1,3-Dibromo-5,5-dimethylhydantoin as a Precatalyst for Activation of Carbonyl Functionality

Article abstract of DOI:10.3390/molecules24142608

Activation of carbonyl moiety is one of the most rudimentary approaches in organic synthesis and is crucial for a plethora of industrial-scale condensation reactions. In esterification and aldol condensation, which represent two of the most important reactions, the susceptibility of the carbonyl group to nucleophile attack allows the construction of a variety of useful organic compounds. In this context, there is a constant need for development of and improvement in the methods for addition-elimination reactions via activation of carbonyl functionality. In this paper, an advanced methodology for the direct esterification of carboxylic acids and alcohols, and for aldol condensation of aldehydes using widely available, inexpensive, and metal-free 1,3-dibromo-5,5-dimethylhydantoin under neat reaction conditions is reported. The method is air- and moisture-tolerant, allowing simple synthetic and isolation procedures for both reactions presented in this paper. The reaction pathway for esterification is proposed and a scale-up of certain industrially important derivatives is performed.

Full text of DOI:10.3390/molecules24142608

molecules
Article
1,3-Dibromo-5,5-dimethylhydantoin as a Precatalyst
for Activation of Carbonyl Functionality
1,2
1,3
and Stojan Stavber 1,2,
*
ˇ
Klara Cebular
, Bojan Đ. Božic´
1
Department of Physical and Organic Chemistry, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia
Jožef Stefan International Postgraduate School, Jamova 39, 1000 Ljubljana, Slovenia
Institute of Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Studentski trg 16,
11000 Belgrade, Serbia
2
3
*
Correspondence: stojan.stavber@ijs.si; Tel.: +386-147-73-660; Fax: +386-142-35-400
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 19 June 2019; Accepted: 15 July 2019; Published: 17 July 2019
Abstract: Activation of carbonyl moiety is one of the most rudimentary approaches in organic
synthesis and is crucial for a plethora of industrial-scale condensation reactions. In esterification and
aldol condensation, which represent two of the most important reactions, the susceptibility of the
carbonyl group to nucleophile attack allows the construction of a variety of useful organic compounds.
In this context, there is a constant need for development of and improvement in the methods for
addition-elimination reactions via activation of carbonyl functionality. In this paper, an advanced
methodology for the direct esterification of carboxylic acids and alcohols, and for aldol condensation
of aldehydes using widely available, inexpensive, and metal-free 1,3-dibromo-5,5-dimethylhydantoin
under neat reaction conditions is reported. The method is air- and moisture-tolerant, allowing simple
synthetic and isolation procedures for both reactions presented in this paper. The reaction pathway
for esterification is proposed and a scale-up of certain industrially important derivatives is performed.
Keywords: esterification; 1,3-dibromo-5,5-dimethylhydantoin; metal-free catalyst; aryl acids;
alkyl acids
1. Introduction
(Trans)esterification is one of the most prominent transformations of carbonyl functionality
in academia and industry due to the undeniable significance of the ester functional group in
biological systems [
pharmaceuticals, flavor chemicals, fine chemicals, adhesives, lubricants, electronic materials, etc. [
It is a vital reaction in the preparation of fatty acid methyl esters (FAME), which play a crucial role
in producing detergents [ ] and biodiesel fuel [ ] and in microbial source tracking (MST) [ ].
In developing active pharmaceutical ingredients (APIs), esterification is a valuable tool for modifying
the physicochemical properties of drugs [ ]. Esters with low molecular mass are widely used as
fragrances and are components of essential oils [ ] and pheromones [10], while certain steroidal esters
1] and in the fabrication of a variety of products, such as cosmetics, plasticizers,
2].
3
4,5
6,7
8
9
are known as antifungal agents [11], as biocompatible and biodegradable polyesters for biomedical
applications [12], or show antiproliferative and pro-apoptotic effects in cancer treatment [13]. Moreover,
cholesterol esters and triglycerides belong to the main classes of lipids, which form the bulk of animal
fats and vegetable oils. A particularly interesting cholesterol ester is cholesteryl acetate, since aside from
being a component of gallstones, it has been readily exploited in constructing electronic displays [14].
On the other hand, bile acids play an important role in the digestion of lipids and in lipophilic vitamin
reabsorbtion [15], and act as effective excipients (intestinal absorption enhancers, promoters, etc.) [16
]
(Figure 1).
Molecules 2019, 24, 2608; doi:10.3390/molecules24142608
www.mdpi.com/journal/molecules

