Endergonic addition of N -methylamines to aromatic ketones driven by photochemical offset of the entropic cost

Article abstract of DOI:10.1039/c9cc06011a

Intermolecular addition reactions are generally accompanied by an entropic penalty due to the decrease of molecular numbers during the reaction, which sometimes makes the reaction endergonic. Here we demonstrate that such an endergonic reaction can be promoted with light-energy as a driving force; N-methylamines were added to aromatic ketones to produce aminoalcohols under UV-light irradiation. The reaction represents an obvious example showing that the photochemical approach is effective to offset such an entropic cost, and thereby to drive thermodynamically uphill addition reactions. Moreover the present reactions are highly expedient from the synthetic view point, being transition-metal-catalyst-free, scalable, highly atom economical, and regioselective. The product amines can be converted in one step to functional multi-arylated enamines, which are potentially valuable compounds in electronic materials.

Full text of DOI:10.1039/c9cc06011a

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Endergonic addition of N-methylamines to
aromatic ketones driven by photochemical
Cite this:DOI: 10.1039/c9cc06011a
offset of the entropic cost†
Received 2nd August 2019,
Accepted 5th September 2019
ab
Takahiro Iwamoto,
*
Atsushi Hosokawaab and Masaharu Nakamura*ab
DOI: 10.1039/c9cc06011a
rsc.li/chemcomm
Intermolecular addition reactions are generally accompanied by an often entropically unfavorable because such bimolecular bond
entropic penalty due to the decrease of molecular numbers during formation decreases the number of molecules in the reaction
the reaction, which sometimes makes the reaction endergonic. system.
Here we demonstrate that such an endergonic reaction can be
If enthalpic gain cannot compensate for the entropy loss
promoted with light-energy as a driving force; N-methylamines (negative TDS), the reaction does not proceed spontaneously
were added to aromatic ketones to produce aminoalcohols under without input of external energy (endergonic reaction, DG 4 0,
UV-light irradiation. The reaction represents an obvious example Scheme 1a).3 As a striking example of using a photochemical
showing that the photochemical approach is effective to offset reaction to overcome such thermodynamic constraint, Murakami
such an entropic cost, and thereby to drive thermodynamically et al. reported the light-driven carboxylation of o-alkylphenyl
uphill addition reactions. Moreover the present reactions are highly ketones with carbon dioxide, which is the formal addition of a
expedient from the synthetic view point, being transition-metal- C–H bond to carbon dioxide (Scheme 1b).2g Moreover, Knowles et al.
catalyst-free, scalable, highly atom economical, and regioselective.
The product amines can be converted in one step to functional
multi-arylated enamines, which are potentially valuable compounds
in electronic materials.
Photoreactions and photocatalysis have received extensive attention
in synthetic chemistry over the past few decades.1 One prominent
feature of photochemical approaches to synthetic chemistry is to
make a thermodynamically uphill reaction feasible by using light
energy as a driving force. Such a reaction is attractive not only as a
method for the storage of solar energy in the form of chemical
energy, but also as a synthetic method for the production of
functional organic molecules. Several examples of light-driven uphill
reactions, such as olefin isomerization, [2+2]cycloaddition and a few
more, are known.2 However, applications for light-driven reactions
are still limited. Thus, to expand the field of such advantageous
photoreactions, further efforts on reaction design based on thermo-
dynamics are needed.
Intermolecular addition reactions to unsaturated bonds
play a vital role in organic synthesis for the construction of
functional molecules. Thermodynamically, these reactions are
a Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
E-mail: iwamoto@scl.kyoto-u.ac.jp, masaharu@scl.kyoto-u.ac.jp
b Department of Energy and Hydrocarbon Chemistry, Graduate School of
Engineering, Kyoto University, Kyoto 615-8510, Japan
Scheme 1 The photochemical approach to offset the entropic cost of
† Electronic supplementary information (ESI) available: Experimental procedures,
endergonic intermolecular addition to an unsaturated bond.
theoretical calculation, and spectroscopic data. See DOI: 10.1039/c9cc06011a
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recently reported the hydroamination of C–C double bonds using a initial stage of the reaction (see below for details of a plausible
photocatalyst.2i It is noteworthy that this reaction is exothermic, reaction mechanism). Control experiments indicated that light
yet still endergonic due to the large entropic cost. However, despite irradiation was pivotal for the reaction (entry 5).7
the significant impact of these reports, the design of photo-
We examined the theoretical thermodynamics of the reaction
chemical approaches to drive endergonic reactions having critical using DFT calculations. The calculation implies that the reaction
entropic cost has rarely been reported. Herein, we report a new light- is endergonic with a DG value of 15.4 kcal molÀ1 (entry 1, Table 2).
driven endergonic addition reaction to demonstrate that such a The DH and DS values were calculated to be 0.3 kcal molÀ1 and
photochemical approach is effective at driving endergonic reactions À51 cal molÀ1
K
À1, respectively. In general, DFT calculations
overestimate entropic costs, and thus, to evaluate the entropic
by offsetting the entropic cost.
