Sunlight assisted direct amide formation: Via a charge-transfer complex

Article abstract of DOI:10.1039/c7cc05300b

We report on the use of charge-transfer complexes between amines and carbon tetrachloride, as a novel way to activate the amine for photochemical reactions. This principle is demonstrated in a mild, transition metal free, visible light assisted, dealkylative amide formation from feedstock carboxylic acids and amines. The low absorption coefficient of the complex allows deep light penetration and thus scale up to a gram scale.

Full text of DOI:10.1039/c7cc05300b

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
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Sun Light Assisted Direct Amide Formation via a Charge-transfer
Complex
Received 00th January 20xx,
Accepted 00th January 20xx
[
a][b]
Authors*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report on the use of charge-transfer complexes between A drawback of many light-induced reactions is that the
amines and carbon tetrachloride, as novel way to activate the chromophores used are such potent absorbers of light that it
amine for photochemical reactions. This principle is does not penetrate deep enough into the solution, leading to
demonstrated in a mild, transition metal free, visible light problems with scalability. Indeed the aforementioned flow
assisted, dealkylative amide formation from feedstock processes have been developed as an elegant solution to this
carboxylic acids and amines. The low absorption coefficient issue but does require additional investment in infra-
4
of the complex allows deep light penetration and thus scale- structure.
up to gram scale.
In the present paper, we report a visible light assisted direct
amide formation from feedstock carboxylic acids and amines.
Visible light-induced homogeneous photochemistry and The importance and challenge of developing new amide bond
9
,10
photocatalysis has become a staple of research in organic forming reactions is often overlooked due to the relative
synthesis in recent years. Most reported modern applications ease by which this reaction may be carried out, however
1
1
1
use arc lamps or blue-light LEDs as the light source and wasteful existing methods might be.
Given the
transition metal complexes, mostly of ruthenium or iridium, as preponderance of amide formations in industry we believe
2
the light harvesting species and/or photocatalyst. The that this contribution may prove of value. The process relies
development of flow systems has allowed for dramatic scale- on a weakly absorbing complex
,1b,4
3
between an amine
1 and
3
up of these reactions to industrial scale.
However, while tetrachloromethane (2) (Scheme 1). A key advantage of this
the advantages of LEDs over conventional arc lamps, such as process is that it both avoids the use of expensive and toxic
mercury lamps, is indisputable, an even more convenient and transition metals. It can be run at gram scale and be driven
abundant light source is solar light. Indeed, the harvesting of using any visible light source, such as a mercury arc lap, blue
5
6
solar energy for generating electricity and fuels are amongst LED and more importantly, the sun.
R1
the fastest growing research fields, involving both scientific
and engineering aspects. While most LED-induced
photochemistry has been developed in Europe and North
America, a large segment of the developing world, including
those undergoing rapid industrialization, has plentiful solar
R1
R2
N
R3
Cl
CCl
3
R2
+
CCl4
N
R3
3
1
2
charge-transfer complex
R1
O
1
R
visible light
-H
+
7
R2
N
R4
light available. In addition, many synthetic photocatalytic
O
O
HN R2
R2
6
N
-
HCl
R3
4
5
R4
3
processes rely on the use of heavy or rare metals such as a
ruthenium and iridium which are expensive and could have
detrimental environmental effects. Photochemistry and
photocatalysis based on directly addressing inexpensive readily
available organic reagents has received comparatively less
-CHCl3
R
3
R
7
O
R1
R2
-
H+
O
intra
inter
O
molecular
molecular
N
R1
R3
R
1
8
R4
O
+
R2
O
R2
O
R2
R4
N
R3
N
N
8
11
R3
attention.
R3
1
0
9
O
R
4
Scheme 1. Proposed use of amines
and nucleophile to form amides
1 as precursors for acid activating agent 2
5
7.
Lautenberger has shown that trimethylamine (TEA), and
tetrachloromethane (CCl ) give rise to a light absorbing charge-
4
1
2,13
transfer complexes i.e.
3.
