Site-Selective, Remote sp3 C?H Carboxylation Enabled by the Merger of Photoredox and Nickel Catalysis

Article abstract of DOI:10.1002/chem.201902095

A photoinduced carboxylation of alkyl halides with CO₂ at remote sp³ C?H sites enabled by the merger of photoredox and Ni catalysis is described. This protocol features a predictable reactivity and site selectivity that can be modulated by the ligand backbone. Preliminary studies reinforce a rationale based on a dynamic displacement of the catalyst throughout the alkyl side chain.

Full text of DOI:10.1002/chem.201902095

A Journal of
Accepted Article
Title: Site-Selective, Remote sp3 C–H Carboxylation Enabled by the
Merger of Photoredox and Nickel Catalysis
Authors: Ruben Martin, Basudev Sahoo, Peter Bellotti, Francisco Juliá-
Hernández, Qing-Yuan Meng, Stefano Crespi, and Burkhard
König
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201902095
Link to VoR: http://dx.doi.org/10.1002/chem.201902095
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10.1002/chem.201902095
Chemistry - A European Journal
COMMUNICATION
Site-Selective, Remote sp3 C–H Carboxylation Enabled by the
Merger of Photoredox and Nickel Catalysis
Basudev Sahoo,‡ Peter Bellotti,‡ Francisco Juliá-Hernández, Qing-Yuan Meng, Stefano Crespi,*
Burkhard König* and Ruben Martin*
Abstract: A photoinduced carboxylation of alkyl halides with CO2 at
remote sp3 C–H sites enabled by the merger of photoredox and Ni
catalysis is described. This protocol features a predictable reactivity
and site-selectivity that can be modulated by the ligand backbone.
Preliminary studies reinforce a rationale based on a dynamic
displacement of the catalyst throughout the alkyl side-chain.
photochemical techniques[7] remain confined to the activation of
sp3 C–H bonds adjacent to heteroatoms or aromatic rings,
invariably requiring high-intensity UV-irradiation (Scheme 1, path
b).[8] The latter is particularly problematic given the wide number
of functional groups that absorb in the UV region, leading to
deleterious side-reactions arising from photoexcitation of the
substrate itself, thus reinforcing the need for a sp3 C–H
carboxylation technique with improved flexibility, generality and
practicality. A significant step-forward in sp3 C–H carboxylation
has been recently reported by our group within the context of
chain-walking reactions; however, stoichiometric amounts of
metal salts are inevitably required,[4d],[9] thus hampering the
implementation of these processes in industrial endeavors.[10]
Prompted by our interest in nickel catalysis and visible light-
induced processes,[3b-g,4b-d,9] we wondered whether the merger of
these two techniques might enable a CO2 insertion at remote sp3
C–H sites in the absence of stoichiometric metal salts, thus
offering an unrecognized opportunity in metallaphotoredox[11,12]
and carboxylation reactions.[1] Herein, we report the successful
realization of this goal by using alkyl halides as precursors
(Scheme 1, bottom). The protocol is characterized by a site-
selectivity pattern that can be modulated by a subtle modification
of the ligand backbone, thus resulting in the functionalization at
benzylic or even at primary sp3 C–H sites, arguably the
strongest C–H bonds in the alkyl series. Preliminary mechanistic
studies suggest that a dynamic displacement of the nickel
catalyst throughout the hydrocarbon side chain via Ni(II)
intermediates comes into play.[13]
Metal-catalyzed reductive carboxylation reactions of organic
(pseudo)halides with abundant and inexpensive carbon dioxide
(CO2)[1] have provided new vistas for preparing industrially-
relevant carboxylic acids in the absence of stoichiometric
organometallic reagents.[2] Although this area of expertise has
reached remarkable levels of sophistication, the vast majority of
sp3 carboxylation reactions primarily rely on ipso-CO2 insertions
at prefunctionalized sites (Scheme 1, path a).[3,4]
current portfolio for carboxylation reactions at sp3 sites
ipso CO2
high intensity
insertion
UV light
Ni
H
X
CO2H
= Ar, H
= Ar, NR2
activated sp3
C-H bonds
X = Br, Cl, NR3
path a
path b
metallaphotoredox site-selective remote sp3 C-H carboxylation (this work)
remote sp3 sites
Ni / L7
visible
light
Ni / L1
visible
light
Hb Br
Ha
n
m
Hb
CO2H
mild conditions
no metal reductants
excellent site-selectivity
CO2H
n
m
Ha
n
m
(L1)NiBr2 (5 mol%)
4-CzIPN (1 mol%)
CO2H
Ha
Ph
Ph
Ha
HEH (1.5 equiv)
Br
+
Ph
Scheme 1. Merging Ni and photoredox catalysts for sp3 C–H carboxylation.
