Photochemical Activation of Aromatic Aldehydes: Synthesis of Amides, Hydroxamic Acids and Esters

Article abstract of DOI:10.1002/chem.202100655

A cheap, facile and metal-free photochemical protocol for the activation of aromatic aldehydes has been developed. Utilizing thioxanthen-9-one as the photocatalyst and cheap household lamps as the light source, a variety of aromatic aldehydes have been activated and subsequently converted in a one-pot reaction into amides, hydroxamic acids and esters in good to high yields. The applicability of this method was highlighted in the synthesis of Moclobemide, a drug against depression and social anxiety. Extended and detailed mechanistic studies have been conducted, in order to determine a plausible mechanism for the reaction.

Full text of DOI:10.1002/chem.202100655

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Chemistry—A European Journal
Photochemical Activation of Aromatic Aldehydes: Synthesis
of Amides, Hydroxamic Acids and Esters
Nikolaos F. Nikitas+,[a] Mary K. Apostolopoulou+,[a] Elpida Skolia,[a] Anna Tsoukaki,[a] and
Christoforos G. Kokotos*[a]
Abstract: A cheap, facile and metal-free photochemical
protocol for the activation of aromatic aldehydes has been
developed. Utilizing thioxanthen-9-one as the photocatalyst
and cheap household lamps as the light source, a variety of
aromatic aldehydes have been activated and subsequently
converted in a one-pot reaction into amides, hydroxamic
acids and esters in good to high yields. The applicability of
this method was highlighted in the synthesis of Moclobe-
mide, a drug against depression and social anxiety. Extended
and detailed mechanistic studies have been conducted, in
order to determine a plausible mechanism for the reaction.
Introduction
Photochemistry, the use of light to promote organic trans-
formations, is a field of catalysis known for more than a century.
Nevertheless, it received limited attention until 2008, when
photoredox catalysis, a new and powerful activation platform
for the development of unprecedented reactivities that utilizes
light-harnessing metal complexes, altered the way that modern
researchers treat radical species.[1] However, there are certain
drawbacks regarding the employed metal complexes, such as
high cost and toxicity. An alternative solution is the use of small
organic molecules as the photocatalysts.[2]
Modern organic chemistry has a continuous and growing
interest in the use of environmentally friendly methods for the
preparation of versatile organic intermediates and important
final products. Acid chlorides, due to their versatility as reactive
intermediates, comprise potentially useful scaffolds for organic
synthesis. Traditionally, acid chlorides are prepared from the
corresponding carboxylic acids with the use of oxalyl chloride,
thionyl chloride, phosphorous trichloride or phosphorous
pentachloride (Scheme 1, A).[3a–c] Although extremely popular in
use for the synthesis of acyl chlorides, these reagents are
dangerous and toxic, due the formation of corrosive fumes,
making them improper for large scale synthesis, while the
reactions demand long reaction times and often require reflux
conditions. More recent studies have focused on the use of
light to favor the transition metal-catalyzed formation of acid
chlorides from carboxylic acids, aldehydes or aryl and alkyl
halides (Scheme 1, B)[3d–f] However, these methods employ
Scheme 1. Approaches for the activation of carbonyl derivatives and their
conversion to acyl chlorides.
metal catalysts. Therefore, there is still a need for new, greener
and more accessible protocols for the activation of carbonyl
derivatives (Scheme 1, C).
