H–C–N orbital over- quinuclidinium radical cation. In the absence of TBAP,
lap in this rigid bicyclic structure (30, 31). As outlined in higher levels of substrate concentration were required to
Fig. 2A, we envisioned an initial excitation of the well achieve useful efficiencies. However, under those conditions,
known photocatalyst,
dF(CF )ppy =
Ir[dF(CF
2-(2,4-difluorophenyl)-5- bonds was observed. Importantly, in all cases outlined in
3
)ppy]
2
(dtbbpy)PF
6
non-selective C–H abstraction of weaker, less hydridic C–H
[
3
(
trifluoromethyl)pyridine, dtbbpy = 4,4’-di-tert-butyl-2,2’- Fig. 3, we only observed alkylation products arising from the
+
bipyridine] (1), to *Ir[dF(CF
light. Reductive quenching of 2 (E1/2 = +1.21 V vs. SCE in various substrates.
CH
CH
3
)ppy]
2
(dtbbpy) (2) with visible activation of the hydroxyalkyl C–H bonds present in the
red
ox
3
CN) (32) via oxidation of 3 (E1/2 = +1.1 V vs. SCE in
CN) (33, 34) would then afford radical cation 4 and selective α-hydroxy C–H functionalization in the presence of
We next turned our attention to defining the capacity for
3
Ir(II) (5). At this stage, the electrophilic quinuclidinium rad- C–H bonds that have similar polarity and strength. Specifi-
ical 4 should abstract a hydrogen atom from an alcohol (6) cally we selected tetrahydrofuran (THF) as a prototypical
to afford α-hydroxy radical 7 and quinuclidinium ion 8 [H– ether substrate, which would normally undergo C–H activa-
+
N BDE = 100 kcal/mol, (33)]. Nucleophilic addition of α-oxy tion via HAT with rates similar to alcohol substrates. In-
radical 7 to an electron-deficient alkene would furnish alkyl deed, we found that the dual catalytic system involving
radical 9. Single electron reduction of this electron-deficient quinuclidine and photoredox catalyst 1 enabled the efficient
red
radical 9 by Ir(II) (5) (E1/2 = –1.37 V vs. SCE in CH CN), alkylation of THF with rates that were competitive with 1-
3
would then afford the α-alkylated product 10 following pro- hexanol in competition experiments, affording a 1.7:1 mix-
tonation and lactonization, while simultaneously regenerat- ture of lactone and ether products (Fig. 4A) (37). However,
ing both the photocatalyst (5→1) and the HAT catalyst (8→3) the addition of 25 mol% of TBAP catalyst enabled a dra-
(
35, 36).
We initially validated our proposed alkylation protocol exclusively the alcohol C–H alkylation product (75% lactone,
by subjecting 1-hexanol (11) and methyl acrylate to blue 1% ether).
matic increase in overall reaction selectivity to afford almost
light in the presence of amine 3 (10 mol%) and photocata-
To further understand the role of hydrogen-bonding in
lyst 1, which afforded after 24 hours γ-nonalactone (12) in this H-bond-assisted C-alkylation process, a series of compu-
6
7% yield after acidic work-up (Fig. 2B). We next evaluated a tational calculations and NMR experiments were undertak-
/
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en. These studies were to evaluate the interaction of 1- cycle (Fig. 2A). However, an intramolecular competition
hexanol with various hydrogen-bonding catalysts (high- experiment of mono-deuterated alcohol 31 afforded a mix-
lighted in Fig. 2B) and to determine their accompanying ture of deuterated and undeuterated lactones (P
D
and P )
H
effect on the α-hydroxy C–H bond strength. Density func- with a 1.6:1 ratio (Fig. 4C). This result demonstrates that
tional theory (DFT) calculations, were performed using an even though C–H/D abstraction is not rate-limiting, it rep-
unrestricted B3LYP functional with a 6–31G basis set. In the resents the selectivity-determining step of the C-alkylation
presence of either phosphate, diphenyl phosphate, or tri- of hexanol 31. The recovered starting material from this
fluoroacetate tetrabutylammonium salts, a BDE weakening experiment did not contain any fully protonated 1-hexanol
of approximately 3 kcal/mol was calculated (see Supplemen- nor d -hexanol, confirming that C–H/D abstraction is irre-
2
tary Material). While this represents a significant change in versible in this process. The irreversibility of the C–H ab-
the α-C–H BDE of 1-hexanol from 94.1 kcal/mol to 91.0 straction step was further confirmed by two additional
kcal/mol when bonded to the TBAP catalyst, it clearly experiments: first, in an intermolecular competition be-
demonstrates that BDE is not the only factor defining this tween 1-hexanol and di-deuterated hexanol 32 (Fig. 4D), in
HAT selectivity and bond polarization effects are likely im- which no amount of mono-deuterated alcohol 31 was de-
portant.
tected during the process; and second, in the C-alkylation of
NMR experiments were also performed to explore the in- enantiopure alcohol 33 (Fig. 4E), in which no racemization
fluence of both quinuclidine and TBAP as hydrogen-bonding of starting material was observed upon recovery of excess
catalysts for 1-hexanol. In the absence of either additive, the starting material (40). Taken together, these results are con-
1
3
C NMR chemical shift of the α carbon of 1-hexanol (δC1) in sistent with the mechanistic scenario (iii): a dual role of
1
CDCl
(38) appeared at 63.1 ppm with JCH[hexanol]=141.1 Hz. TBAP in both accelerating the C–H abstraction from alco-
3
Addition of an equimolar amount of quinuclidine resulted hols and enhancing the rate of addition of the resulting rad-
in a 0.4 ppm upfield shift (δC1hexanol:3=62.7 ppm) and a slight ical to Michael acceptors (41).