H
CO2H
K2CO3 (1.0 equiv), H2O
CO2 (1 bar), DMF
1a
2a
2a’
Blue-LEDs, 25 °C
From both a conceptual and practical standpoint, the ability to
expand the boundaries of CO2 fixation into unactivated sp3 C–H
sites would be a particularly attractive scenario.[5] Unfortunately,
the available sp3 C–H carboxylation portfolio indicates that a
vast number of daunting challenges remain.[6] At present,
yield (%)[a],[b]
entry
2a:2a’
deviation from standard conditions
1
66 (56)
36
none
90:10
70:30
71:29
62:38
72:28
85:15
90:10
90:10
85:15
84:16
42:58
—
2
(L2)NiBr2 instead of (L1)NiBr2
(L3)NiBr2 instead of (L1)NiBr2
(L4)NiBr2 instead of (L1)NiBr2
(L5)NiBr2 instead of (L1)NiBr2
(L6)NiBr2 instead of (L1)NiBr2
NiBr2·glyme/L1 instead of (L1)NiBr2
using HEH (1.0 equiv)
3
28
4
30
5
42
6
55
[*]
B. Sahoo, F. Juliá-Hernández, Prof. R. Martin
Institute of Chemical Research of Catalonia (ICIQ)
The Barcelona Institute of Science and Technology
Av. Països Catalans 16, 43007 Tarragona (Spain)
E-mail: rmartinromo@iciq.es
7
58
8
59
9
50
using 4Å MS instead of H2O
using LiBr (1.0 equiv)
10
11
12
61
Prof. R. Martin
35
Cs2CO3 instead of K2CO3
no (L1)NiBr2, no 4-CzIPN or no light
ICREA, Passeig Lluïs Companys, 23, 08010 Barcelona Spain
0
P. Bellotti, Q. –Y. Meng, S, Crespi, Prof. B. König
Institut für Organische Chemie, Universität Regensburg
Universitätstrasse 31, 93053 Regensburg (Germany)
E-mail: Stefano.Crespi@chemie.uni-regensburg.de
E-mail: Burkhard.Koenig@chemie.uni-regensburg.de
These authors contributed equally to this work
R1=Me; R2=H (L1)
Cbz
NC
CN
R2
R1=Me; R2=Me (L2)
R1=Me; R2=OMe (L3)
R1=Me; R2=Ph (L4)
R2
Cbz
N
N
R1
Cbz
Cbz
R1
R1=Me; R2=4-F-C6H4 (L5)
R1=Et; R2=H (L6)
[‡]
4-CzIPN
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/chem.201902095
Chemistry - A European Journal
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benzylic sp3 C–H sites. As shown in Scheme 3, similar reactivity
and site-selectivity were obtained for a plethora of homobenzyl
bromides independent of whether they possessed electron-rich
or electron-poor substituents on the aryl ring. It is worth noting,
however, that electron-donating groups provided the best yields
of the series (2e, 2g, 2h).[16] As shown for 2a, the reaction can
be scaled-up without significant erosion in yield or site-selectivity.