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Figure 1. Structures of a selection of significant ester and aldol products.
The most extensively studied and commonly utilized esterification reaction is direct condensation
between carboxylic acid and alcohol (Fischer esterification) [17]. Conventional approaches involve
excessive reagents/dehydrative agents or use activated carboxylic acid derivatives in the presence
of a stoichiometric base, leading to considerable amounts of byproducts and waste at the end of the
process, and culminating in resource-consuming purification [18
esterification [20], lacking these disadvantages, has become the preferred method among researchers,
employing a vast number of catalysts: Brønsted acids/bases [21 22], Lewis acids [23], metal catalysts [24],
solid-supported catalysts [25 26], solid acids [27 28], ionic liquids [29 30], PPh3-based catalysts [31],
enzymes [32], zeolites [33], etc.
,19]. Consequently, catalytic direct
,
,
,
,
However, in the context of sustainable industrial processes, there is an omnipresent struggle
between the economical and ecological aspects of production. Therefore, an ideal method for a
condensation reaction should include the use of an easily manipulable, low-cost, non-metal, water- and
air-tolerant catalyst under mild, solvent-free reaction conditions without the need for simultaneous
water removal, stoichiometric amounts of activators or large excesses of reagents. Furthermore,
the methodology should be applicable to a broad substrate scope with high selectivity, providing high
product yields, allowing scaling-up, and involving a simple purification procedure.
1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) belongs to the group of cost-effective N-halamine
disinfectants, which are becoming increasingly popular due to their long-term stability in dry storage
or in a wide pH range of aqueous solutions, their safety for humans and the environment, and their
ability to rapidly kill most microorganisms [34]. Furthermore, relative to inorganic halogens, they
are less corrosive, more stable, and relatively cheap [35]. In addition, DBDMH is among the more
established, commercially available N-halo reagents that are gradually attracting attention for being
safe, stable, easily-handled solids that can be utilized under mild conditions for highly selective organic
transformations [36–39]. Their distinctive chemical properties, owing to the presence of an N-X bond,
instil them with broad, synthetic usability, especially as a source of halenium ions (X+) or halogen
radicals (X•) [40]. Although DBDMH-mediated acetyl ester preparation has previously been reported,
this method is limited only to acylation and includes the use of an activated carboxylic acid derivative
(acetic anhydride) in the presence of a halogenated solvent (CH2Cl2) [41].
Our previous work described a convenient esterification method mediated by N-bromosuccinimide
in substoichiometric amounts for direct esterification [42]. With this in mind, and in the context of our
continued interest in improving and developing environmentally acceptable synthetic protocols [43–48],
we now report the precatalytic activity of easily manipulable, metal-free DBDMH in the direct
esterification of carboxylic acids and alcohols and in the aldol condensation of aldehydes.

