Hydrodecarboxylation of Carboxylic and Malonic Acid Derivatives via Organic Photoredox Catalysis: Substrate Scope and Mechanistic Insight

Article abstract of DOI:10.1021/jacs.5b07770

A direct, catalytic hydrodecarboxylation of primary, secondary, and tertiary carboxylic acids is reported. The catalytic system consists of a Fukuzumi acridinium photooxidant with phenyldisulfide acting as a redox-active cocatalyst. Substoichiometric quantities of Hünigs base are used to reveal the carboxylate. Use of trifluoroethanol as a solvent allowed for significant improvements in substrate compatibilities, as the method reported is not limited to carboxylic acids bearing α heteroatoms or phenyl substitution. This method has been applied to the direct double decarboxylation of malonic acid derivatives, which allows for the convenient use of dimethyl malonate as a methylene synthon. Kinetic analysis of the reaction is presented showing a lack of a kinetic isotope effect when generating deuterothiophenol in situ as a hydrogen atom donor. Further kinetic analysis demonstrated first-order kinetics with respect to the carboxylate, while the reaction is zero-order in acridinium catalyst, consistent with another finding suggesting the reaction is light limiting and carboxylate oxidation is likely turnover limiting. Stern-Volmer analysis was carried out in order to determine the efficiency for the carboxylates to quench the acridinium excited state.

Full text of DOI:10.1021/jacs.5b07770

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Article
Hydrodecarboxylation of Carboxylic and Malonic Acid Derivatives via
Organic Photoredox Catalysis: Substrate Scope and Mechanistic Insight
Jeremy D. Griffin, Mary A. Zeller, and David A. Nicewicz
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 20 Aug 2015
Downloaded from http://pubs.acs.org on August 20, 2015
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Journal of the American Chemical Society
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Hydrodecarboxylation of Carboxylic and Malonic Acid Derivatives via
Organic Photoredox Catalysis: Substrate Scope and Mechanistic Insight
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Jeremy D. Griffin, Mary A. Zeller, and David A. Nicewicz*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-3290
Supporting Information Placeholder
ABSTRACT: A direct, catalytic hydrodecarboxylation of primary, secondary, and tertiary carboxylic acids is reported. The catalytic sysꢀ
tem consists of a Fukuzumi acridinium photooxidant with phenyldisulfide acting as a redoxꢀactive coꢀcatalyst. Substoichiometric quantiꢀ
ties of Hünig’s base are used to reveal the carboxylate. Use of trifluoroethanol as a solvent allowed for significant improvements in subꢀ
strate compatibilities, as the method reported is not limited to carboxylic acids bearing alpha heteroatoms or phenyl substitution. This
method has been applied to the direct double decarboxylation of malonic acid derivatives, which allows for the convenient use of dimethyl
malonate as a methylene synthon. Kinetic analysis of the reaction is presented showing a lack of a kinetic isotope effect when generating
deuterothiophenol in situ as a hydrogen atom donor. Further kinetic analysis demonstrated first order kinetics with respect to the carboxꢀ
ylate while the reaction is zeroꢀorder in acridinium catalyst, consistent with another finding suggesting the reaction is light limiting and
carboxylate oxidation is likely turnover limiting. SternꢀVolmer analysis was carried out in order to determine the efficiency for the carboxꢀ
ylates to quench the acridinium excited state.
INTRODUCTION
Scheme 1: Progression of Hydrodecarboxylation Strategies
Barton, et. al., 1983: PTOC Ester Hydrodecarboxylation
The utility of carboxylic acids and esters as functional handles
and activating groups is vital to the strategic deployment of clasꢀ
sical CꢀC bond forming reactions in complex synthetic sequences
via enolate and Michael reactivity.1,2 Furthermore, carboxylic
acids and esters are also commonly used to activate dienophiles
for DielsꢀAlder cycloadditions,3 a reaction that is ubiquitous in
complex molecule synthesis. Though carbonyls are valuable for
their ability to facilitate carbonꢀcarbon bond formation, the carꢀ
boxylic acid functionality is not always desired in downstream
adducts which would necessitate removal. Excising carboxylic
acid functionality via a hydrodecarboxylation strategy allows for
the use of carbonyls as traceless functional handles for assembling
molecular complexity.