Importantly, phenols (2g), amides (2h), ketones (2j) or esters
(2k) do not interfere with productive carboxylation at the benzylic
sp3 C–H site. Phenol (2g) gave higher yields, most likely through
Lewis-acidic assistance of K+ during the CO2-insertion (Scheme
3, middle).[17] Albeit in lower yields, we found that our protocol
can be extended to electron-rich unprotected indoles (2l) or
secondary homobenzylic bromides (2m). The latter result is
particularly interesting, particularly if one takes into consideration
the inherent structural limitations observed in otherwise related
carboxylation of benzyl halides possessing a-substituents other
than methyl groups.[3f-h]
Scheme 2. Optimization of the reaction conditions. 1a (0.20 mmol), (L1)NiBr2
(5 mol%), 4-CzIPN (1 mol%), HEH (1.5 equiv), K2CO3 (1.0 equiv), H2O (5.0
equiv), CO2 (1 bar), Blue-LEDs in DMF (0.1 M) at 25 ºC for 5 h. [a] Yields
[b]
determined by NMR using 1,3,5-trimethoxybenzene as standard.
Isolated
yield, average of two independent runs. 4-CzIPN: 2,4,5,6-tetra(carbazol-9-yl)-
isophthalonitrile; DMF = dimethylformamide; Cz = carbazole; HEH = diethyl
1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.
Our investigations began by studying the Ni-catalyzed
carboxylation of homobenzylic bromide (1a) with CO2 (1 bar)
(Scheme 2). After systematic evaluation of all reaction
parameters,[14] we found that a protocol based on (L1)NiBr2,
organic photocatalyst 4-CzIPN, K2CO3 and Hantzsch ester (HEH)
as terminal reductant provided the best results, giving rise to the
targeted carboxylic acid in 56% isolated yield with a 90:10
branched:linear selectivity (entry 1). As initially anticipated,
subtle modifications on the ligand backbone resulted in a
markedly decrease in reactivity; while the inclusion of
substituents adjacent to the nitrogen atom was shown to be
critical for success,[15] it became apparent that aryl or alkyl
groups at C4 and/or C7 had a deleterious effect in both
selectivity and reactivity (entries 2-6). Intriguingly, the utilization
of desiccants led to lower yields of 2a (entry 9), thus revealing a
non-innocent role exerted by water.[4d] Unlike related Ni-
catalyzed carboxylations of organic (pseudo)halides,[3] the
presence of additives such as LiBr was not necessary for the
reaction to occur (entry 10); note, however, that K2CO3 provided
better results than Cs2CO3 (entry 11), showing the influence that
the escorting cation might have on reactivity. As anticipated,
control experiments in the absence of either (L1)NiBr2, 4-CzIPN
or light resulted in no conversion to 2a (entry 12).
