Charge-transfer-directed radical substitution enables para-selective C-H functionalization

Article abstract of DOI:10.1038/nchem.2529

Efficient C-H functionalization requires selectivity for specific C-H bonds. Progress has been made for directed aromatic substitution reactions to achieve ortho and meta selectivity, but a general strategy for para-selective C-H functionalization has remained elusive. Herein we introduce a previously unappreciated concept that enables nearly complete para selectivity. We propose that radicals with high electron affinity elicit arene-to-radical charge transfer in the transition state of radical addition, which is the factor primarily responsible for high positional selectivity. We demonstrate with a simple theoretical tool that the selectivity is predictable and show the utility of the concept through a direct synthesis of aryl piperazines. Our results contradict the notion, widely held by organic chemists, that radical aromatic substitution reactions are inherently unselective. The concept of radical substitution directed by charge transfer could serve as the basis for the development of new, highly selective C-H functionalization reactions.

Full text of DOI:10.1038/nchem.2529

ARTICLES
PUBLISHED ONLINE: 6 JUNE 2016 | DOI: 10.1038/NCHEM.2529
Charge-transfer-directed radical substitution
enables para-selective C–H functionalization
Gregory B. Boursalian1,2, Won Seok Ham1, Anthony R. Mazzotti1 and Tobias Ritter1,2
*
Efficient C–H functionalization requires selectivity for specific C–H bonds. Progress has been made for directed aromatic
substitution reactions to achieve ortho and meta selectivity, but a general strategy for para-selective C–H functionalization
has remained elusive. Herein we introduce a previously unappreciated concept that enables nearly complete para
selectivity. We propose that radicals with high electron affinity elicit arene-to-radical charge transfer in the transition
state of radical addition, which is the factor primarily responsible for high positional selectivity. We demonstrate with a
simple theoretical tool that the selectivity is predictable and show the utility of the concept through a direct synthesis of
aryl piperazines. Our results contradict the notion, widely held by organic chemists, that radical aromatic substitution
reactions are inherently unselective. The concept of radical substitution directed by charge transfer could serve as the
basis for the development of new, highly selective C–H functionalization reactions.
istorically, electrophilic aromatic substitution is perhaps the positional selectivity when an appropriately electrophilic radical is
most important reaction class for the functionalization of used. We show that for most substrates, including monosubstituted
H
aromatic C–H bonds, but typically affords mixtures of pro- arenes, only one of the possible positional isomers is observed in
ducts (Fig. 1a)1. Reactions catalysed by transition metals have gen- significant amounts. The charge-transfer-directed concept does
erally struggled with the same limitations in positional selectivity, not require a coordinating DG, as do chelation-assisted C–H
except when a coordinating directing group (DG) on the arene sub- functionalization reactions, because selectivity is determined by
strate is utilized to position the catalyst within close proximity of a the electronic structure in the transition state as opposed to enforced
specific C–H bond2,3. This chelation-assisted approach has been proximity of the catalyst.
successful in enabling C–H functionalization ortho4,5, and in some
cases meta6, to the coordinating DG (Fig. 1b). Steric hindrance Results and discussion
has been explored as a strategy to control positional selectivity in Radical substitution directed by charge transfer. The doubly cationic
C–H functionalization, but product mixtures still result, particularly radical TEDA2+• (TEDA, N-(chloromethyl)triethylenediamine),
for monosubstituted arenes7–9. There are isolated reports of non-
derived from a single-electron reduction of Selectfluor, is capable
chelation-assisted aromatic C–H functionalization reactions with of engaging in radical aromatic substitution to yield N-aryl-
anomalously high para selectivity for monosubstituted arenes; Nʹ-chloromethyldiazoniabicyclo[2.2.2]octane salts, which we term
however, these reactions either require solvent quantities of arene Ar–TEDA compounds (Fig. 2) (see pages S25–S27 in the
or work only on activated arenes, and the origin of their para selec- Supplementary Information for evidence that implicates TEDA2+•
tivity is unknown, which precludes generalization to the design of
as the C–N bond-forming species). The reaction is enabled by a
other para-selective functionalization reactions10–12. Thus, no dual catalyst combination: Pd catalyst 1, which we introduced in a
general strategy currently exists for highly para-selective C–H func- previous report, and Ru(bipy)3(PF6)2 (bipy, bipyridine) (Fig. 2a)14.