AIBN
DCC
DMAP
O
O
Bu3SnH
Me
Me
Me
H
16
OH
O
N
16
16
PhMe
O
Na
S
S
N
80 °C
93% yield
Hatanaka, et. al., 2007: Stoichiometric Hydrodecarboxylation
phenanthroline (1.0 equiv)
1,4-dicyanobenzene (1.0 equiv)
Me Me
Me
(2.0 equiv)
O
SH
UV Irradiation
8
Me
H
The Barton decarboxylation4–7 is perhaps the most commonly
utilized method for the reduction of carboxylic acids to alkanes
via a hydrodecarboxylation mechanism,8–10 however requires preꢀ
functionalization of the carboxylic acid (PTOC ester formation)
and utilizes stoichiometric amounts of toxic tin hydrides as the
source of hydrogen atoms (Scheme 1). Modifications of the Barꢀ
ton decarboxylation employ thiols,11,12 silanes,13 or chloroform14
as Hꢀatom donors, but necessitate superstoichiometric quantities
of Hꢀatom donor or produce significant amounts of unwanted
byproducts. Electrochemical methods for decarboxylation have
also been employed, such as the Kolbe electrolysis which proꢀ
ceeds through the single electron oxidation of a carboxylate to
form an acyloxyl radical.15,16 These radicals are known to rapidly
rearrange to expel CO2 and form carbonꢀcentered radicals.17,18 On
the surface of an electrode these radicals can be successively oxiꢀ
dized to the corresponding cation, known as the nonꢀKolbe pathꢀ
way.19
Me
OH
14
14
82% yield
This Work: Catalytic Hydrodecarboxylation
Me
Mes-Acr-Ph
5 mol %
Mes-Acr-Ph
10 mol % (PhS)2
O
Me
Bn
Bn
H
Me
OH
Blue LEDs
N
97% yield
BF4
Ph
Several methods for hydrodecarboxylation and decarboxylaꢀ
tive coupling25 have been developed using Pd,26–31 Cu,32–35
Ag33,36,37 and Rh38 but these methods are limited to aryl and alꢀ
kynyl carboxylic acids. Photoredox catalysis has been utilized to
implement decarboxylative functionalizations, including additions
to arenes39–42 and alkenes,43–50 as well as decarboxylative fluorinaꢀ
tions51–53 and decarboxylation of keto carboxylic acids to form
ketones.54 Wallentin and coworkers recently reported a photoreꢀ
dox method for the hydrodecarboxylation of stabilized carboxylic
acids, such as protected amino acid derivatives, and phenyl acetic
acid derivatives using a similar catalyst system to our own; howꢀ
ever aliphatic carboxylic acids were not found to be viable subꢀ
strates using this method.24 Thus, a method for the direct catalytic
To avoid dimerization of radicals and successive radical oxiꢀ
dation, several methods for the catalytic hydrodecarboxylation
and decarboxylative coupling reactions have been developed usꢀ
ing both ground state,20,21 and photochemical oxidants.22–24 These
methods often utilize stoichiometric amounts of a terminal oxiꢀ
dant and hydrogen atom donor.22,23
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hydrodecarboxylation of unstabilized aliphatic carboxylic acids
can be up to five units greater in methanol than in water (the pKa
1
2
3
4
5
6
7
8
has remained elusive.
of acetic acid in water is 4.76 vs 9.63 in methanol), while the pKa
of protonated amines are similar in both solvents (triethylammoꢀ
nium is 10.75 in water and 10.78 in methanol)67. This prompted
us to conduct a thorough examination of the base employed in the
reaction. The more strongly basic 2,4,6ꢀcollidine gave improved
yields (Entry 5), as did the even more basic, N,Nꢀ
diisopropylethylamine (DIPEA, Entry 6). Though it may be
somewhat surprising that oxidizable amine bases are compatible
in these reactions as they are known to form aminium radical
cations in similar photoredox systems,68,69 their use can be rationꢀ
alized by noting that they likely predominately exist in solution as
the ammonium salts which are insulated from oxidation. Due to
the success with the MeOH:H2O system, we considered other
polar alcohol solvents, and found that trifluoroethanol (TFE, Enꢀ
try 8) gave a marked improvement. Primary aliphatic carboxylic
acids such as hydrocinnamic acid were poor substrates when usꢀ
ing 9:1 MeOH:H2O as solvent (Entry 9), however using TFE as a
solvent dramatically improved their reactivity (Entry 10). Control
experiments revealed that base was necessary for reactivity (Entry
7) as was phenyl disulfide (Entry 11).
A direct catalytic hydrodecarboxylation of aliphatic carboxꢀ
ylic acids and malonic acid derivatives would be complementary
to these methods. Hydrodecarboxylation of malonic acid derivaꢀ
tives could be particularly interesting from a synthetic standpoint
because it would allow for the use of malonate as a “(ꢀ)CH2(ꢀ)“
synthon by directly reducing the corresponding malonic acid. This
would have the advantage over conventional methods, which
require several additional steps to reach the desired product. There
are also numerous examples of reactions that rely on malonates to
increase the rate of intramolecular reactions such as intramolecuꢀ
lar DielsꢀAlder reactions or olefin metathesis.55 Although, maloꢀ
nates are useful for facilitating ThorpeꢀIngold effects and as funcꢀ
tional handles, they are not always desirable in the final product.
Traditional methods for removing both carboxylates would reꢀ
quire several steps including thermal decomposition of the maloꢀ
nic acid at high temperatures, then formation of the Barton ester
and decomposition thereof to remove the second carboxylate.
Thus, we set out to develop a general method for decarboxylating
unstabilized carboxylic acids and malonic acid derivatives.
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Table 1: Optimization of Reaction Conditions
Due to the low oxidation potential of aliphatic carboxylates
(vide infra), we believed that the direct, catalytic, photoredox
hydrodecarboxylation of aliphatic carboxylic acids should not, in
theory, be limited to those acids stabilized by either heteroatomic
functionality or aryl substitution. Thus, we found it surprising that
the photoredox hydrodecarboxylation of aliphatic carboxylic acids
was apparently more difficult to achieve. We hoped to provide
mechanistic insight into the factors contributing to this problem,
as we believed it could lead to the transformation being developed
further.