photocarboxylation of well-defined alkyl bromides at remote sp3 C-H sites
(L7)NiBr2 (10 mol%)
Me
4-CzIPN (1 mol%)
Br
N
HEH (2.0 equiv)
CO2H
n
L7
Ha
n
Rb2CO3 (2.0 equiv)
CO2 (1 bar), DMF
Blue-LEDs, 10 ˚C
N
H
4a-j
3a-j
Me
Me
R
CO2H
CO2H
4a (R = n-Pr), 48% (l:b = 99:1)[a]
4b (R=i-Pr), 44% (l:b = 99:1)[a]
4c (R=CH2Ph), 52% (l:b = 99:1)
CO2H
4a, 42% (l:b = 99:1)[a]
CO2H
4d, 40% (l:b = 99:1)[b]
Me
Me
CN
N
(L1)NiBr2 (5 mol%)
Cl
Me
L1
Ha
CO2H
4-CzIPN (1 mol%)
HEH (1.5 equiv)
Br
R
N
N
CO2H
CO2H
CO2H
Het
Het
4e, 56% (l:b = 80:20)
R
K2CO3 (1.0 equiv), H2O
CO2 (1 bar), DMF
4g, 46% (l:b = 94:6)[a]
46% (l:b = 99:1)[a]
4f, 50% (l:b = 99:1)
1a-m
2a-m
Me
O
H
Blue-LEDs, 25 °C
OMe
N
Me
Ph
O
CO2H
CO2H
CO2H
O
MeO
O
Me
Me
Me
CO2H
4h, 50% (l:b = 99:1)[a]
CO2H
4i, 53% (l:b = 99:1)
CO2H
4j, 51% (l:b = 99:1)[a]
Me
2b, 51%,[a]
2a, 56%,[a] 48%[a],[b]
CO2H
2c, 52%,[c]
photocarboxylation of n-heptanes via regioconvergent scenarios
CO2H
R
Me
Me
Me
H
Me
(L7)NiBr2/4-CzIPN
Br2
Me
Br
2d (R=Me), 48%,[d]
2e (R=OMe), 57%,[a]
2f (R=Ph), 45%,[a]
2g (R=OH), 70%,[c]
2h (R=NHAc), 65%,[a]
CO2 (1 bar), DMF
Blue-LEDs, 10 ˚C
CO2H
MnO2
H
4a, 31% (99:1)
from n-heptane
statistical mixtures
Scheme 4. Catalytic carboxylation at remote sp3 C–H sites by merging Ni &
photoredox catalysis. Conditions: 3 (0.25 mmol), (L7)NiBr2 (10 mol%), 4-
CzIPN (1 mol%), HEH (2.0 equiv), Rb2CO3 (2.0 equiv), CO2 (1 bar), DMF (0.08
M), Blue-LEDs in DMF at 10 ºC for 20 h; yields of isolated products, average
2i, 49%[d]
intermediate of 2i
CO2H
CO2H
Me
R
CO2H
Me
[a]
[b]
O
Me
of two independent runs.
TBAI (1.0 equiv) as additive.
Obtained upon
HN
hydrolytic workup using methyl 5-bromohexanoate. Regioconvergent
photocarboxylation of n-heptane: Br2 (0.25 mmol), MnO2 (0.50 mmol) in n-
heptane (1.25 mL) followed by the conditions highlighted above for 4a.
MeO
2j (R=Me), 53%[c]
2k (R=OMe), 48%[e]
2l, 38%[f]
2m, 22%
Scheme 3. Benzylic sp3 C–H carboxylation by merging Ni & photoredox
While the results summarized in Scheme 3 clearly illustrated the
feasibility of a benzylic sp3 C–H carboxylation in the absence of
metal reductants, there was a reasonable doubt on whether our
protocol could be extended to carboxylation events at distal,
primary sp3 C–H sites. Undoubtedly, the successful realization of
such a void terrain would unlock new fundamental reactivity
within the metallaphotoredox arena[11.12] while expanding our
catalysis. Conditions: see Scheme 2 (entry 1); yields of isolated products,
[b]
average of two independent runs. [a] b:l = 90:10.
1.0 mmol scale. [c] b:l =
85:15. [d] b:l = 93:7. [e] Isolated as methyl ester. [f] b:l = 80:20. For additional
substrates, see SI.[14]
With optimized conditions in hand, we next set out to explore the
generality of our light-induced Ni-catalyzed carboxylation at
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10.1002/chem.201902095
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COMMUNICATION
repertoire when activating strong primary sp3 C–H bonds in the
presence of a priori more reactive sites.[18] As expected, the
ligand had a non-negligible impact on both efficiency and site-
selectivity.[15] Indeed, the reaction of 2-bromoheptane (3a) under
the optimized conditions of Scheme 3 based on a Ni/L1 regime
resulted in traces, if any, of 1-octanoic acid (4a). However, a
protocol based on Ni/L7 furnished 4a in 48% yield and with
exquisite site-selectivity (99:1).[19] Importantly, while an exquisite
site-selectivity was found for a Ni/L9 protocol based on Mn as
terminal reductant,[9] a Ni/L9 photochemical event resulted in a
significant erosion in yield and site-selectivity, thus showing the
subtleties of our photocatalytic chain-walking carboxylation.[14]
As shown in Scheme 4, a variety of linear carboxylic acids could
be prepared from a range of alkyl bromides in excellent site-
selectivities via formal [1,n]-migration of the Ni atom throughout
the side chain. Although modest yields, the outcome of our
remote Ni/photoredox carboxylation at primary sp3 C–H sites
should be assessed against the challenge that it addresses.