tionalization. Such a strategy would constitute a novel complement Photoirradiation is not required for the reaction, which works
to the classic electrophilic aromatic substitution paradigm, equally well when shielded from light. For most arenes only one
especially if no particular DG is required.
of the possible positional isomers of the Ar–TEDA product is
Herein we describe how aromatic substitution by highly electro- observed as judged by NMR spectroscopy; fluorobenzene, for
philic radicals, which are capable of eliciting significant charge example, yields the para-substituted product in >99:1 positional
transfer from the arene in the transition state of addition, exhibits selectivity (Supplementary Fig. 2). All monosubstituted arenes
high selectivity for positions para to substituents on the arene tested gave the para-substituted product as the only significant
(Fig. 1c). Radical aromatic substitution reactions normally do not isomer. Disubstituted arenes and some heteroarenes similarly
proceed with synthetically useful positional selectivity on substi- undergo clean substitution at the position para to the group with
tuted arenes. For example, in the 2007 edition of Advanced the strongest directing effect. Thus, the synthesis of the Ar–TEDA
Organic Chemistry by Carey and Sundberg, it is claimed that compounds described here constitutes a general non-chelation-
“There are some inherent limits to the usefulness of such reactions.
assisted C–H functionalization reaction, with the arene as the
Radical substitutions are only moderately sensitive to substituent limiting reagent and with nearly exclusive positional selectivity
directing effects, so that substituted reactants usually give a across a broad range of substitution patterns.
mixture of products. This means that the practical utility is
limited to symmetrical reactants, such as benzene, where the 12.4 eV, calculated by density functional theory (DFT). The high
position of attack is immaterial.”13. The results reported herein
The TEDA2+• radical is electrophilic, with an electron affinity of
electron affinity of TEDA2+• should favour a large contribution of
demonstrate that, contrary to prior assumptions, radical aromatic charge transfer in the transition state of addition (Fig. 2b), which
substitution can furnish novel, useful products with high chemo- and in turn leads to a high selectivity for aromatic substitution at the
1Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA. 2Max-Planck-Institut für
Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany. e-mail: ritter@mpi-muelheim.mpg.de
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2529
ARTICLES
position from which the charge transfer is the greatest15–17
.
a
b
c
Electrophilic aromatic substitution
Therefore, a predictive tool for the positional selectivity of the reac-
tion would be a metric that indicates the greatest extent of charge
transfer that can be expected on attack at a given position. We
found Fukui nucleophilicity indices to be well suited to this
purpose. The Fukui nucleophilicity index of an atom, determined
by simple quantum chemical calculations, is a measure of how
readily electron density is transferred to an incoming electrophilic
species attacking at the relevant atom18–20. Fukui indices are
especially convenient as a predictive tool because the Fukui nucleo-
philicity index of all the atoms in a given molecule is determined by
a pair of simple calculations on the arene itself; there is no need to
map the potential-energy surface of the reaction by computing the
transition states of various pathways.
Figure 2c shows several Ar–TEDA products and the correspond-
ing starting material, with each aromatic carbon atom of the starting
material labelled with its Fukui nucleophilicity index. This index
successfully predicts the site of substitution by TEDA2+• in almost
all cases. Certain 1,4-disubstituted arenes, including 1,4-dichloro-
benzene and 4-chloroanisole, yield ipso substitution of the
halogen as the primary product21. Gratifyingly, Fukui nucleophili-
city indices correctly predict even the observed ipso substitution
in these cases. If a non-substitutable functional group is present at
the site with the highest Fukui index, substitution at the site with
the next-highest Fukui index is observed, as for methyl 4-methoxy-
benzoate (2g). Although steric hindrance to an ortho attack may
serve to augment further the para selectivity of the reaction, the
fact that even fluorobenzene, with a single small substituent, gives
>99:1 selectivity renders steric hindrance unlikely as the primary
factor governing selectivity.