We envisioned using Fukuzumi acridinium photooxidants,56
which have recently been employed in photoredox systems in our
lab,57–65 as they are cited to have excited state reduction potentials
of greater than +2.0 V.57 Carboxylic acids have been used in variꢀ
ous other transformations in our lab, indicating that the carboxylic
acid is not itself oxidizable,57,60,65 however we believed that
deprotonation by a strong, nonꢀcoordinating base could reveal the
carboxylate and render them more susceptible to oxidation. This
is further evidenced by the fact that carboxylic acids have oxidaꢀ
tion potentials higher than the solvent window in acetonitrile,
whereas tetrabutylammonium carboxylates are cited to have oxiꢀ
dation potentials close to +1.2 V.66 This indicates that base selecꢀ
tion would be critical to the success of the proposed oxidative
decarboxylation.
O
Mes-Acr-Ph (5 mol %)
H
Ph
OH
Ph
(PhS)2 (10 mol %)
R R
R R
Base, Solvent [0.5 M]
1a; R = Me
1b; R = H
450 nm LEDs, 24 h
Entry Substrate
Solvent
Basea
Yieldb
<10%
<10%
<10%
21%
1
2
CHCl3
MeCN
MeOH
2,6ꢀlutidine
2,6ꢀlutidine
2,6ꢀlutidine
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
3
4
MeOH/H2O (9:1) 2,6ꢀlutidine
5
MeOH/H2O (9:1)
MeOH/H2O (9:1)
MeOH/H2O (9:1)
CF3CH2OH
collidine
iꢀPr2NEt
–
51%
6
81%
7
No rxn
77%
8
iꢀPr2NEt
iꢀPr2NEt
iꢀPr2NEt
iꢀPr2NEt
9c
10c
11c,d
MeOH/H2O (9:1)
CF3CH2OH
14%
97%
CF3CH2OH
<10%
Reactions carried out on a 0.3 mmol scale in N2ꢀsparged solvents [0.5M]
at ambient temperature. a20 mol % base loading. bYields determined by 1H
NMR analysis of crude reactions.cReaction run for 72 h. dReaction without
phenyl disulfide.
RESULTS AND DISCUSSION
Aware that solvent could play an important role in the success
of the transformation, we began by conducting a solvent screen
using both protic and aprotic solvents with a range of polarity. We
began optimization with conditions similar to those previously
reported by our lab63 and with the aliphatic tertiary acid 1a, as we
believed the formation of the tertiary carbon centered radical
would be relatively facile and the substrate could represent a feaꢀ
sible expansion of previous substrate limitations. After some iniꢀ
tial screening Mes-Acr-Ph was found to be the catalyst of choice,
potentially because it is less susceptible to deactivation via
dealkylation than the more widely used MesꢀAcrꢀMe.64 Under
these conditions, we did observe product formation, albeit in very
low yields (Table 1, Entry 1). Changing the solvent to more polar
solvents such as acetonitrile and methanol seemed to have no
effect (Entries 2 & 3). Using a 9:1 MeOH:H2O solvent system,
gains in yields were observed (Entry 4). This indicates that inꢀ
creasing the equilibrium concentration of carboxylate relative to
the carboxylic acid was important. The pKa of carboxylic acids
With these optimized conditions, we decided to explore the
scope of this reaction (Chart 1). Primary (2a-c), secondary (2d),
tertiary (2e) alkyl substituted carboxylic acids were all competent
substrates. Further investigation of the scope of this reaction reꢀ
vealed that electron deficient (2b) and moderately electron rich
arenes (2c) were tolerated under the standard reaction conditions,
while electron rich arenes, such as p-methoxyhydrocinnamic acid,
were not viable substrates presumably due to competitive oxidaꢀ
tion of the aromatic ring with the carboxylate functional group.
Substrates bearing biꢀ (2f) and monoaryl (2g) substitution adjaꢀ
cent to the carboxylate were found to be excellent substrates. Proꢀ
tected amino acids (2h) and other protected amineꢀcontaining
substrates (2i and 2j) were also tolerated using this method. Subꢀ
strates bearing αꢀesters (2k) could be efficiently decarboxylated
under these conditions. Fatty acid tridecanoic acid initially gave
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Journal of the American Chemical Society
only trace amounts of dodecane (2l). Tridecanoic acid was only
tion time (96 hrs, 85%). The increased reaction time required for
1
2
3
4
5
6
7
sparingly soluble in TFE, therefore an additional solvent screen
was conducted, and revealed that using 4:1 TFE:EtOAc [0.3M]
improved the reactivity substantially. Inreasing disulfide loading
from 10 to 20 mol % was also found to be optimal for this subꢀ
strate. Remarkably, the highly functionalized natural product
Enoxolone (2m) underwent hydrodecarboxylation in good yield
as a mixture of diastereomers (3:1), albeit with an extended reacꢀ
this substrate is most likely due to the limited solubility of the
substrate in TFE, even at lower concentrations. However, with the
use of ethyl acetate as a coꢀsolvent the reaction time could be
reduced to 24 hours, with an improved yield. Using ethyl acetate
as a coꢀsolvent also improved reactivity for substrate 2j, which
also exhibited low solubility in TFE.