Acid chlorides constitute efficient intermediates for the
synthesis of many useful organic moieties, such as amides,
hydroxamic acids and esters. The amide bond is one of the
most important bonds in biological macromolecules, exhibiting
high stability, polarity and diversity.[4] Conventionally, amide
bonds are constructed by coupling of carboxylic acid deriva-
tives with amines using various activating reagents (Scheme 2,
A1).[5] These protocols liberate stoichiometric equivalents of
toxic by-products and are generally incompatible with sterically
congested amides. More recently, a plethora of methods have
been developed for the construction of amide bonds, including
the transition-metal-catalyzed amidation.[6] For example, Yama-
[a] N. F. Nikitas,+ M. K. Apostolopoulou,+ E. Skolia, A. Tsoukaki,
Prof. Dr. C. G. Kokotos
Laboratory of Organic Chemistry, Department of Chemistry
National and Kapodistrian University of Athens
Panepistimioupolis 15771, Athens (Greece)
E-mail: ckokotos@chem.uoa.gr
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202100655
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enzymes that are associated with a number of diseases.[7] The
first successful attempt for the synthesis of hydroxamic acids
from aldehydes utilized the Angeli-Rimini reaction, which
requires the use of N-hydroxybenzenesulfonamide in the
presence of a strong base (Scheme 2, B1).[8] Nowadays, this
method is seldomly used, because of the difficulty to remove
the benzenesulfinic acid that is formed and its low yields. To
date, various methods for the preparation of hydroxamic acids
have been developed, including the reaction of nitroarenes and
nitrosoarenes with aldehydes,[9b,e] the oxidative amidation of
alcohols,[9g] the utilization of Ag nanoclusters,[9i] the direct
transformation of aldehydes to hydroxamic acids via N-hydrox-
ysuccinimide ester formation,[9f] the hydroacylation of dialkyl
azodicarboxylates in the presence of phenylglyoxylic acid[9h] and
the reaction of activated carboxylic acids, acyl halides or esters
with O-protected, N,O-protected[9a,d] and unprotected
hydroxylamines,[9c] which consists the most common approach
for the synthesis of hydroxamic acids (Scheme 2, B2). However,
these synthetic approaches often require drastic conditions,
long reaction times, the use of expensive reagents and present
difficulties in the product isolation.
Esters are also one of the most significant functional groups
encountered in organic synthesis. They are abundant in various
natural products, polymers, pharmaceuticals, and synthetic
intermediates.[10] Classical methods for ester synthesis are based
on nucleophilic substitution of carboxylic acid derivatives with
alcohols (Scheme 2, C1).[10c] An alternative approach is the
oxidative esterification of aldehydes with alcohols,[11] mainly
through the formation of a hemiacetal intermediate, that is
subsequently oxidized to the ester (Scheme 2, C2). Over the
past decades, many direct esterifications of aldehydes through
the oxidation of hemiacetals have been reported with several
organic and inorganic oxidants.[12] Oxidative esterifications of
aldehydes catalyzed by transition metals and N-heterocyclic
carbenes (NHCs) have also been investigated.[12] Some more
recent methodologies explore ester formation induced by
visible light using transition metals as photocatalysts.[13] How-
ever, most of these methods suffer from drawbacks due to the
steric attributes of the substrates, the instability of the hemi-
acetal intermediate, the limited substrate scope and the harsh
and sensitive reaction conditions used. In addition, catalyst cost
and negative environmental impact constitute impractical
aspects for large-scale use.
Scheme 2. Approaches for the synthesis of amides, hydroxamic acids and
esters from acids or aldehydes.
As presented above, these important classes of compounds
are traditionally produced by a simple precursor, such as an
acid chloride. However, most current methods for their
preparation exhibit difficulties and limitations. Being active for
many years in the field of photochemistry,[14] our group has
successfully synthesized many different categories of com-
pounds, utilizing a great variety of photocatalysts, cheap
household lamps as the irradiation source and studying
simultaneously the mechanism of the reaction. Herein, we
introduce an alternative, direct and metal-free protocol that
requires light, for the synthesis of acyl chlorides from aromatic
aldehydes and a mild and safe source of Cl, more specifically N-
chlorosuccinimide (NCS). Then, the corresponding acyl chlorides
can easily be transformed into amides, hydroxamic acids and
moto, Barbas, Luca and Cho independently reported the
synthesis of amides from aldehydes through the formation of
activated intermediates via acyl radicals (Scheme 2, A2).[3d,6q–t]
However, most of these methods have some limitations, mainly
the limited substrate scope of amines, the use of metals as the
catalyst and the unfavorable stoichiometric ratios of the
reagents.