Indeed, under our experimental
in
conditions, addition of TEA to a solution containing CCl
4
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4
dichloromethane ([CCl ]>>[TEA]) results in the formation of a nm is negligible (See ESI). Based on this result, we envisioned
new light absorbing species (See Figure 1a and the ESI), the synthetic use of this complex in photoredox reactions
presumably the 1:1 TEA∙∙∙CCl complex. According to the assisted by sunlight while filtering off the UV section of the
concentration-dependent changes in the absorption spectrum, spectrum using the borosilicate glass walls of a the glass vessel
4
-1
the formation constant of the complex is around 0.15 M , i.e. as the filter (See ESI for filter properties). It should be noted
a slightly endergonic association. While triethylamine can bind that the use of amines in photocatalytic reactions has been
1
to only one molecule of CCl
dichloromethane ([CCl
behavior, probably due to the formation of higher cation radicals and then, after loss of a proton, iminium ions
stoichiometry complexes at high TEA to CCl ratios. Gas-phase e.g. (Scheme 1). The proposed scheme would achieve this in
calculations (G4) on the trimethylamine (TMA) and CCl system the absence of a transition metal catalyst.
shows that the 1:1 TMA∙∙∙CCl complex is a minimum energy
4
, addition of CCl
4
to excess TEA in reported previously. In such reactions amines are oxidized by
4
]<[TEA]) results in a more complex the light activated transition metal photocatalyst to form first
4
4
4
4
structure on the TMA + CCl surface potential, with a Cl-:N
4
distance of only 2.86 Å (Figure 1b). The calculated gas-phase
thermodynamic parameters of the 1:1 complex are: ꢀG°=+3.1
.
kcal mol ,
-1
.
-1
.
-1. -1
ꢀH°=-3.7 kcal mol ,ꢀS°=-22.7 cal mol K . The
thermodynamic properties of the 1:1 TEA∙∙∙CCl complex, were
4
extracted from the dependence of the association constant on
temperature using a Van't Hoff plot. The complexation is
.
-1
indeed endergonic,
.
ꢀH°=+2.06±0.2 kcal mol , ꢀS°=+4.1±0.8
-1. -1
.
-1
cal mol K , ꢀG°=+0.9±0.45 kcal mol , (See Figure 2).
a
Fig. 2 Temperature dependence of the formation constant of the 1:1 TEA∙∙∙CCl
complex.
4
Indeed, the irradiation of the charge-transfer complex using
visible light led to the formation of iminium ion (Scheme 1)
as proven by H and C NMR (see ESI). We surmised that the
incipient iminium ion might react as both a dehydrating and
activating agent for the deprotonated carboxylic acid
Scheme 1). In this scheme the initially formed imininum ion
is attacked by the carboxylate to give hemi-aminal ester
4
1
13
4
2
(
4
5
6.
b)
Subsequent intramolecular attack on the electrophilic carbonyl
function by either the amine of the aminal moiety, or through
intermolecular attack by
reaction), leads to intermediate
intermediate would collapse to give the product amide 10 and
one equivalent of aldehyde 11 In the event of an
intermolecular process a molecule of amine would also be
generated in the collapse of to form 10 and 11
7
(generated in the course of the
8
or respectively. Either
9
.
7
9
.
Thus, the overall dehydration would be divided into loss of
oxygen from the carboxylic acid (to give aldehyde 11) and loss
of one proton from the amine and one proton from the
carboxylic acid, thus requiring the use of at least two
equivalents of base. A potential side-reaction was the
possibility of decarboxylation of the carboxylic acid with loss of
carbon dioxide via a radical pathway.
Fig.
concentrations of TEA (0, 0.048, 0.072, 0.096, 0.119, 0.143, 0.167, 0.191, 0.215,
1
a) UV-VIS spectra of
a
solution of 5.18
M
CCl4 and increasing
0
.239, 0.263, 0.287 M) in DCM at 25±0.5 °C. b) Calculated structure (G4) of the
TMA∙∙∙CCl4 complex (trimethylamine is used as a model for TEA)..
Other tri-alkyl amines, such as tributylamine, were also found
4
to form similar charge-transfer complexes with CCl with
similar absorption characteristics. However, mono-alkyl
amines and di-alkyl amines, such as butylamine and dibutyl-
Consistent with our supposition, excitation of the charge-
transfer complex
3 using LED as a source of visible light in the
4
amine, form considerably weaker complexes with CCl . These
presence of benzoic acid in the presence of potassium
carbonate (6.5 equiv.) under nitrogen led to formation of N,N-
diethylbenzamide 10c in 80% yield (Scheme 2). Importantly,
carrying out the reaction using sunlight in a standard boro-
silicate glass vessel, leads to the isolation of the product in
complexes absorb at shorter wavelengths (See ESI). These UV-
VIS spectra show that while the charge-transfer complexes
absorbs strongly in the UV part of the spectrum they still retain
significant absorption in the near visible spectrum above 350
4
nm. In contrast, the absorption of both TEA and CCl at >350
2
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similar yield of 83% (Scheme 2, 10c). While total light exposure diisopropylethylamine (Hünig’s base) could be used in the
was longer using sunlight (18h) than with LED (8h) it should be reaction as well, leading to formation of the hindered and
2
noted that the light flux for the LED was 55-65 mW/cm challenging to make ethyl-isopropyl-amide of 2-napthoic
2
compared to a light flux of 0.2 mW/cm (early morning and carboxylic acid (10n).