8
9
Chart 1: Hydrodecarboxylation Reaction Scope
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Mes-Acr-Ph (5 mol %)
O
(PhS)2 (10 mol %)
R1
R1
R2 R3
H
OH
H
R2 R3
i-Pr2NEt (20 mol %)
450 nm LEDs, TFE [0.5 M]
Me
H
H
H
Me Me
H
2a
Cl
Me
2b
2d
2e
2c
85% yield (24 h)a
97% yield (72 h)a
68% yield (24 h)a
83% yield (24 h)a
84% yield (24 h)a
77% yield (24 h)a
H
H
Me
H
H
N
N
PhthN
H
CBz
Cbz
2j
2f
82% yield (24 h)b
2g
2h
2i
60% yield (48 hrs)b,c
84% yield (24 h)b
92% yield (48 h)b
68% yield (48 h)b
H
Me
Me
O
CO2Et
Me
H
Me Me
H
10
H
H
Me
2m
2l
95% yield (24 h)b,c
HO
2k
74% yield (48 h)b
H
49% yield (48 hrs)a,c,d
3:1 dr
Me
Me
Reactions carried out in N2ꢀsparged TFE [0.5 M]. aYields for volatile compounds were determined by GC. bAverage of two isolated yields on >100mg scale.
c[0.3M] in TFE/EtOAc (4:1). d 20 mol% Ph2S2.
We propose a mechanism for this reaction in which the carꢀ
boxylic acid (1) is deprotonated, then single electron oxidation by
Mes-Acr-Ph* results in the formation of an acyloxyl radical (2),
which then rapidly rearranges to form carbon dioxide and a carꢀ
bonꢀcentered radical (3). Hydrogen atom abstraction from thioꢀ
phenol by 3 furnishes the final hydrodecarboxylation adduct. In
prior work, we have mechanistic evidence that supports the genꢀ
eration of phenylthiyl radical via photoinduced S-S bond homolyꢀ
sis.70 The thiyl radical then reꢀoxidizes the reduced catalyst, and is
protonated to furnish the active hydrogen atom donor (Scheme 2).
Scheme 2: Proposed Mechanism for Decarboxylation
O
O
R1
R2 R3
H
R1
R2 R3
R1
R1
O
(1)
O
(2)
R2 R3
R2 R3
(3)
–CO2
Me
Me
Me
PhS•
hυ
PhSH
N
Next, we elected to extend this method to the decarboxylation
of malonic acid derivatives. We found that our previously optiꢀ
mized conditions did not result in the doubly decarboxylated
product and only small amounts of monoꢀdecarboxylated product.
We posited that this was due to hydrogen bonding events from the
second acid moiety on the malonic acid increasing the oxidation
potential of the carboxylate. A comparison of benzyl malonic acid
and substrate 2k supports this hypothesis (Figure 1). Almost no
reactivity occurs of the malonic acid under the standard condiꢀ
tions, while the monoacid can be efficiently decarboxylated.
Mes-Acr-Ph∗
Ph
(PhS)2
Mes-Acr-Ph•
Me
hυ
Me
N
O
Me
PhS
R1
OH
R2 R3
Ph
Mes-Acr-Ph
We presumed that using increased base loading could improve
the reactivity, and indeed using 1.2 equivalents of DIPEA instead
of 0.2 equivalents resulted in small amounts of toluene from pheꢀ
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Journal of the American Chemical Society
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Reactions carried out in N2ꢀsparged TFE [0.5 M]. aYields for volatile
nyl malonic acid, however we believed that the reactivity and
scope could be improved through the use of a stronger base. We
were pleased to see that when using 1.0 equivalent of KOt-Bu
instead of DIPEA under otherwise standard reactions conditions,
we were able to isolate the corresponding doubly decarboxylated
products. These reactions were found to require longer reactions
times, due to the increased amount of carboxylate relative to the
catalyst. Not surprisingly, increased catalyst (7.5 mol %) and
disulfide (15 mol %) loading was found to improve the efficiency
of the reaction. In most cases the mass balance consisted of the
monoꢀdecarboxylated and doubly decarboxylated products, with a
small amount of unreacted starting material. Importantly, a conꢀ
trol experiment revealed no reaction occurred without the incluꢀ
sion of the Mes-Acr-Ph photocatalyst, excluding thermal decomꢀ
position as a potential mechanism.
b
compounds were determined by GC. 1.1 equiv of KOH used in place of
1
2
3
4
5
6
7
8
KOtꢀBu. cAverage of two isolated yields on >100mg scale.
Several mechanistic studies were conducted to understand the
role of TFE as very large gains in yields were observed, particuꢀ
larly for the primary carboxylic acid substrates, when using TFE
as a solvent. This behavior would not be solely explained by poꢀ
larity, as the MeOH:H2O system is more polar (the dielectric conꢀ
stants of 9:1 MeOH:H2O and TFE are 36.8 and 27.1 F/m respecꢀ
tively).71,72 We considered the possibility of TFE supplementing
thiophenol as a hydrogen atom donor in this reaction as our lab
and others have shown that alcohols (αꢀCꢀH bonds) can act as
hydrogen atom donors.61 However, exclusion of disulfide in the
reaction led to only trace amounts of product formation, indicatꢀ
ing either that TFE is not a competitive Hꢀatom donor in this reacꢀ
tion or that the corresponding radical formed is unable to reꢀ
oxidize the catalyst (Table 1, Entry 11). This was also confirmed
with a deuterium labeling study in which 2,2,2ꢀtrifluoroethanolꢀd2
(d2-TFE) was used as a solvent under otherwise standard condiꢀ
tions: no deuterium incorporation in the product was observed at
full reaction conversion (Figure 2a). When using 2,2,2ꢀ
Trifluoroethanolꢀd1 (d1-TFE) as a solvent, 63% deuterium incorꢀ
poration was observed at reaction completion, supporting a mechꢀ
anism in which thiophenol is generated in situ and acts as a hyꢀ
drogen atom donor, as thiolate being formed in the reaction could
deprotonate an equivalent of carboxylic acid, regenerating the Hꢀ
atom donor (Figure 2b).