1
3
1
decrease in the one-bond
C– H coupling constant
CH[hexanol:3] = 140.4 Hz). For comparison, a 1:1 mixture of 1- posed C–H activation pathway was attained in the form of
hexanol and TBAP gave rise to a similarly upfield shift in initial rate data for the conversion of cyclopropyl radical
Finally, compelling experimental evidence for our pro-
1
(
J
1
3
the C signal for C1 of 1-hexanol (δC1hexanol:TBAP = 62.6 ppm; clock alcohol 35 to aldehyde 36 in the presence and ab-
ΔδC1=0.5 ppm), with JCH(hexanol:TBAP) = 140.3 Hz. These data sence of TBAP catalyst (Fig. 4F). Specifically, we reasoned
1
clearly indicate that both quinuclidine and TBAP can induce that C–H abstraction from 35 to generate the 2-
bond weakening of the α-C1–H of 1-hexanol via hydrogen (alkoxycarbonyl)cyclopropylcarbinyl radical (rate constant
1
0
–1
bonding. These data are also consistent with decreased s- for rearrangement = 5–8 × 10 s at 25°C (42–44)] would be
character in the hybrid carbon orbitals of the C–H bond rate-limiting. As such, enhancement in the rate of C–H ab-
(
i.e., increased hydridicity) of hexanol upon H-bond for- straction via H-bond-assisted C–H activation should be
mation (39).
clearly manifested in the observed rate of conversion of 35
To more thoroughly outline the factors governing both to 36 in the presence and absence of TBAP catalyst. Indeed,
the rate and selectivity of the C-alkylation of alcohols, a under our photoredox/HAT conditions, a nine-fold rate en-
suite of mechanistic experiments was undertaken. The ini- hancement in the rate of conversion of alcohol 35 to alde-
tial rate of the reaction of 1-hexanol with methyl acrylate hyde 36 was observed upon addition of 25 mol% TBAP (45).
showed first-order dependence on [hexanol]init and [acry- This result clearly corroborates our mechanistic proposal,
late]init. The observed increase in the initial rate of reaction wherein TBAP facilitates C–H abstraction from alcohols via
in the presence of TBAP (Fig. 2B), coupled with first-order hydrogen bond activation. The activation concept presented
dependence on both reactants, implies that TBAP serves to here is likely pertinent to a wide range of C–H abstraction
lower the energy barrier of: (i) the C–H abstraction step reactions.
(
due to α-C–H bond weakening); (ii) the C–C bond forming
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ACKNOWLEDGMENTS
The authors are grateful for financial support provided by the NIH General Medical
Sciences (R01 GM078201-05) and gifts from Merck and Amgen. J.L.J. is grateful
for an NIH Postdoctoral Fellowship (F32GM109536-01) and J.A.T. thanks Bristol-
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Fig. 1. Proposed hydrogen bond assisted C–H activation of alcohols. See (13–15) for
BDE values.
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Fig. 2. Reaction development. (A) H-bond-assisted C–H activation of alcohols: proposed mechanistic
pathway for the C-alkylation of alcohols with Michael acceptors. SET = single-electron transfer. HAT =
1
hydrogen atom transfer. (B) Evaluation of hydrogen-bonding catalysts. Yield determined by H NMR
using an internal standard. (C) Selected scope of simple alcohol addition to methyl acrylate (only
products are shown; experimental conditions as in B). Isolated yields are reported.
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Fig. 3. Selected alcohol scope for H-
bond-assisted C–H activation.
Additions to methyl acrylate were
carried out at 27°C for 24 hours,
unless otherwise noted. Isolated
yields are reported. See SM for
detailed experimental procedures and
full scope of
acceptors. †40 hours reaction time.
48 hours reaction time. *1:1 mixture
alcohols/Michael
‡
of E/Z isomers. No alkylation of
positions marked with blue circles
observed in any case.
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Fig. 4. Mechanistic studies. (A)
H-bond-dependent selectivity of α-
oxy C–H alkylation. (B) Kinetic
isotope effect determined from
two parallel kinetic analyses. (C)
Kinetic isotope effect determined
from intramolecular competition
experiment. (D) Kinetic isotope
effect
determined
from
intermolecular
competition
experiment. (E) Evaluation of the
enantiomeric excess of unreacted
alcohol
under
standard
C-
alkylation conditions. (F) Effect of
TBAP on the rate of C–H
abstraction from 35.
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