R
R
R
X
X
+
X
Chelation-assisted approach: ortho or meta selective
DG
DG
[M]
DG
H
X
[M]
X
Charge-transfer directed approach: para selective
R
R
H
R
X
High-electron-
affinity radical
X
H
X
Figure 1 | Selective C–H functionalization. a, Electrophilic aromatic
substitution generally yields mixtures of isomers. b, Lewis basic DGs direct
functionalization to proximal bonds by chelation assistance. c, Charge-
transfer-directed approach: arene-to-radical charge transfer, elicited by
highly electrophilic radicals, leads to a high para selectivity.
substitution of monosubstituted arenes that bear electron-donating
groups27–29. We discovered that for sufficiently electrophilic radicals,
charge transfer in the transition state of addition can lead to a high
selectivity for the para position over the ortho one. We rationalized
the phenomenon in terms of charge transfer in the transition state,
and introduced Fukui indices as a tool for predicting the site of
substitution. The second positive charge of the TEDA2+• aminium
radical increases the electron affinity to 12.4 eV and, at this level,
nearly absolute selectivity for the para position is observed for
monosubstituted arenes.
The general applicability of the charge-transfer-directed concept
depends on whether other radicals of comparable electron affinity to
that of TEDA2+• can be designed. The uncommonly high electron
affinity of TEDA2+• results from its two positive charges; doubly cat-
ionic organic radicals are rare, presumably because there has been a
lack of generally appreciated applications and because strategies to
access them are unexplored. We anticipate that the correlation
between electron affinity and positional selectivity described
herein will stimulate research in radicals of high electron affinity
because of their potential to address the long-standing challenge
of positional selectivity in C–H functionalization.
The high degree of positional selectivity we report here is
unusual, especially in the context of radical aromatic substitution.
A reason may be the lack of studies of substitution reactions with
radicals of high electron affinity. Although the TEDA2+• radical
dication has been proposed as an intermediate in recently reported
aliphatic C–H oxidation methodologies that utilize Selectfluor22–24
,
to our knowledge the addition of this radical to unsaturated
systems has not been investigated. The radicals employed most
commonly in a synthetic context are uncharged carbon-, oxygen-,
nitrogen- and halogen-based radicals, which have electron affinities
in the range 0.8–3.6 eV, far below the value for TEDA2+• (12.4 eV
(Fig. 3)). Aromatic substitution reactions of most neutral radicals
are known to proceed with low selectivity13. For example, the
phenyl radical has an electron affinity of 1.1 eV and, under the con-
ditions reported by Li and co-workers, undergoes aromatic substi-
tution with fluorobenzene to give an ortho:meta:para (o:m:p) ratio
of 47:16:37 (ref. 25). The neutral phthalimide radical has a higher
electron affinity (3.7 eV). We found that the phthalimide radical,
when generated under conditions reported by Sanford and co-
workers26, undergoes aromatic substitution with fluorobenzene in
an o:m:p ratio of 37:11:52; the selectivity for the para position is
higher, although the other isomers still abound.
Positive charge increases electron affinity and, based on our
findings and proposal, positively charged radicals should result in
more-selective arene substitution reactions. Monocationic aminium
radicals have electron affinities in the range 7–8 eV, and their
aromatic substitution reactivity was investigated thoroughly in
seminal work by Minisci and co-workers, who noted the higher
selectivity of aminium radical addition compared with that of
less-electrophilic radicals27–29. Under Minisci’s conditions, the
monocationic aminium radical derived from piperidine (electron
affinity of 7.7 eV) adds to fluorobenzene more selectively than
the neutral phthalimide radical, to afford an o:m:p ratio of
11:10:79. Minisci described the selectivity of monocationic
aminium radicals as similar to the selectivity of electrophilic
aromatic substitution, affording products of ortho and para
Furthermore, radicals of electron affinity comparable to that of
TEDA2+• need not, in principle, be based on cationic aminium rad-
icals. For example, DFT calculations indicate that alkoxyl radicals
exhibit a similar trend with increasing positive charge, although
the septet oxygen atom itself lacks
a
formal charge
(Supplementary Fig. 11). Thus, in principle, highly electrophilic rad-
icals could be designed for the installation of a variety of functional
groups, not just C–N bonds.