We examined the addition of N-methylamine to aromatic term more precisely, the translational entropy was corrected
ketones, where the C–H bond of the methyl group on the amine using the method of Whitesides.8 The corrected calculation indi-
adds across the unsaturated C–O bond of the ketone (Scheme 1c). cated a similar thermodynamic tendency (entry 2). Based on these
Although the intramolecular Norrish–Yang-type variant of this results, we concluded that the reaction is thermodynamically
reaction has been well-studied and applied to a wide range of unfavorable, and the energetic cost is mainly due to entropy loss.
synthetic targets,4 the intermolecular process remains elusive. In addition, the large negative change of the translational entropy
Several examples of this reaction have recently been achieved (DStrans = À24 cal molÀ1 KÀ1) implies that the entropic cost is largely
via radical–radical coupling induced by photoredox catalysts.5 derived from the decrease of the number of molecules during the
However, development of the reaction under photocatalyst-free course of the reaction. In this reaction, the light energy consequently
conditions still poses a challenge, probably because control of offsets such entropic cost to serve as a driving force.
the radical generation rate, which is needed for selective radical–
radical coupling, is difficult in noncatalytic systems.6
To demonstrate the practical synthetic utility of this reaction,
we first explored the scope of the amines in the reaction with
Our study of this transformation began with the reaction of benzophenone (Table 3). In these reactions, either LiOtBu or
benzophenone (1a) with N-methyldiphenylamine (2a) in aceto- NaOtBu was used as the base. Amines bearing diverse functional
nitrile under irradiation by an LED lamp (365 nm). Light groups, including methyl, fluoro, bromo, boryl, and alkoxycarbonyl,
irradiation of the mixture in the absence of any additive reacted efficiently to give the desired products in moderate to good
provided the desired coupling product 3a in only 10% yield, yields (3b–3h). The yield was reduced for a secondary amine (3i).
along with the formation of compound 4 and carbazole 5 (entry 1, N-Methylcarbazole also reacted to produce 3j in moderate yield.
Table 1). After optimization of the reaction conditions (see ESI†), Subsequently, we investigated the scope of the aromatic ketones.
we found that addition of a substoichiometric amount of base Electron-rich, neutral, and electron-deficient aromatic ketones all
significantly increased the selectivity; the use of LiOtBu (0.2 eq.) smoothly coupled with N-methyldiphenylamine to form the desired
or NaOtBu (0.2 eq.) was optimal for affording product 3a in 73% products in good to excellent yields (3k–3n). Heteroaromatic ketones
and 80% yield, respectively (entries 2 and 3). Notably, further such as xantone and thioxantone also underwent the coupling,
increase in the amount of base did not improve the yield (entry 4). albeit in lower yields (3o and 3p). The low isolated yields are partially
We assumed that MOtBu assists in the generation of the a-amino- due to gradual decomposition of the products during purification
radical by deprotonation of the aminium radical, which is generated with column chromatography.
by electron transfer from the amine to a photoexcited ketone, at the
This coupling method is also adaptable to a large-scale
synthesis; the reaction of 1a and N,N-dimethylaniline on a 48 mmol
scale provided 11.0 g of the coupling product 3d. Notably, the yield
was comparable with that at the 1 mmol scale by elongation of the
reaction time (40 h). A double coupling reaction was also feasible; a
diketone reacted at both ketone sites with both N-dimethylaniline
(3q) and N-methyldiphenylamine (3r).
Table 1 Addition of N-methylamine 2a to benzophenone (1a) under
photocatalyst-free conditions
Table 2 Thermodynamics estimated by DFT calculations
Yield (%)
Conversion
of 1a (%)
DG
DH
DS
DStrans
Entry
Base (eq.)
3a
4
5
Entry (kcal molÀ1
)
(kcal molÀ1
)
(cal molÀ1 KÀ1
)
(cal molÀ1 KÀ1
)
1
2
3
None
10
73
80
57
81
4
100
100
98
97
11
1a
15.4
10.7
0.3
0.3
À51
À35
À40
À24
LiOtBu (0.2)
NaOtBu (0.2)
NaOtBu (0.5)
NaOtBu (0.2)
N.D.