Hydroxamic acids are strong metal ion chelators possessing
a wide spectrum of biological activities, such as antibacterial,
antifungal, anti-inflammatory, anti-asthmatic properties, and
have shown therapeutic activity as potential inhibitors of
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esters (Scheme 2, D). The catalyst employed, thioxanthen-9-one,
is a cheap and commercially available compound which has
been previously explored in our group[15] and demonstrates
high activity when irradiated. The reaction requires exception-
ally mild conditions to proceed, as it occurs at room temper-
ature under household bulb irradiation. A variety of substituted
benzaldehydes has been tested and converted into the
corresponding products in high yields. Key advantages of this
process are that when combined with the second substitution
step, it provides an one-pot synthesis method that is cheap and
environmentally friendly, since it avoids the use of any
expensive and toxic transition metal-based catalysts, it is
operationally simple and the starting reagents, as well as the
visible light sources, are inexpensive and readily available.
reaction time was 7 h, long enough so as to achieve the best
yields, but not too long, in order to avoid the hydrolysis of the
acyl chloride to the corresponding carboxylic acid (Table 1,
entries 3, 11 and 12). Decreasing the amount of 2, the catalyst
loading or the solvent decreased the yield of the reaction, while
a further increase of them did not increase the yield (Table 2,
entries 1–6). We then studied the performance of the reaction
with and without the catalyst, without air and without light
(Table 2, entries 7–9). In the absence of the photocatalyst or
light no reaction took place.
Having in hand the optimized reaction conditions for the
activation of aldehydes (Table 1, entry 3), a one-pot method
was developed for the synthesis of amides (Scheme 3). When
optimizing the conditions for the reaction, we discovered that
the addition of 3 equivalents of benzyl amine to the reaction
mixture of 3a afforded N-benzylbenzamide (6a) in 90% yield.[16]
The substrate scope was then examined (Scheme 3).
Aromatic aldehydes were excellent substrates for the reaction.
The reaction proceeded with both electron-rich and -deficient
aryl aldehydes, affording the corresponding products in good
yields (6a–6l). It is important to highlight that the reaction
tolerates the presence of a nitro group, both in meta and para
position (6f and 6j), halides including fluoro (6b), chloro (6c)
and bromo (6d), as well as heterocyclic substrates (6l). When
an aliphatic moiety, derived from the natural product cam-
phanic acid, was attached at the para position of the aryl
aldehyde, product 6m was isolated in lower yield. Aliphatic
aldehydes were not suitable substrates, probably due to the
lower stability of aliphatic acyl radicals,[17] while in the same
time, aliphatic aldehydes are susceptible to various hydrogen
atom abstraction events by succinimidyl radical and chlorine
atom formed in the reaction, which leads to by-product forming
pathways to complex reaction mixtures. Different amines were
also tested. Aliphatic amines responded really well in this one-
Results and Discussion
We initiated our study utilizing benzaldehyde (1a) as the
substrate and N-chlorosuccinimide (NCS, 2) as the source of [Cl].
In the optimization, a variety of different photoinitiators-photo-
catalysts, solvents and stoichiometries were tested (Table 1).
Among the different compounds tested, thioxanthen-9-one (4c)
afforded the highest yield (Table 1, entries 1–5).[16] The optimum
solvent proved to be MeCN (Table 1, entries 3 vs 6–11). The
only other solvent that afforded good yields was a mixture of
MeCN/MeOH, which indicates that MeCN might play a signifi-
cant role for the reaction (Table 1, entry 9). When examining the
reaction time, we came to the conclusion that the optimum
Table 1. Optimization of the reaction conditions for the photochemical
synthesis of 3a from 1a.[a]
Table 2. Optimization of the reaction stoichiometry for the photochemical
synthesis of 3a from 1a.[a]
Entry
Catalyst
Solvent
Reaction Time [h]
Yield [%][b]
Entry Catalyst loading [mol
%]
Solvent
[mL]
NCS
(equiv.)