Particularly noteworthy was the site-selectivity pattern observed
for 4g-4j, with CO2 insertion occurring at the strongest, primary
sp3 C–H sites. Given that primary alkyl radicals are beyond
reach via hydrogen-atom transfer (HAT),[20] these results
constitute an orthogonal gateway with existing UV-mediated
carboxylations occurring at weaker benzylic sites or adjacent to
heteroatoms via open-shell species (Scheme 1, path b).[8]
Equally interesting was the functional group compatibility in the
presence of esters (4d), nitriles (4f), ketones (4j), alkyl chlorides
(4e) or amides (4i). Notably, the alkyl bromide derived from a
nonsteroidal anti-inflammatory drug such as Nabumetone
delivered 4h in 99:1 ratio.[21] Similarly, 4b was obtained as a
single regioisomer, indicating that the reaction took place at the
most accessible sp3 C–H site. Although competitive C3-
carboxylation events might occur with electron-rich indoles,[22]
this was not the case (4g). Particularly rewarding was the ability
to convert n-heptane into 4a (l:b = 99:1) via bromination/chain-
walking photocarboxylation (Scheme 4, bottom), standing as a
testament to the prospective impact of our protocol to repurpose
chemical feedstocks (alkanes and CO2) in a controllable fashion.
Although unraveling the underpinnings of our Ni/photoredox
chain-walking carboxylation at sp3 C–H sites should await further
investigations, we decided to shed light into the mechanism via
combined experimental and theoretical studies (Scheme 5).[14]
Synergistic spectroelectrochemical measurements and in-situ
UV-vis spectroscopy on (L1)NiBr2 and (L7)NiBr2 revealed that
low-valent Ni(I) and Ni(0) species are formed during light
irradiation in the presence of 4-CzIPN and Hantzsch ester.[14,23]
The assumption that the benzylic carboxylation featured a rather
facile b-H elimination from cationic Ni(II) species was
experimentally corroborated by detecting styrenes in small
amounts, the concentration of which decays to zero after
consumption of the alkyl bromide.[14] In addition, olefins were not
detected in the absence of Ni/L1 or Ni/L7, arguing against base-
promoted E2-elimination/olefin carboxylation event. DFT
calculations confirmed that species B–D had similar energy and
that these species coexist in rapid equilibrium via rather facile b-
H elimination from cationic Ni(II) intermediates.[24,25] Importantly,
DFT calculations revealed a rather unfavorable CO2 insertion for
Ni(II) species D, either via outer- or inner-sphere mechanisms,
reinforcing the notion that CO2 takes place at a Ni(I) center (E)
generated upon single electron transfer (SET), thus giving rise to
a Ni(I)-carboxylate F.[26] A final SET can provide 4a-I while
recovering back the propagating Ni(0)/L7 (A) species. While the
activation energy for the SET reduction could not be obtained
via DFT calculations, the absence of a kinetic Isotope effect and
the preferential regioselectivity observed at remote primary sp3
C–H sites (4a-I vs 4a-I') suggests that the formation of Ni(I)
species might be the rate-determining step of the reaction. A
similar rationale can be drawn for homobenzylic bromides, with
an energetic profile that favors CO2 incorporation at benzylic sp3
C–H sites.[14] In this case, the selectivity at benzylic sites can be
explained by both kinetic and thermodynamic grounds.[14]
In summary, we have described the merger of photoredox and
Ni catalysis as a platform for enabling carboxylation at remote
sp3 C–H sites under atmospheric pressure of CO2 while
obviating the need for stoichiometric metal reductants. The
salient features of this method are the mild conditions and a site-
selectivity pattern that can be modulated by the nature of the
ligand employed, offering an unrecognized opportunity in the
metallaphotoredox arena for the activation of sp3 C–H bonds.