Application to the synthesis of aryl piperazines. As one synthetic
application of the concept of charge-transfer-directed radical
substitution, we developed a two-step, one-pot synthesis of aryl
piperazines from the corresponding aryl C–H compounds
(Fig. 4). The procedure involves the reduction of the aryl–TEDA
compounds by sodium thiosulfate, which converts the TEDA
moiety into a piperazine heterocycle. Piperazines are a common
motif in pharmaceuticals and other materials; they constitute the
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2529
ARTICLES
a
b
Cl
Cl
N
N
R
+
F
R
2 equiv. Selectfluor
F
N
N
5 mol% 1
–e
10 mol% Ru(bipy)3(PF6)2
–H
R
N
MeCN
N
N
Cl
TEDA2+
H
N
N
N
N
O
O
N
N
Cl
Pd
Cl
TEDA2+
(BF4)2
2a
R
N
88%
EA = 12.4 eV
>99:1
1
c
Me
Cl
Fukui index
colour scale
1.4
2.4
Highest
0.64
0.42
0.64
0.42
0.71
0.44
0.68
0.48
reactivity
2c
2b
85%
N
N
N
N
80%
2.3
2.5
Toluene
Chlorobenzene
Cl
Cl
Lowest
reactivity
OMe
OMe
F
0.89
1.3
0.93
0.23
1.2
2e
1.4
0.39
1.1
2d
N
86%
0.02
N
84%
0.74
2.1
2-Fluoroanisole
2.4
N
N
Anisole
Cl
Cl
0.89
OMe
N
Cl
0.93
0.23
1.2
0.02
N
O
2f
2g
94%
98%
2.1
0.54
0.32
CO2Me
0.06
TEDA2+
1.4
Methyl 4-methoxybenzoate
Fluorenone
Cl
OMe
0.99
2b
0.96
0.19
0.83
0.43
2d
26%†
48%*
N
N
N
0.49
1.3
1.4
N
Cl
1,4-Dichlorobenzene
4-Chloroanisole
Cl
Figure 2 | Charge-transfer-directed aromatic substitution. a, Conversion of fluorobenzene into the corresponding Ar–TEDA compound. b, Positional
selectivity of TEDA2+• substitution results from the stabilizing effect of the arene-to-radical charge transfer in the transition state of the addition. EA refers
to the gas-phase adiabatic electron affinity calculated by DFT. c, The position of substitution by TEDA2+• is predictable by Fukui indices. The Fukui
indices depicted are multiplied by ten for simplicity of presentation. DFT computations of the Fukui indices and the electron affinity of TEDA2+• were
performed at the (U)B3LYP/6-311G(d) level of theory, with a continuum polarization solvent model for the Fukui index calculations. The Fukui indices
are computed for one conformation of the molecule, so indices of positions that are symmetrically disposed about a substituent need not be equal
(see the Supplementary Information for full computational details). *Substitution in the 2-position was observed in 11% yield in addition to the ipso
substitution (see the Supplementary Information). †Substitution in the 2-position was observed in 10% yield in addition to the ipso substitution
(see the Supplementary Information).