Yield
[%][b]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e[d]
4c
4c
4c
4c
4c
4c
4c
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
EtOAc
MeOH
MeCN/MeOH (1:1)
7
7
7
7
7
7
7
7
7
7
5
16
48
43
88 (80)[c]
52
1
2
3
4
5
6
10
20
30
20
20
20
0
0.8
0.8
0.8
0.4
1.6
0.8
0.8
0.8
0.8
1.3
1.3
1.3
1.3
1.3
2
1.3
1.3
1.3
38
88 (80)[c]
87
49
85
66
0
64
0
30
54
23
40
78
25
55
35
7
9
8[d]
9[e]
20
20
10
11
12
CH2Cl2
MeCN
MeCN
[a] All reactions were carried out with 1a (0.50 mmol), 2 (0.25–1.00 mmol),
MeCN (0.4–1.6 mL) and thioxanthen-9-one (4c) (5–30 mol%), under 2×
85 W household lamps irradiation. [b] Yields were determined by GC-MS.
[c] Yield of product, after purification by fast column chromatography
(filtration). [d] The reaction was performed under Ar atmosphere. [e] The
reaction was performed in the dark.
[a] All reactions were carried out with 1a (0.50 mmol), N-chlorosuccinimide
(2) (0.65 mmol), solvent (0.8 mL) and catalyst (20 mol%), under 2×85 W
household lamps irradiation. [b] Yields were determined by GC-MS. [c]
Yield of product, after purification by fast column chromatography
(filtration). [d] Catalyst loading 5 mol%.
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Scheme 4. Substrate scope for the synthesis of hydroxamic acids.
Scheme 3. Substrate scope for the synthesis of amides.
pot protocol, furnishing the corresponding benzamides with
linear, branched or cyclic aliphatic chains (6n–6t). Derivatives
of natural products, like oleyl amine and L-valine methyl ester
were tested, leading to products 6u and 6v.
Next, we turned our attention to the application of this
photochemical reaction for the one-pot synthesis of hydroxamic
acids (Scheme 4). We began with exploring the optimum
conditions for the second step of the reaction, whilst keeping
the first step the same. We examined the preferred base,
solvent and quantities.[16] Hydroxamic acids are generally
difficult in the isolation via column chromatography. The use of
an inorganic base (K2CO3) facilitated the purification of the final
product in comparison to organic bases, such as Et3N, which
afforded higher yields (with 3 equiv. vs 6 equiv. for K2CO3), so
K2CO3 was chosen as the most efficient base for the reaction.
Hydroxylamine hydrochloride, as well as N- and O-benzyl
protected hydroxylamine derivatives reacted successfully with
several substituted aromatic aldehydes and afforded the
corresponding hydroxamic acids in good yields (Scheme 4).
Both electron-rich and -deficient substituted aryl aldehydes
reacted effectively, since the reaction proceeds well with both
the presence of a nitro group (Scheme 4, 8d, 8e and 8f) and of
a methoxy group (Scheme 4, 8j, 8k and 8l).
Scheme 5. Substrate scope for the synthesis of esters.
Furthermore, we investigated a one-pot method for the
synthesis of esters from aldehydes and alcohols (Scheme 5). To
achieve the highest yields for the reaction, we first determined
the optimum conditions.[16] A variety of different aromatic
aldehydes were tested, providing the desired products in very
good yields. Aldehydes bearing electron-withdrawing groups as
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well as electron-donating groups reacted effectively. The
substituents at meta (10h and 10i) and ortho (10j) positions of
the ring did not affect the reactivity. Different alcohols reacted
successfully as well. The reaction with phenol gave the
corresponding product in good yield (10n). Effective reactions
with perillyl alcohol (10r), oleyl alcohol (10t), citronellol (10u),
menthol (10v) and cholesterol (10w) showed promising results
for the application of this method to naturally-occurring
compound chemistry.