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(a)
Mes-Acr-Ph (5 mol %)
O
O
O
(PhS)2 (10 mol %)
Bn
(1)
HO
OH
HO
i-Pr2NEt (20 mol %)
450 nm LEDs, TFE [0.5 M]
No Double Decarboxylation
Bn
21% yield
(b)
Mes-Acr-Ph (5 mol %)
O
O
O
(PhS)2 (10 mol %)
Bn
(2)
EtO
OH
EtO
i-Pr2NEt (20 mol %)
2k
Bn
450 nm LEDs, TFE [0.5 M]
83% yield
Figure 1: Comparison between efficiency of decarboxylation of (a) maloꢀ
nic acids and (b) malonate monoꢀesters. Control experiments were done
without catalyst to ensure a thermal decomposition pathway was not acꢀ
tive.
(a)
Mes-Acr-Ph (5 mol %)
O
(PhS)2 (10 mol %)
H/D
(3)
Ph
OH
Ph
i-Pr2NEt (20 mol %)
During our investigation of the reaction scope, we observed
that aryl malonic acid derivatives were particularly prone to hyꢀ
drodecarboxylation, potentially because of an ability to stabilize
the resulting radical (3a and 3b). We were also able to demonꢀ
strate that alkylꢀsubstituted malonic acid derivatives were viable
substrates for decarboxylation in this system, although they reꢀ
quired prolonged reaction times. Dialkyl substituted malonic acids
2ꢀbenzylꢀ2ꢀmethylmalonic acid, indanꢀ2,2ꢀdicarboxylic acid, and
2ꢀbenzylꢀ2ꢀ(3ꢀoxobutyl)malonic acid were able to be decarboxꢀ
ylated to give products 3c-e, respectively. Unfortunately, monoalꢀ
kyl substituted benzyl malonic acid gave poor yields of the doubly
decarboxylated product 3f (Chart 2).
Me Me
Me Me
450 nm LEDs, d2-TFE [0.5 M]
0% d-incorporation
(b)
Ph
Mes-Acr-Ph (5 mol %)
O
(PhS)2 (10 mol %)
H/D
(4)
OH
Ph
i-Pr2NEt (20 mol %)
Me Me
Me Me
450 nm LEDs, d1-TFE [0.5 M]
63% d-incorporation
D
D
F3C
OH
F3C
OD
d2-TFE
d1-TFE
Chart 2: Malonic Acid Derivative Decarboxylation
Figure 2: Deuterium labeling experiments (a) decarboxylation of 2,2ꢀ
dimethyl 3ꢀphenyl propanoic acid run in d2ꢀTFE to determine if TFE was
a catalytically active hydrogen atom donor. (b) Decarboxylation in d1ꢀTFE
showing that the proton from the carboxylic acid starting material is inꢀ
corporated in the product.
Mes-Acr-Ph (7.5 mol %)
O
O
(PhS)2 (15 mol %)
H
H
HO
H
OH
1 eq KOt-Bu
R1 R2
R1 R2
450 nm LEDs, TFE [0.5 M]
Since it was evident that TFE was not contributing significantꢀ
ly as a hydrogen atom donor, further investigations were underꢀ
taken to elucidate its role. We measured the fluorescence lifetime
of Mes-Acr-Ph using timeꢀcorrelated single electron counting
(TCSEC) in both methanol and TFE. The fluorescence lifetime
was found to be 10.8 ns in TFE. In methanol the catalyst disꢀ
played two fluorescence decay components having lifetimes of
0.49 and 5.5 ns (see figure S4), both significantly shorter than in
TFE. We also found that significant catalyst decomposition ocꢀ
curred upon standing in a solution of 9:1 MeOH:H2O overnight
with blue LED irradiation. This suggests that both the increased
catalyst excited state lifetime of Mes-Acr-Ph in TFE and the
decreased nucleophilicity73 of TFE relative to methanol, makes
TFE an ideal solvent for this reaction. Though other solvents have
H
H
H
H
H
S
3a
3b
3c
60% yield (24 h)a
56% yield (24 h)a
64% yield (72 h)a,b
O
Me
H
H
Me
H
H
H
H
3d
48% yield (72 h)a
3e
3f
45% yield (72 h)c
23% yield (72 h)a
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Journal of the American Chemical Society
been shown to demonstrate relatively long excited state lifetimes
Therefore, the lack of a kinetic isotope effect could be indicative
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8
for acridinium catalysts, TFE meets the requirements of being a
polar protic solvent, which is apparently necessary to stabilize
carboxylate formation in this reaction.
of carboxylate oxidation being rate limiting.