Further work along these lines is currently in progress.
TSB-C
ΔG‡ = +12.5
Br–
PC•–
Br Ni Br
Ni
PC•–
Ni
H
Ha
2x
SET
3a
PC
B (-42.0)
n-Bu
n-Bu
TSC-D
C (-30.4)
ΔG‡ = +1.7
Br–
+
PC
Ni
Ni
A (0.0)
PC
Acknowledgements
H
-
CO2
Ni
E' (-108.6)
n-Bu
We thank ICIQ and MINECO (CTQ2015-65496-R) for support. B.
Sahoo and P. Bellotti thank European Union’s Horizon 2020
under the Marie Sklodowska-Curie grant agreement (795961)
and Elitenetzwerk Bayern (SynCat) for financial support. We
thank C. Riesinger for the initial optimization of the reaction
conditions, F. Fricke for the help with substrate scope, R.
Hoheisel for spectroelectrochemical measurements, and B. F.
Gu for helpful discussions.
PC*
H
HEH
D (-41.0)
SET
+ CO2
n-Bu
n-Bu
4a-I
PC•–
-
PC•–
CO2
(-154.9)
n-Bu
HEH•+
SET
4-CzIPN
L7
PC
4a'-I
(-154.9)
Ni
Ni
PC
O
O
H
Ni
Ni
Ni
Ni(0)
Ni(I)
E (-107.6)
F (-137.9)
n-Bu
CO2
Ni(II)
n-Bu
Keywords: carboxylation • photocatalysis • nickel • chain-
The relative Gibbs free Energy (kcal mol-1) at the SMD(DMF)-BS-UωB97X-D/def2-
TZVP//BS-UωB97X-D/6-31G(d) of the intermediates are reported in brackets. All
the energies are relative to A, see ref 14.
walking • carbon dioxide
[1]
For selected reviews, see: a) A. Tortajada, F. Juliá-Hernández, M.
Börjesson, T. Moragas, R. Martin, Angew. Chem. Int. Ed. 2018, 57,
15948-15982; Angew. Chem. 2018, 130, 16178-16214; b) F. Juliá-
Scheme 5. Mechanistic rationale for the photocarboxylation of 3a.
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10.1002/chem.201902095
Chemistry - A European Journal
COMMUNICATION
Hernández, M. Gaydou, E. Serano, M. van Gemmeren, R. Martin, Top.
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[3]
H. Maag, Prodrugs of Carboxylic Acids; Springer: New York, 2007.
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a Ni/L7 regime
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Ni(I) species could not be optimized, suggesting that
a scenario
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This article is protected by copyright. All rights reserved.

10.1002/chem.201902095
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Basudev Sahoo, Peter Bellotti,
Francisco Juliá-Hernández, Qing-Yuan
Meng, Stefano Crespi*, Burkhard König*
and Ruben Martin*
Page No. – Page No.
Title
The merger of Ni and photoredox catalysis enables a CO2 insertion at remote sp3
C–H sites under visible light irradiation and in the absence of metal reductants. The
salient features of this method are the mild conditions and a site-selectivity pattern
that can be modulated by subtle modifications of the ligand backbone, offering an
unrecognized opportunity in the metallaphotoredox arena and a complementary
reactivity mode to existing functionalization techniques at remote sp3 C–H sites.
Site-selective, remote sp3 C–H
carboxylation enabled by the merger
of photoredox and nickel catalysis
This article is protected by copyright. All rights reserved.