Since this one-pot protocol provides a facile route to amide
bond formation, it prompted us to synthesize a molecule of
pharmaceutical relevance. Moclobemide 12 is a drug that is
used against depression and social anxiety.[18] Starting from 4-
chlorobenzaldehyde (1c), amide 11 was afforded in a single
step, in 78% combined yield, utilizing our protocol (Scheme 6).
Amide 11 was then converted into Moclobemide 12 in 50%
yield, using a second one-pot method, previously developed in
our laboratory.[19] These results indicated that the developed
method is applicable to the synthesis of naturally-occurring
molecules and pharmaceutically-relevant compounds.
In order to study the reaction mechanism, a variety of tools
were employed. Based on literature and the pioneering work of
Yoon,[20] the quantum yield of the photochemical reaction was
calculated (Φ=26),[16] indicating a chain propagation mecha-
nism. Next, UV-Vis experiments were performed.[16] Upon mixing
thioxanthen-9-one (4c), benzaldehyde (1a) and N-chlorosucci-
nimide (2) in MeCN, no increase in the UV absorbance was
observed. These results excluded the possibility of an EDA
complex formation.[21,22]
Figure 1. A. Stern-Volmer plot from the fluorescence quenching of thio-
xanthen-9-one (4c) (1 mM in MeCN) with benzaldehyde (1a). B. Stern-
Volmer plot from the fluorescence quenching of thioxanthen-9-one (4c)
(1 mM in MeCN) with N-chlorosuccinimide (2).
We then turned our attention in employing fluorescence
quenching studies (Figure 1, A and B).[16] After irradiation of
thioxanthen-9-one (4c) (1 mM in MeCN) at 312 nm, its
fluorescence was measured at 441 nm. When the added
amount of benzaldehyde (1a) increased, there was a decrease
in the fluorescence (Figure 1, A). In addition, when increasing
the added amount of N-chlorosuccinimide, there was a subtle
decrease in the fluorescence, when low concentrations of N-
chlorosuccinimide were employed (slope 10.5) and an increased
slope of decrease was observed (slope 32), when the concen-
trations of N-chlorosuccinimide were higher (Figure 1, B). These
results indicate that probably both reagents interact with the
excited state of the photocatalyst, indicating that the product
formation is a combination of two different mechanistic path-
ways. Although as far as N-chlorosuccinimide is concerned, the
slope of the Stern-Volmer is comparable with the slope of
benzaldehyde (although lower in all cases) only in high
concentrations. Fluorescence quenching studies were also
performed in other solvents (CH2Cl2 and toluene).[16] The results
were similar where benzaldehyde was concerned, but when it
came to N-chlorosuccinimide (2), in these solvents, there was
no decrease in the fluorescence. This reaffirmed that MeCN
could be playing an important role in the reaction mechanism,
facilitating the interaction between thioxanthen-9-one (4c) and
N-chlorosuccinimide (2). The relativity of the Stern-Volmer plots
in MeCN and the other organic solvents suggest that an energy
transfer mechanism might be taking place to some extent.
Based on literature,[23] one can use the Stern-Volmer plots and
the quenching constants in different solvents, and when these
are similar, then an energy transfer (EnT) pathway is more likely
to happen than an electron transfer procedure, which is solvent
dependent.[23] Further mechanistic studies proved the radical
nature of the reaction, since addition of TEMPO or BHT prevents
the formation of the product.[16] Instead, when the reaction
mixture with TEMPO and BHT was irradiated for 7 h, an adduct
deriving from the benzoyl radical with TEMPO and with BHT
respectively, was observed by GC-MS, confirming the gener-
ation of the benzoyl radical from benzaldehyde.