Further kinetic analysis showed that the reaction is first order
with respect to the carboxylate, while being zero order with reꢀ
spect to Mes-Acr-Ph; this finding is suggestive of a light limiting
reaction. (Table S4). Indeed the reaction was found to be very
light dependent. Reactions were normally irradiated with two
LED lamps over the course of the reaction, as there is a dramatic
decrease in the initial rate of the reaction when only one lamp is
used to irradiate the reaction vessel (Figure 4). The light dependꢀ
ence of the reaction suggests that the method could be improved
through the use of a flow reactor setup, which could allow for a
greater absorbance of light because of an increased surface area.
To determine if a hydrogen atom transfer step could be rate
limiting, the rate of decarboxylation was measured for a tertiary
carboxylic acid under standard conditions and for the deuterated
analog in d1-TFE (Figure 3). This would generate d1ꢀthiophenol
in situ and with no other sources of exchangeable protons, should
allow for the determination of a KIE. The kinetics were deterꢀ
mined using the initial rates method with good mass balance obꢀ
served. A very short induction period was observed in some cases,
most likely due to the limited solubility of the disulfide at the
beginning of the reaction, which was not found to significantly
affect the reaction kinetics after multiple trials with each set of
conditions. A KIE near unity was observed (1.01) when rates
were measured in separate vessels. A competition experiment in
which a mixture of 1:1 proteo and deutero acid in a 1:1 mixture of
TFE:d1ꢀTFE resulted in greater than 20:1 proton incorporation in
the final product observed.
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20
1 Lamp
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5
2 Lamps
(a)
Mes-Acr-Ph (5 mol %)
O
(PhS)2 (10 mol %)
H
Ph
OH
0
Ph
i-Pr2NEt (20 mol %)
Me Me
0
50
100
150
200
Me Me
450 nm LEDs, TFE [0.5 M]
Time (mins)
Initial Rate: 7.36 x10-6
Figure 4: Comparison of initial rate of reaction for the decarboxylation of
2,2ꢀdimethyl 3ꢀphenyl propanoic acid under irradiation with 2 blue LED
lamps and 1 blue LED lamp
(b)
Mes-Acr-Ph (5 mol %)
O
During the course of optimization and investigating the scope
of the reaction, it became apparent that substrates were decarboxꢀ
ylated much more readily as alkyl substitution at the alpha posiꢀ
tion increased when using a methanol/water system, as only very
small amounts of product were produced for primary carboxylic
acids in this system. It seemed possible that a difference in the
oxidation potential of substrates based on the degree of substituꢀ
tion alpha to the carboxylic acid could explain this trend. To
probe these reactivity differences, redox data was collected for
three carboxylates of increasing amounts of alpha substitution. To
our surprise, there was not a significant difference in oxidation
potential among these substrates (Figure 5). The relatively low
oxidation potentials for carboxylates indicate that electron transfer
from the carboxylate to the excited Mes-Acr-Ph should be very
thermodynamically favorable in each case. With the oxidation
potentials of the three representative carboxylates being very
close to one another, it seems that oxidation potential alone is not
sufficient to describe differences in reactivity.
(PhS)2 (10 mol %)
D
Ph
OD
Ph
i-Pr2NEt (20 mol %)
Me Me
Me Me
450 nm LEDs, d1-TFE [0.5 M]
Initial Rate: 7.43 x10-6
Average KIE=1.01
Figure 3: Initial rates of decarboxylation for (a) 2,2ꢀdimethyl 3ꢀphenyl
propanoic acid and (b) the deuterated analog. The rate of decarboxylation
1
of the deuterated analog was determined using d1ꢀTFE as a solvent; H
NMR analysis shows the complete deuterium incorporation in the product.
Each initial rate was calculated based on 3 trials, giving an average KIE of
1.01.
The lack of KIE observed when reactions were run in separate
vessels indicates that no proton transfer or hydrogen atom transfer
step is likely to be rate limiting in the reaction. This is consistent
with the observation that no products resulting from dimerization
were observed in these reactions. The results of the competition
experiment, while indicating a kinetic preference for hydrogen
atom transfer over deuterium atom transfer, cannot give any inꢀ
formation about the rateꢀlimiting step in the reaction. The large
KIE observed in the competition experiment could be indicative
of an equilibrium isotope effect in which thiophenol is formed in
higher concentrations than deuterothiophenol, via deprotonation
of carboxylic acid or exchange with the solvent (this would be
expected considering the relevant bond dissociation energies).
This could also be compounded by a faster rate of Hꢀatom transfer
than Dꢀatom transfer, however this does not indicate that Hꢀatom
transfer is rate limiting, as this experiment only indicates that Hꢀ
atom transfer is irreversible and product determining. Our lab has
previously discovered that thiyl radical oxidation of the acridine
radical intermediate is essentially diffusion controlled70 and as
previously mentioned, others have determined that the rate of
acyloxyl rearrangement to lose carbon dioxide is also very rapid.
O
O
O
Me
Me
Me
Me
Substrate:
O
O
O
Me
+1.31 V
Me
Ep/2
:
+1.25 V
+1.29 V
Figure 5: Oxidation potentials of the tetrabutylammonium salts of three
representative carboxylic acids were measured in a 0.1M solution of tetꢀ
rabutylammonium hexafluorophosphate in acetonitrile, vs SCE.