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2. Results and Discussion
2.1. Esterification
Initially, benzoic acid (
1
) was chosen as a model substrate to optimize the esterification reaction
protocol. In the typical experimental procedure, the mixture of
70 ◦C in the presence of different catalysts (Figure 2).
1 and methanol (MeOH) was heated at
Figure 2.
N-chlorosuccinimide,
Structures of N-halosuccinimides and 1,3-dihalo-5,5-dimethylhydantoins (NCS:
NBS: N-bromosuccinimide, NIS: N-iodosuccinimide, DCDMH:
1,3-dicholoro-5,5-dimethylhydantoin, DBDMH: 1,3-dibromo-5,5-dimethylhydantoin, DIDMH:
1,3-diiodo-5,5-dimethylhydantoin).
The results of this optimization are presented in Table 1. Among the studied catalysts
(N-halosuccinimides, 1,3-dihalo-5,5-dimethylhydantoins, halogen mineral acids, molecular bromine
and iodine), DBDMH exhibited the highest efficiency (Entry 3). In contrast, no conversion was noticed
in the absence of catalyst (Entry 1). Furthermore, the effect of DBDMH loading was examined by
changing its amount from a 3.5 molar percentage (mol%) to 7 mol% (Table 1, Entries 3, 7, and 8).
No competing reaction was noticed, and although an excellent conversion was obtained even at
3.5 mol% (92%, Entry 8), a quantitative transformation to methyl benzoate was observed in the presence
of 7 mol% of DBDMH (Entry 3). Therefore, further optimization was performed with 7 mol% of
DBDMH. Furthermore, varying the temperature from 30 ◦C to 70 ◦C (Entries 3, 10, and 11) showed a
considerable impact on esterification efficiency, with the optimal temperature being 70 ◦C (Entry 3).
Under dry reaction conditions, the efficiency of esterification dropped for a substantial 20% (Entry 9),
which suggests a water-assisted mechanism, as discussed below (Scheme 1).
To gain a clearer insight into the course of the reaction pathway, esterification of benzoic acid with
methanol in the presence of 7 mol% of DBDMH under optimal reaction conditions was performed,
with the reaction mixture being sampled every 10–15 min for the first 75 min of the reaction time and
the spectra of each sample subsequently measured by 1H-NMR (Figure 3). Moreover, the pH of the
reaction mixture was also measured after 10, 30, and 60 min. The results presented in Figure 3 show
the decomposition of DBDMH to 5,5-dimethylhydantoin (DMH) over the first 60 min. Interestingly,
esterification started after the complete conversion of DBDMH to DMH, after 75 min. Furthermore,
no conversion to the ester product was observed when a control experiment was performed by heating
a mixture of benzoic acid and methanol under optimal reaction conditions at 70 ◦C in the presence of
7 mol% DMH, suggesting that the formation of bromine specie(s) during DBDMH decomposition is
crucial for the esterification reaction and that the role of DBDMH is precatalytic rather than catalytic
(Table 2, Entry 3). Figure 3 shows a considerable drop in pH value from 4.0–4.5 to 0–0.5 over 60 min,
which stayed unchanged throughout the remainder of the reaction (24 h).

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Table 1. Optimization of reaction conditions 1.
Conv. [%] 2
(Yield [%])
Loading
[mol%]
Entry
Catalyst
Temp. [◦C]
Time [h]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
/
/
7
7
7
7
7
5
3.5
7
7
7
7
7
7
7
7
70
70
70
70
70
70
70
70
70
50
30
70
70
70
70
70
20
20
20
20
20
20
20
20
20
20
20
14
8
0
DCDMH
DBDMH
DIDMH
HBr
88 (85)
100 (95)
30 (26)
84 (80) 3
6 (3)
95 (90)
92 (88)
80 (77) 4
75 (72)
0
90 (85)
86 (82)
79 (75)
70 (66)
15 (10)
I2
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
6
4
2
1
Reaction conditions:
1 (1.0 mmol), MeOH (0.5 mL), NXS, DXDMH, HCl (37%), HBr (48%), HI (57%), Br2, I2, T, t.
2
3
Conversions were determined by 1H-NMR analysis of the crude reaction mixtures. Data from reference [42].
4 Freshly dried MeOH was used, and the reaction performed over anhydrous Na2SO4 and under nitrogen atmosphere.
Scheme 1. Plausible reaction pathway.