N.D.
N.D.
N.D.
Trace
Trace
Trace
N.D.
2a,b
a
DFT calculation were performed using B3LYP-GD3(BJ)/6-311++G(d,p)
with the PCM solvent model (solvent = acetonitrile). Energies were
4
5a
N.D.
b
calculated at 298.15 K and 1 atm. Translational entropy was corrected
a
In the absence of light-irradiation.
using the method of Whiteside.7
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Table 3 Substrate scopea
Scheme 3 (a) Plausible mechanism and (b) selective deprotonation path-
way to produce the a-amino radical.
a
Reactions were performed with the ketone (1.0 mmol), amine (2 eq.)
and base (0.2 eq.) in CH3CN at r.t. for 24 h under UV LED lamp
irradiation (365 nm). GC yields are shown, with isolated yields in
Scheme 4 Synthesis of functional p-conjugated enamines by dehydration
of the aminoalcohols.
b
c
parentheses. NaOtBu was used as the base. LiOtBu was used as
d
e
the base. Amine (4 eq.) and LiOtBu (0.4 eq.) were used. Reaction
time was 40 h.
between the nitrogen center and the C–H bond.9 In the case of
deprotonation at the N-ethyl or N-benzyl group, orbital overlap
To study the regioselectivity, we examined unsymmetrical between the nitrogen and the C–H bond diminishes due to
amines having two potentially reactive sites on the nitrogen steric repulsion, resulting in the small stereoelectronic effect
atom (Scheme 2). When N-ethyl-N-methylaniline was subjected (Scheme 3b). Consequently, deprotonation would occur selec-
to the optimal conditions, the reaction proceeded predominantly tively at the N-methyl carbon.
at the N-methyl group. Furthermore, in the case of N-benzyl-N-
To demonstrate the synthetic utility of the reaction, we
methylaniline, the addition was observed to take place exclusively converted the amine products to functional p-conjugated enamines
at the N-methyl group. We assumed that this excellent regio- (Scheme 4).10 Several aminoalcohols were smoothly transformed
selectivity toward the N-methyl group resulted from the selective into the corresponding enamines simply by heating at 60 1C in the
generation of an a-amino radical, which would be generated by presence of molecular sieves. This method has obvious advantages
electron transfer from the amine to the photoexcited ketone, over previous synthetic methods,10,11 such as the use of readily
followed by deprotonation of the resulting aminium radical available N-methylamines and aromatic ketones as substrates, no
(Scheme 3a). Deprotonation of an aminium radical is already need to use a transition-metal catalyst, and high atom efficiency.
known to be significantly affected by stereoelectronic effects
In conclusion, we have developed a light-driven thermo-
dynamically unfavorable addition of N-methylamine to aromatic
ketones under photocatalyst-free conditions. Theoretical calculations
indicate that light energy serves as the driving force by offsetting the
entropic cost. It should be noted that such an entropic cost generally
accompanies the numerous addition reactions used to assemble the
building blocks to construct a product. This study demonstrates that
a photochemical approach provides a powerful method to drive such
entropically unfavorable reactions without requiring any driving
force from chemical reagent or heat. Since previous studies of
light-driven reactions mostly focused on the enthalpic term,
Scheme 2 Regioselective addition of unsymmetrical amines to benzo-
phenone (1a).
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N. L. Frye and R. R. Knowles, J. Am. Chem. Soc., 2019, 141, 1457.
For a review of water splitting, which is one of the most studied
light-driven uphill reactions, see: (k) A. J. Bard and M. A. Fox, Acc. Chem.
namely endothermic reactions, we anticipate that design of
light-driven uphill reactions focusing on the entropic cost will
open up a distinctive reaction space in photoreaction chemistry.
This method has several synthetic advantages, such as high
selectivity and scalability, as well as high atom economy.
Furthermore, the reaction enables a novel synthetic route to
access functional enamines from easily available substrates.
This work was supported by a Grant-in-Aid for Young
Scientists B (15K17854) and Early-Career Scientists (18K14215)
from JSPS. This work was also supported in part by the Asahi
Glass Foundation and Grant for Basic Science Research Project
from The Sumitomo Foundation. Elemental analyses and mass
spectrometry were provided by the JURC at ICR, Kyoto University.
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Conflicts of interest
There are no conflicts to declare.
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