2
late evening) up to 59 mW/cm at noon using sun light.
O
O
R2
R3
h (sun light)
K2CO3 (6.8 equiv.)
R2
R4
R4
Importantly, no reaction took place in the dark. The reaction is
inhibited by oxygen, and does not produce product until
oxygen is depleted. Accordingly, the optimized conditions
include carrying out the reaction under an inert atmosphere.
This observation is consistent with a mechanism in which the
OH
R1
N
N
R3
CCl4: DCM (3: 1)
5
(1 equiv.)
12 (7.5 equiv.)
10a-10q
O
O
O
O
Me
N
N
N
N
Me
charge transfer complex
3 is converted into the iminium ion 4
1
0a
10b
10c
h, 80%b
24h, 83%
1
0d
8
and CHCl (Scheme 1) through a free radical process. While the
3
9
h, Quanta
21h, 79%
O
24h, 63%
O
O
O
reaction requires an excess of amine (ca. 7 equiv.) for forming
an efficient concentration of the complex, this component is
inexpensive and may potentially be recycled. The finding that
potassium carbonate is an essential additive was initially
baffling as the excess of amine used ought to be sufficient to
remove the two equivalents of acid generated in the reaction
N
N
N
N
MeO
F3C
2
O N
1
0h
1
0e
10f
10g
2
4h, 45%
O
22h, 88%
O
22h, 65%
9
h, 72%
O
O
N
N
N
N
(Scheme 1). We surmise that the potassium carbonate acts
S
N
10j
1
0k
10l
primarily not as a base but as a dispersant and reflector of the
incident light, and thus increases the light pathway through
the reaction mixture many fold. Indeed, in its absence the rate
of reaction drops significantly. 6.5 equivalents of regular
commercial particle size appear to be the optimal quantity.
Using smaller or higher amounts, or finer particle sizes, all lead
to reduction of reaction rate.
10i
2%
8h, 96%
gram scale, 18 h, 82%
0 gram scale: 56h,92%
10 gram scale: 65h, 82%
9
h,
5
25h, 69%
22h, 56%
3
1
e
f
O
O
O
Ph
O
N
N
nBu
N
N
H
Ph
10m
6h, 48%
10n
10o
10r
62h, 65% g
62h, 35% (81% brsm)c
2
30h, 50%
O
O
O
O
Subsequently, the scope of the reaction was examined. Alkyl
carboxylic acids such as acetic acid and phenyl acetic acid react
with triethylamine to afford the corresponding diethylamides
nBu
nBu
nBu
N
N
N
H
N
nBu
+
+
1
0p, 40%
10p 41%
10q, 26%
10q 6%
1
0a and 10b in quantitative and 79% yield respectively
Scheme 2). A variety of aromatic carboxylic acids and amines
Scheme 2, 10c
10q) are also substrates for the reaction. The performed under N
2h, 81%d
48h, 32% (65% brsm)c,d
3
(
(
Scheme 2. Reaction scope and general conditions. All the reactions were
. Reaction times are given in parenthes, and refer to total
-
2
sunlight exposure only. Products were isolated by column chromatography.
yields in these reactions range from 52% for 2-
a
Yields are given for isolated products unless otherwise indicated. Conversion by
b
c
thiophenylcarboxylic acid (10i) and up to 96% for 2-napthoic HPLC. Using an LED as the light source. 57% 2-naphthoic acid and 51% 4-
Methylbenzoic acid were recovered respectively. Combined yields of products.
d
e
acid (10k). Benzoic acids substituted by electron-withdrawing
groups are excellent substrates for the reaction. Thus, para-
f
filtered of and replaced twice during the reaction. with mechanical stirring
K
2
CO
at 85% conversion as determined by NMR. Preliminary work: 7 equiv. DABCO, 1
3
g
trifluorobenzoic acid affords the respective amide with equiv. Acid and 1.5 eequiv. N-butyl-amine. Yield determined at 80% conversion.
triethylamine in 88% yield (10f) and para-Nitro-benzoic acid
reacts with triethylamine to afford the corresponding diethyl- The reaction of dibutyl amine with 4-methylbenzoic acid
amide 10g in 72% yield. Electron donating substituted (Scheme 2) while not of practical synthetic interest due to the
aromatic acids also undergo the amidation reaction, albeit in very low absorbance of the dibutylamine-CCl
4
complex above
slighter lower yield: 45 % (Scheme 2, 10e).