Utilizing the knowledge that comes from the experiments
above, we can propose a plausible mechanism for the photo-
chemical reaction of benzaldehyde to benzoyl chloride. Upon
irradiation by light, the photocatalyst, thioxanthen-9-one (4c), is
Scheme 6. Synthesis of moclobemide.
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excited to singlet state I, followed by intersystem crossing,
leading to triplet thioxanthen-9-one II. Biradical species II is
capable of performing hydrogen atom abstraction (HAT) from a
relatively weak CÀ H bond, like that of the formyl group (BDE ca.
87 kcal/mol).[24] This leads to the formation of an α-hydroxyl
radical III of the catalyst and benzoyl radical IV, as supported by
GC-MS (trapped by Tempo or BHT). The benzoyl radical can
then react with N-chlorosuccinimide, forming acyl chloride (3a)
and succinimidyl radical V, which can advance the propagation
upon reverse HAT with the aldehyde or can regenerate the
active form of the catalyst upon HAT of III, which can then
again perform a new catalytic cycle (Scheme 7). This mechanism
is also in place when solvents other than MeCN are employed
or low concentration of NCS are present.
In MeCN, quenching of thioxanthen-9-one (4c) also
occurred by N-chlorosuccinimide (2) (in higher concentrations
of NCS and with a comparable quenching to benzaldehyde),
indicating that there is an interaction between these two
compounds, providing us a hint to support a second mecha-
nism that appears to be happening simultaneously (Scheme 8).
Alternatively, thioxanthen-9-one (4c) is also a known photo-
sensitizer, capable to transfer its triplet state energy to other
chemical species. More specifically, the excited photocatalyst II
activates N-chlorosuccinimide via energy transfer and itself
returns to its ground state. The excited N-chlorosuccinimide VI
is then subjected to homolytic cleavage, providing a chlorine
atom VII and succinimidyl radical V. Both radicals are really
potent hydrogen atom abstractors,[25] that can react with
benzaldehyde forming benzoyl radical V. The benzoyl radical
can then react with one other molecule of N-chlorosuccinimide,
forming the desired product and succinimidyl radical VI, which
can sustain a radical chain propagation (Scheme 8). When the
reaction took place in the presence of 2-methyl-2-butene, a
known Cl2 scavenger,[26] the final product was formed in 16%
yield (NMR yield), supporting the formation of a chlorine atom
and its involvement in the product forming route. This
mechanism can be operating upon high concentrations of N-
chlorosuccinimide. Thus, in MeCN, both mechanisms presented
in Schemes 7 and 8 might be operative, with the former being
the major pathway.
Scheme 7. Proposed reaction mechanism 1.
Conclusions
In summary, a green, sustainable, metal-free and practical new
protocol for the one-pot synthesis of amides, hydroxamic acids
and esters from activated aldehydes was developed by using
acyl chlorides as the intermediates. The reaction takes place
under mild conditions including an organic molecule as the
photocatalyst and household bulb irradiation in order to
generate the acyl radical. A variety of substrates bearing
different functionalities were tested successfully, leading to
products in moderate to excellent yields. The process was
applied in the synthesis of moclobemide, a currently employed
drug for the treatment of anxiety. Mechanistic studies were
performed in order to shed light on the action of thioxanthen-
9-one. This novel approach employs cheap, green and sustain-
able materials in order to synthesize more complex com-
pounds.
Experimental Section
General procedure for the synthesis of the amides: In a glass vial,
aldehyde 1 (0.50 mmol), N-chloro-succinimide (2) (87 mg, 1.3 equiv.,
0.65 mmol) and thioxanthen-9-one (4c) (21 mg, 20 mol%,
0.10 mmol) were diluted in MeCN (0.8 mL). The vial was left stirring
Scheme 8. Proposed reaction mechanism 2.
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under household bulb irradiation (2×85 W household lamps) for
7 h. The desired intermediate was identified by GC-MS and the
reaction mixture was utilized directly to the next step of the
reaction. Amine (3.0 equiv., 1.50 mmol) was added to the reaction
mixture and the reaction mixture was left stirring at room temper-
ature for 16 h. The solvent was removed in vacuo and the desired
product was purified by column chromatography.