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Figure 3. Timeline of the 1H-NMR spectra and pH measurements for esterification of benzoic acid
with methanol.
Table 2. pH measurements and conversion percentages of control esterification reactions 1,2
.
Entry
Components of the Mixture
pH 3
Conv. [%]
1
2
MeOH
MeOH + DMH
5.5
5.5
0
0
3
4
5
6
7
8
9
10
11
12
13
MeOH + benzoic acid + DMH
MeOH + DBDMH
3.5–4.0
0.0–0.5
3.5–4.0
0.0–0.5
0.0–0.5
3.0–3.5
4.0–4.5
5.0
0
0
0
MeOH + benzoic acid
MeOH + benzoic acid + DBDMH
MeOH + benzoic acid + DBDMH + anh. Na2SO4
MeOH + DCDMH
100 (95)
80 (77)
4
0
0
0
MeOH + DIDMH
n-octanol
n-octanol + DBDMH 5
0–0.5
5.0
0–0.5
<1% (octyl octanoate)
n-octanol + benzoic acid
n-octanol + benzoic acid/DBDMH
0
70 (65)
1
Reaction conditions: carboxylic acid (1 mmol), MeOH (0.5 mL), precatalyst (0.07 mmol), 70 ◦C, 20 h; 2 Conversions
were determined after 20 h by 1H-NMR spectroscopy. pH was measured after a reaction time of 1 h; 4 MeOH was
dried with molecular sieves (4Å) and the reaction was performed under nitrogen atmosphere in the presence of
Na2SO4; 5 Trace amounts of octyl octanoate were detected after 20 h.
3
These promising results encouraged us to investigate the efficiency of DBDMH in mediating the
direct esterification of carboxylic acids with alcohols (Tables 3–7). In all cases, octanoic acid (
2) showed
significantly higher activity towards esterification than benzoic acid ( ), yielding higher conversions
1
(Table 3). Since, unlike in the case of octanoic acid, the carbonyl C-atom in the electron accepting
carboxyl group of benzoic acid can receive electron density from resonance stabilization of the phenyl
ring, benzoic acid is less reactive toward the nucleophile attack than octanoic acid. As reaction-limiting
factors were found to include the nucleophilic character and steric properties of the substrate, different
alcohols were tested (a–j, Table 3). The elongation of the alcohol alkyl chain (a, d, and f) had a
stronger impact on the esterification efficiency of benzoic acid than on that of octanoic acid. In general,
DBDMH mediation exhibited significantly higher conversions relative to N-bromosuccinimide (NBS),
especially in the case of the secondary alcohols isopropanol (
yielded only trace products or no conversion at all [42]. The reaction limitation was observed for
the bulky tertiary alcohols t-BuOH ( ) and adamantanol ( ), as well as for phenol ( ). However,
c) and cyclopentanol (g), as NBS mediation
e
i
h