350 nm (See ESI) provides additional clues to the mechanistic
The reaction is not limited to triethylamine. A variety of understanding of the reaction. In this reaction the butyl amide
unsymmetrically substituted linear and cyclic alkylamines also 10q and dibutyl amide 10q’ products were isolated in ca. 4:1
ratio in a combined 32% yield. Clearly, the dibutylamide 10q’
lead to amide formation with 2-napthoic acid (Scheme 2, 10l-
0q). The reaction with dimethyl-butylamine leads to can only be formed via an intermolecular process (Scheme 1).
1
formation of a 1:1 mixture of demethylated (10p) and In contrast, methyl-butylamide 10q could in principle form
debutylated(10p') products in a combined 81% yield. The ratio, through either an intramolecular or an intermolecular process.
which contradicts the 2:1 ratio favoring 10p expected on However, the intermolecular process can only take place after
statistics, presumably reflects the higher stability of the more mono-butylamine is generated during the first cycle of the
substituted N-butylidene-N-methylmethanaminium ion over reaction. Initially butyl-amine would be present at very low
the less substituted N-methyl-N-methylenebutan-1-aminium concentration. In kinetic studies we do not observe an
ion. It is therefore surprising that both methyl-pyrrolidine and induction lag in product formation. Thus it is likely that amide
methyl-piperidine lead to formation of the corresponding formation takes place through both the intermolecular and
pyrrolidine and piperidine amides in 56% and 48% yields intramolecular mechanisms proposed in Scheme 1.
respectively (10l and 10m) rather than suffering ring-opening Further support of the mechanism proposed in Scheme 1
to
a
greater extent. Notably, even highly hindered arose from the reaction of 2-napthoic acid with
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tribenzylamide. Extended irradiation (62 h total ) with sunlight
followed by water workup afforded the expected amide
product 10p in 35% yield (81% based on recovered starting
material) as well as benzaldehyde in 162% isolated yield
Notes and references
1
(a) J. W. Beatty and C. R. J. Stephenson, Acc. Chem. Res.,
015, 48, 1474; (b) J. J. Douglas, M. J. Sevrin and C. R. J.
2
(
based on the amount of tribenzylamine used). This shows
Stephenson, Org. Process Res. Dev., 2016, 20, 1134; (c) M. D.
Karkas, J. A. Porco and C. R. J. Stephenson, Chem. Rev., 2016,
how iminium ion may function as the dehydrating agent in the
reaction.
1
16
Stephenson, Acc. Chem. Res., 2016, 49, 2295; (e) C. K. Prier,
D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013, 113
322; (f) R. A. Angnes, Z. Li, C. R. D. Correia and G. B.
, 9683; (d) D. Staveness, I. Bosque and C. R. J.
The reaction can be scaled up to 3 and 10 grams scale. Thus
carrying out the reaction of 2-naphotic acid and triethylamine
could be carried out in a standard 2L vessel to afford the
product 10k on a 10 gram scale in 92% yield. This indicates the
advantage of using a low absorbing light harvesting complex.
While the irradiation time at 3 gram scale is twice that
required at 650 mg scale, this is a result of other factors such
as the heterogeneous conditions. Using a higher light
absorbing complex the reaction time would have been
extended by at least one order of magnitude. An issue on
,
5
Hammond, Org. Biomol. Chem., 2015, 13, 9152; (g) M. H.
Shaw, J. Twilton and D. W. C. MacMillan, J. Org. Chem., 2016,
8
1
, 6898.
I. Willner, T. Tsfania and Y. Eichen, J. Org. Chem., 1990, 55
656.
2
3
4
5
,
2
D. Cambié, C. Bottecchia, N. J. W. Straathof, V. Hessel and T.
Noël, Chem. Rev., 2016, 116, 10276.