General procedure for the synthesis of the hydroxamic acids: In a
glass vial, aldehyde (0.50 mmol), N-chloro-succinimide (2) (87 mg,
1.3 equiv., 0.65 mmol) and thioxanthen-9-one (4c) (21 mg,
20 mol%, 0.10 mmol) were diluted in MeCN (0.8 mL). The vial was
sealed left stirring under household bulb irradiation (2×85 W
household lamps) for 7 h. After removal of the solvent in vacuo, the
reaction mixture was diluted with dichloromethane (4 mL), trans-
ferred into a round-bottom flask and hydroxylamine hydrochloride
(6.0 equiv., 3.00 mmol) and K2CO3 (6.0 equiv., 0.30 mmol) were
added. The reaction mixture was left stirring at room temperature
for 16 h. The solvent was removed in vacuo and the desired product
was purified by column chromatography.
General procedure for the synthesis of the esters: In a glass vial,
aldehyde (0.50 mmol), N-chloro-succinimide (2) (87 mg, 1.3 equiv.,
0.65 mmol) and thioxanthen-9-one (4c) (21 mg, 20 mol%,
0.10 mmol) were diluted in MeCN (0.8 mL). The vial was left stirring
under household bulb irradiation (2×85 W household lamps) for
7 h. After removal of the solvent in vacuo, the reaction mixture was
diluted with THF (2 mL), transferred to a round-bottom flask and
DMAP (244 mg, 2.00 mmol, 4.0 equiv.) and the desired alcohol
(1.50 mmol, 3.0 equiv.) were added. The reaction mixture was left
stirring under reflux for 16 h. The solvent was removed in vacuo
and the desired product was purified by column chromatography.
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Acknowledgements
The authors gratefully acknowledge the Hellenic Foundation for
Research and Innovation (HFRI) for financial support through a
grant, which is financed by 1st Call for H.F.R.I. Research Projects
to Support Faculty Members & Researchers and the procure-
ment of high-cost research equipment grant (grant number
655). N.F.N. would like to thank the State Scholarships
Foundation (IKY) for financial support through a doctoral
fellowship, which is co-financed by Greece and the European
Union (European Social Fund-ESF) through the Operational
Programme “Human Resources Development, Education and
Lifelong Learning” in the context of the project “Strengthening
Human Resources Research Potential via Doctorate Research”
(MIS-5000432), implemented by the State Scholarships Founda-
tion (IKY)”. The authors would like to thank M. Orfanakis and F.
Margetakis for seting up the reaction for the synthesis of 10a.
Also, COST Action CÀ H Activation in Organic Synthesis (CHAOS)
CA15106 is acknowledged for helpful discussions.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: aromatic aldehydes · amides · esters · hydroxamic
acids · green chemistry · photochemistry
Chem. Eur. J. 2021, 27, 1–9
www.chemeurj.org
7
© 2021 Wiley-VCH GmbH
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These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202100655
Chemistry—A European Journal
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Manuscript received: February 21, 2021
Accepted manuscript online: March 27, 2021
Version of record online: ■■■, ■■■■
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Chem. Eur. J. 2021, 27, 1–9
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© 2021 Wiley-VCH GmbH
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FULL PAPER
N. F. Nikitas, M. K. Apostolopoulou, E.
Skolia, A. Tsoukaki, Prof. Dr. C. G.
Kokotos*
1 – 9
Photochemical Activation of
Aromatic Aldehydes: Synthesis of
Amides, Hydroxamic Acids and
Esters
Photochemistry. A facile, mild and
metal-free one-pot protocol for the
activation of aromatic aldehydes and
their conversion into amides, hydroxa-
mic acids and esters was developed,
using cheap household lamps as the
light source and thioxanthen-9-one as
the photocatalyst.