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ARTICLES
Calculated
electron
affinity
Experimentally
observed
selectivity
F
Cl
N
F
N
Cl
N
N
12.4 eV
N
>99:1
para
N
Cl
11 ortho
F
F
10 meta
N
H
N
79 para
7.7 eV
N
H
O
N
F
F
O
37
ortho
O
52
para
N
O
O
11 meta
N
3.7 eV
O
F
F
37
47
ortho
para
1.1 eV
16 meta
Figure 3 | Selectivity for para substitution increases with increasing electron affinity of the radical. Electron affinities refer to the gas-phase adiabatic
electron affinity calculated at the (U)B3LYP/6-311G(d) level of theory.
third most-common heterocycle present in the small-molecule differ only slightly in their electron-donating ability and the
pharmaceuticals listed in the US Food and Drug Administration product was isolated as a 3.3:1 mixture of isomers. Although
Orange Book30. Aryl piperazines are commonly synthesized by TEDA2+• is known to engage in sp3 C–H bond cleavage, we
Buchwald–Hartwig cross-coupling reactions of aryl electrophiles observed no evidence of such side reactions in our investigations,
with piperazine derivatives31. The direct synthesis of aryl even though several substrates contain weak C–H bonds adjacent
piperazines reported here is advantageous because it does not to aromatic rings (for example, 3f) or ether oxygen atoms (for
require a pre-functionalized substrate, such as an aryl halide. example, 3e and 3k); the addition of TEDA2+• to the unsaturated
Importantly, this advantage relies on the high and predictable aromatic system outcompetes C–H bond cleavage.
positional selectivity of the reaction, which enables the high-yield
For most substrates, nearly full conversion into the Ar–TEDA
synthesis of a single desired positional isomer. The reaction is compound is observed, and in several cases the yield of the piperazine
operationally simple, and can be performed under air with after the thiosulfate-mediated stage is lower. For example, the antic-
commercial-quality solvent. Furthermore, the piperazine moiety is holesterol drug fenofibrate undergoes Ar–TEDA formation in 88%
obtained with an unprotected secondary amine, ready for yield, but on treatment with sodium thiosulfate at 100 °C the yield
subsequent manipulation.
of piperazine 3x is 51%. The Ar–TEDA formation reaction exhibits
A variety of arenes, including five- and six-membered heteroar- significant functional group tolerance, despite the highly reactive
enes, undergo piperazination. Generally, the attack of TEDA2+• and electrophilic nature of the TEDA2+• radical intermediate; for
ortho to the substituents is unfavourable, and occurs only for most substrates in Fig. 4, the majority of mass balance is lost in the
arenes in which the preferred para position for substitution is piperazine formation step, not in the Ar–TEDA formation step.
blocked by a group that cannot undergo ipso substitution. This
We show here that the doubly cationic nitrogen-based radical
observation can be applied to block piperazination of certain pos- TEDA2+• undergoes radical substitution with arenes with a higher pos-
itions, or even entire arene rings, as in substrates 3r and 3t. itional selectivity than that of any conventional methodology for arene
Product 3g demonstrates the limits of the positional selectivity of substitution. We put forth a previously underappreciated rationale to
the reaction: the two substituents in 2-methyl-tert-butylbenzene explain and predict positional selectivities in charge-transfer-directed
4
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ARTICLES
i. 1.5 equiv. Selectfluor,
2.5 mol% 1,
NH
7.5 mol% Ru(bipy)3(PF6)2,
MeCN, 23 °C
H
N
R
R
3
ii. Na2S2O3, H2O, 100 °C
Percent yield
Positional selectivity
Me
N
Me Me
OMe
Me
N
F
Cl
N
OMe
Me
Me
Me
CO2Me
*
*
N
N
N
N
N
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
3a
91%
3b
79%
3c
3d
3e
80%
15.7:1
3f
62%
3g
80%
3.3:1
3h
89%
71%†
64%‡
OMe
O
N
OMe
F
CN
OMe
NH
O
N
N
NH
N
N
N
N
CO2Me
N
H
N
H
N
H
N
H
3j
3k
56%§
3l
79%§
3m
3n
3o
71%
90%
57%
54%
NH
NH
NH
O
NH
N
N
N
N
*
F
N
N
NH
N
OMe
3p
N
Me3Si
3q
71%
3r
89%
3s
58%||
3t
77%
51%
5.2:1
Cl
NH
O
N
O
EtO
O
N
S
S
NH
Me
O
N
NH
OMe
N
O
N
O
NH
Me
O
O
O
Me Me
3u
45%
3v
57%
3w
76%
3x
50%
Figure 4 | Two-step, one-pot synthesis of aryl piperazines by charge-transfer-directed C–H functionalization. *Site of piperazination of the other
constitutional isomer. †Reaction temperature of 40 °C. ‡Reaction temperature of 45 °C in the first step. §For the first step, 2.5 equiv. Selectfluor, 5.0 mol% 1
and 10 mol% Ru(bipy)2(PF6)2. ||For the first step, 1.0 equiv. Selectfluor.