2 3
scaleup to 10 g is that the reflecting material K CO is crushed
Z. J. Garlets, J. D. Nguyen and C. R. J. Stephenson, Isr. J.
Chem., 2014, 54, 351.
by heavy magnets and that powdered reflector inhibits the
reaction. Accordingly, potassium carbonate had to be removed
twice during the reaction and replaced with fresh material.
One potential solution is to use mechanical stirring which is
less prone to crush the particles leading to 80% yield at 85%
conversion after 65 hours. However, these are engineering
issues and will therefore not be discussed further here.
Notably the reaction is clean with only starting materials and
product observed.
(a) G. J. Hedley, A. Ruseckas and I. D. W. Samuel, Chem. Rev.,
2
1
2
017, 117, 796; (b) H. Chen and S. Yang, Adv. Mater., 2017,
603994; (c) S. Xiao, Q. Zhang and W. You, Adv. Mater.,
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Scholes, Nat. Mater., 2017, 16, 35; (e) Y. Zeng, J. Chen, T. Yu,
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2
6
7
(a) A. Kleidon, L. Miller and F. Gans, in Top. Curr. Chem. , eds.
H. Tüysüz and C. K. Chan, Springer, 2016; (b) Z. Han and R.
While only secondary and tertiary amines form charge-transfer
complexes that absorb in the visible region, a preliminary
experiment showed that a primary amine can form amides in
the reaction by using DABCO as a sacrificial amine. This also
makes it possible to reduce the amount of nucleophilic amine
to 1.5 equivalent. Thus napthoic acid reacts with butylamine to
afford amide 10r in 65% unoptimized yield at 80% conversion.
Clearly this new reaction has a different mechanism since
DABCO cannot form imine and further studies on this new
reaction will be reported at a later date.
Eisenberg, Acc. Chem. Res., 2014, 47
Christoforidis and P. Fornasiero, ChemCatChem, 2017,
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9,
1
(
9
Lett., 2016, 18, 5572.
8
9
1
J. Chen, J. Cen, X. Xu and X. Li, Catal. Sci. Technol, 2016, 6,
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49.
In conclusion, we present here the principle of using charge
R. M. de Figueiredo, J.-S. Suppo and J.-M. Campagne, Chem
Rev., 2016, 116, 12029.
4
transfer complexes between amines and CCl to drive synthetic
reactions. Proof of principle is achieved in an efficient LED or
sunlight-driven dealkylative condensation of a variety of
amines with carboxylic acids. The reaction can be run at gram
scale. The procedure is operationally simple and the starting
materials as well as the light sources are inexpensive and
readily available. No expensive coupling reagents are needed
and the excess reagents and solvents should be easily
recyclable in an industrial setting. A mechanism has been
proposed, in which iminium ion formation occurs through light
activation of the charge transfer complex between amine and
0 For some examples of photo oxidative amination of
aldehydes see: (a) N. Iqbal and E. J. Cho, J. Org. Chem., 2016,
8
1
, 1905; (b) G. N. Papadopoulos and C. G. Kokotos, J. Org.
Chem., 2016, 81, 7023; (c) D. Leow, Org. Lett., 2014, 16
812; For an example of amide formation through a photo
,
5
generated Vilsmeier-Hack reagent see: (d) T. McCallum and
L. Barriault, J. Org. Chem., 2015, 80, 2874-2878.
1
1 (a) V. R. Pattabiraman and J. W. Bode, Nature, 2011, 480
,
4
71; (b) D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R.
Humphrey, J. J. L. Leazer, R. J. Linderman, K. Lorenz, J.
Manley, B. A. Pearlman, A. Wells, A. Zaks and T. Y. Zhang,
CCl
and activator of the carboxylic acid. The mechanism is
supported by extensive experimental studies, and 12 W. J. Lautenberger, E. N. Jones and J. G. Miller, J. Am. Chem.
4
. The iminium ion acts as a combined dehydrating agent
Green Chem., 2007, 9, 411.
computations support the proposed key charge-transfer
complex. The principles outlined herein are currently finding
applications in other settings in our laboratory, the results of
which will be reported in due course.
Soc., 1968, 90, 1110. For a review on charge transfer
excitation see: T. Mori and Y. Inouea, Chem. Soc. Rev. 2013
2, 8122.
3 V. Mitova, N. Koseva and K. Troev, RSC Advances, 2014,
4733.
,
4
1
4,
6
4
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