Electrochemical oxidation potentials suggest electron transfer
should be thermodynamically favorable, however it seemed reaꢀ
sonable that there could be differences in the kinetic barrier for
oxidation between carboxylates bearing differing alpha substituꢀ
tion causing a difference in their apparent reactivity. Therefore,
comparisons were also made between potassium salts of three
carboxylic acids with increasing alkyl substitution at the alpha
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Page 6 of 10
position, in their ability to quench the excited state of the catalyst
It is also of interest to note the magnitude of fluorescence
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3
4
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7
8
in TFE. The quenching constants were determined by Sternꢀ
Volmer analysis of fluorescence quenching, and the quenching
constants are reported in Figure 6. The observed quenching conꢀ
stants (kq) indicate that there is only a small difference in the rate
of quenching of the acridinium excited singlet state in TFE, with
the primary carboxylate possessing the largest kq, albeit by a narꢀ
row margin.
quenching of the excited state. Although the quenching constants
derived from SternꢀVolmer experiments indicate a rapid rate of
oxidation, the quenching efficiency is very low; for potassium
hydrocinnamate (5 mM) only 2% of Mes-Acr-Ph fluorescence is
quenched. This reflects that bimolecular quenching is competitive
with fast decay of the excited state by fluorescence (kF=9.3 x 107
sꢀ1 in TFE) and is consistent with the light dependence shown in
Figure 4. This shows that even though the rate constant for carꢀ
boxylate oxidation is very large, it is still possible for oxidation to
be turnover limiting in the reaction.
Indeed, the rate of the reaction in TFE seems to be nearly inꢀ
dependent of substitution at the alpha position, as shown by a
competition experiment in which equimolar amounts of each carꢀ
boxylate were added to the same reaction vial (Figure 7 top). The
experiment revealed that the primary carboxylic acid was actually
decarboxylated most rapidly in TFE. This observation was counꢀ
ter to what was previously observed in other solvent systems, as
seen from an analogous competition experiment in 9:1
MeOH:H2O in which the selectivity is reversed (Figure 7 bottom).
It should also be noted that the overall rate of conversion in
MeOH:H2O was much slower than what was expected based on
previous observations with the tertiary substrate (Table 1, entry
6), as 24 hours of irradiation was required to reach about 30%
total conversion.
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(a) TFE Competition Experiment:
Substrates:
Product Distribution:
O
Bn
Bn
Bn
H
1.3
1.2
1.0
OH
Mes-Acr-Ph (5 mol %)
O
(PhS)2 (10 mol %)
Bn
H
OH
OH
i-Pr2NEt (20 mol %)
Me
Me
450 nm LEDs, TFE [0.5 M]
O
run to
Bn
Bn
H
O
O
O
30% conversion, 8 hrs
Bn
Me Me
kq (M–1s–1): 2.34×108
Bn
Bn
Substrate:
Me Me
Me Me
O
O
O
Me
2.52×108
3.91×108
(b) 9:1 MeOH:H2O Competition Experiment:
Substrates:
Figure 6: Bimolecular quenching constants measured for the potassium
salts of each carboxylic acid in TFE.
Product Distribution:
O
Bn
Bn
Bn
H
1.0
1.1
1.2
OH
Fukuzumi has demonstrated in a similar system that in an aceꢀ
tonitrile:water mixture there are significant differences in the
ability of a series of primary, secondary, and tertiary alkyl substiꢀ
tuted carboxylates to quench the photoexcited state of a 10ꢀmethyl
acridinium catalyst via an electron transfer mechanism.74 This
could potentially indicate a different mechanism in different solꢀ
vent systems and highlights the importance of solvent in these
systems. We noted in early optimization of this reaction (Tables
S1ꢀS3) that substrates bearing αꢀphenyl groups could be efficientꢀ
ly decarboxylated in chloroform, whereas alkyl substituted carꢀ
boxylic acids were sluggish using this solvent. Wallentin et al.
have also demonstrated the ability for an acridinium photooxidant
to decarboxylate protected amino acids and phenyl acetic acid
derivatives in dichloroethane, but alkylꢀsubstituted acids were not
possible.24
Mes-Acr-Ph (5 mol %)
O
(PhS)2 (10 mol %)
Bn
H
OH
i-Pr2NEt (20 mol %)
Me
Me
450 nm LEDs,
9:1 MeOH:H2O [0.5 M]
O
Bn
Bn
H
run to
OH
30% conversion, 24 hrs
Me Me
Me Me
Figure 7: Competition experiments in (a) TFE and (b) 9:1 MeOH:H2O in
which equimolar amounts (0.25 mmols) of each substrate were in the
same reaction vessel. Other reagents were added in their respective quantiꢀ
ties relative to the total amount of carboxylate in the reaction. The reacꢀ
tions were stopped at about 30% conversion. Yields were measured by
analysis of crude 1H NMR spectra.
Previous results from our lab indicated that a donorꢀacceptor
complex could exist between ground state acridinium catalyst and
alkenes, resulting in a preꢀassociation equilibrium prior to oxidaꢀ
tion.70 Thus, it seemed plausible that a ground state Donorꢀ
Acceptor complex could form between carboxylates and the
ground state Mes-Acr-Ph. Figure 8 shows the absorption spectra
of Mes-Acr-Ph (25ꢀM) before and after the addition of potassiꢀ
um 3ꢀphenyl propanoate (up to 100 mM). After subtraction the
absorbance to the carboxylate, the UV/vis spectrum of the catalyst
was unchanged. Therefore, we found no evidence of the formation
of a ground state chargeꢀtransfer complex.