radical aromatic substitution: high selectivity is achieved through a high
degree of charge transfer in the transition state of addition. This charge-
transfer effect is maximized for radicals with high electron affinity. Our
results can rationalize why known electrophilic radical substitution
reactions of neutral radicals are typically not selective and, more impor-
tantly, how they can provide a framework to guide the design of new,
selective arene substitution chemistry.
Methods
Representative C–H piperazination procedure: 1-(p-tolyl)piperazine (3b). A 100 ml
pressure tube was charged with palladium complex 1 (13.6 mg, 21.4 µmol,
2.50 mol%), Ru(bipy)3(PF6)2 (55.2 mg, 64.2 µmol, 7.50 mol%) and Selectfluor
(455 mg, 1.28 mmol, 1.50 equiv.). Acetonitrile (4.3 ml, 0.20 M) was added, followed
by toluene (91.1 µl, 0.856 mmol, 1.00 equiv.) via a syringe. The reaction mixture was
stirred at 23 °C for 24 hours. Saturated aqueous sodium thiosulfate (8.6 ml) and
water (8.6 ml) were added, the pressure tube was sealed and the reaction mixture was
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2529
ARTICLES
stirred at 100 °C for two hours. After cooling to 23 °C, the reaction mixture was
transferred to a separatory funnel. Dichloromethane (20 ml) and ethylenediamine
(1.5 ml) were added and the organic layer was washed with 6 M aqueous sodium
hydroxide (5 ml). The aqueous layer was extracted with dichloromethane
(2 × 10 ml). The combined organic layers were extracted with 1 M aqueous
hydrochloric acid (2 × 15 ml). Ethylenediamine (5.0 ml) was added to the combined
acidic aqueous layers, followed by basification with 6 M aqueous sodium hydroxide
(8 ml). The basic aqueous layer was extracted with dichloromethane (3 × 15 ml).
The combined organic layers were dried over sodium sulfate, filtered and
concentrated in vacuo to afford a red oil. The residue was purified by
chromatography on silica gel, eluting with a solvent mixture of dichloromethane/
methanol/28% aqueous ammonium hydroxide (97.5/2.0/0.5 v/v/v) to afford 119 mg
of the title compound as a yellow oil (79% yield).
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Full experimental and computational details and the characterization of new
compounds are available in the Supplementary Information.
Received 14 January 2016; accepted 5 April 2016;
published online 6 June 2016
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Acknowledgements
The authors thank the National Institute of General Medical Sciences (GM088237), the
National Institute of Biomedical Imaging and Bioengineering (EB013042), UCB Pharma
and Kwanjeong Educational Foundation for funding. The authors further thank J. McClean
(Harvard University) for helpful discussions.
Author contributions
G.B.B., W.S.H. and A.R.M. designed and performed the experiments and analysed the data.
G.B.B. discovered the Ar–TEDA formation reaction and conceived the mechanistic
proposal and explanation for the positional selectivity. A.R.M. discovered the reduction of
Ar–TEDA compounds to aryl piperazines. G.B.B. and T.R. prepared the manuscript with
input from W.S.H. and A.R.M.
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Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be
addressed to T.R.
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radicals to alkenes—an experimental and theoretical perspective. Angew. Chem.
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•
16. Wong, M. W., Pross, A. & Radom, L. Comparison of the addition of CH3 ,
CH2OH•, and CH2CN• radicals to substituted alkenes: a theoretical study of the Competing financial interests
reaction mechanism. J. Am. Chem. Soc. 116, 6284–6292 (1994).
The authors declare no competing financial interests.
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