It is possible that a back electron transfer process occurring
from the acridine radical to the acyloxyl radical is faster than CO2
loss for primary carboxylic acids in MeOH:H2O, as this electron
transfer is thermodynamically favorable and probably rapid. This
would suggest that for tertiary carboxylic acids CO2 loss is comꢀ
petitive with back electron transfer. However, the competition
experiment in Figure 7 in MeOH:H2O seems to suggest that at
early conversions the rate of product formation is similar for priꢀ
mary, secondary, and tertiary carboxylic acids. As previously
mentioned the overall rate of conversion for the tertiary acid was
slower than expected in the competition experiment. Since there is
only a slight rate enhancement for the tertiary substrate in
MeOH:H2O, it seems plausible that catalyst deactivation is an
issue with the primary substituted acids, consistent with a slower
than expected rate for the tertiary acid in the competition experiꢀ
ment. Thus, while TFE seems to have a role in accelerating these
reactions in the case of the primary alkyl substituted carboxylic
acid, its exact role is unclear.
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Journal of the American Chemical Society
(a)
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Figure 8: UV/vis absorption spectra of the catalyst before and after addꢀ
ing carboxylate salt. The red line shows Mes-Acr-Ph before the addition
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of carboxylate. The yellow line shows the absorption spectrum of the
catalyst after adding the carboxylate. The blue line is the absorption specꢀ
trum of the carboxylate and the dashed black line is the subtraction of the
carboxylate from the absorption spectrum of the catalyst with added
quencher (yellowꢀblue).
(b)
We found it likely that some sort of preꢀassociation complex
was formed between the catalyst and the carboxylate salt. 1H
NMR spectra of Mes-Acr-Ph in CD3OD show that adding inꢀ
creasing amounts of tetrabutylammonium hydrocinnamate cause
an upfield shift in the proton signals of the acridinium, which was
found to be linear with respect to carboxylate concentration (Figꢀ
ure 9a and Figure S7). The peaks were also found to broaden out
significantly at higher concentrations of carboxylate, potentially
indicating a rapid exchange of BF4– counterion with carboxylate
counterion. This can also be observed by 19F NMR in which the
BF4– counterion can be observed to shift up field upon the addiꢀ
tion of increasing amounts of carboxylate (Figure 9b). Again sigꢀ
nificant broadening of the signals is observed upon addition of
large amounts of carboxylate suggesting an exchange process.
Thus, it is likely that a ground state preꢀassociation complex is
present between the carboxylate and acridinium catalyst. This
could help to explain the slight rate enhancement of primary alkyl
substituted substrates over secondary and tertiary alkyl substituted
substrates (Figure 7 top). When exploring the scope of the primaꢀ
ry carboxylic acids it was found that there were some apparent
rate differences among primary carboxylic acids, even in TFE. A
competition experiment between tridecanoic acid and hydrocinꢀ
namic acid to give alkane products 2a and 2l, shows that there is a
rate difference of about 4.7:1, in favor of hydrocinnamic acid, at
early levels of conversion (See S.I. for details). If a preꢀ
association interaction occurs prior to electron transfer the steric
environment around the carboxylate could have an impact on the
reaction rate.
1
Figure 9: (a) H NMR spectra of MesꢀAcrꢀPh BF4 [25mM] in CD3OD.
Residual methanol solvent peak was set to 3.31 ppm in each 1H NMR. (b)
19F NMR spectra of MesꢀAcrꢀPh BF4 [25mM] in CD3OD. Samples were
spiked with 20 ꢁL TFE before taking 19F NMRs and the corresponding
peak was set to ꢀ78.82 ppm in each spectrum. TBA+ RCOOꢀ = tetrabuꢀ
tylammonium hydrocinnamate
CONCLUSION
In summary, we have described a direct organocatalytic protoꢀ
col for the decarboxylation of carboxylic acids to alkanes, includꢀ
ing carboxylic acid substrates previously inaccessible through
other methods. We have also extended this method to malonic
acid derivatives as we believe this provides an efficient route to
the doubly decarboxylated alkyl products. Finally, we have proꢀ
vided insight into the mechanism of this reaction through fluoresꢀ
cence quenching studies, kinetic data, and NMR analysis. We
have found that choice of solvent has a major impact on substrate
compatibility for this transformation.
ASSOCIATED CONTENT
SUPPORTING INFORMATION
Experimental procedures and supporting data. This material
is available free of charge via the Internet at
http://pubs.acs.org.
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1
AUTHOR INFORMATION
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Corresponding Author
*Email: nicewicz@unc.edu
Notes
The authors declare no competing interest.
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ACKNOWLEDGMENT
This work was supported in part by Award No. R01 GM098340 from
the National Institute of General Medical Sciences, a grant from
Eastman Chemical and the David and Lucile Packard Foundation.
The authors would like to thank Nathan Romero for his assistance
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Carboxylic Acid Hydrodecarboxylation:
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photoredox
CO2H
H
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catalysis
97% yield
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12 additional examples
Malonic Acid Hydrodecarboxylation:
organic
HO2C
CO2H
H
H
photoredox
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R1 R2
R1 R2
catalysis
6 examples
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