Molecules 2019, 24, 2608
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if the sterically-demanding adamantyl group was separated from the alcohol group with a CH2 unit,
the conversion increased to 79% for benzoic acid and 99% for alkyl acid (Table 3, 1j 2j). The unreactivity
,
in the case of the phenol molecule can be explained by the aromatic phenol structure, which possesses
lower nucleophilicity due to the resonance delocalization of the oxygen electron pair in the OH group.
1,2,3
Table 3. The effect of alcohol structure on the esterification of benzoic acid (
1
) and octanoic acid (
2)
.
R2OH
R1 = Ph
R1 = Heptyl
2a, 100% (97%) 5
2b, 98% (92%) 4
2c, 90% (86%)
2d, 100% (95%) 6
2e, 0%
MeOH (a)
FCH2CH2OH (b)
i-PrOH (c)
1a, 100% (95%)
1b, 100% (96%) 4
1c, 29% (23%)
1d, 82% (78%)
1e, 0%
n-BuOH (d)
t-BuOH (e)
n-Octanol (f)
Cyclopentanol (g)
Phenol (h)
1f, 70% (65%)
1g, 23% (21)
1h, 0%
2f, 91% (88%)
2g, 100% (94%) 6
2h, 0%
1-Adamantanol (i)
1-Adamantanemethanol (j)
1i, 0%
1j, 79% (75%)
2i, 0%
2j, 99% (94%)
1
Reaction conditions: carboxylic acid (1 mmol), alcohol (1 mmol, 2 mmol, or 0.5 mL), DBDMH (0.07 mmol), 70 ◦C,
20 h. Conversions were determined by 1H-NMR spectroscopy. The values in brackets indicate yields of isolated
2
3
4
5
products. Conversion (yield of isolated product) after 40 h. Conversion (yield of isolated product) after 2 h.
6
Conversion (yield of isolated product) after 15 h.
Table 4. Scope width of aromatic carboxylic acids tested under optimized esterification conditions 1,2,3
.
Methyl Benzoates
Entry
R
Compound
Conversion (Yield) [%]
100% (97%) 5
89% (85%) 6
94% (90%) 6
74% (70%) 6
100% (94%) 6
91% (87%)
100% (98%) 6
83% (78%) 6
30% (25%)
91% (85%)
82% (78%)
0%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4-NO2
4-F
4-Me
4-OMe
3-NO2
3-F
3a
4a
5a
6a
7a
8a
9a
3-Me
3-OMe
2-NO2
2-F
2-Me
2-OMe
2-I
2,4-MeO
3,5-MeO
3,4-MeO
methyl
isonicotinate
10a
11a
12a
13a
14a
15a
16a
17a
18a
62% (58%)
0%
0%
70% (64%) 4,6
17
19a
0%
1
2
Reaction conditions: carboxylic acid (1 mmol), MeOH (0.5 mL), DBDMH (0.07 mmol), 70 ◦C, 20 h. Conversions
were determined by 1H-NMR spectroscopy.
The values in brackets stand for yields of isolated products.
3
4
5
6
Conversion (yield of isolated product) after 40 h. A MeOH volume of 1.5 mL was used. A MeOH volume of
2 mL was used.

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Table 5. Scope of alkyl acids 1,2,3
.
Methyl alkyl esters
1 Reaction conditions: carboxylic acid (1 mmol), MeOH (0.5 mL), DBDMH (0.07 mmol), 70 ◦C, 2–20 h. 2 Conversions
3
4
were determined by 1H-NMR spectroscopy. The values in brackets indicate yields of isolated products. A MeOH
volume of 2 mL was used.
Table 6. Esterification of bile acids 1,2,3
.
Methyl Esters of Cholic Acid Derivatives
1
2
Reaction conditions: carboxylic acid (0.25 mmol), alcohol (0.5–2 mL), DBDMH (0.018 mmol), 70 ◦C, 5–20 h.
3
Conversions were determined by 1H-NMR spectroscopy. The values in brackets indicate yields of isolated
4
products. A 2 mL volume of MeOH was used.
Moreover, a modest limitation of the substrate scope was observed for monosubstituted benzoic
acids, as the reaction only failed in the case of 2-methoxybenzoic acid (Table 4) and hydroxy derivatives.
The lower reactivity in case of ortho-substituted benzoic acids may be attributed to the steric hindrance
of the ortho-positioned groups in the phenyl ring. The more the ortho-positioned group is sterically
abundant, lower is the conversion. On the other hand, unreactivity of hydroxy-substituted derivatives
is caused by the electron-donating properties of the OH group, which gives rise to low electron
deficiency on the carbonyl C-atom, and consequently, lower susceptibility of carbonyl group to
nucleophile attack. Bader charges for the carbon and oxygen atoms of the carbonyl group were

Molecules 2019, 24, 2608
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calculated and the analysis confirmed that the carbonyl C-atom in the case of p-OH-benzoic acid was
not as positively charged, as in the case of benzoic acid (Figure S1 and Table S1). When benzoic acid
derivatives bore multiple electron-rich moieties on the aromatic ring, esterification was more limited,
as only 3,4-dimethoxybenzoic acid produced an acceptable yield (Table 4, Compound 18a). In the case
of isonicotinic acid (Product 19a), the unreactivity probably originated from the higher basicity and
higher nucleophilicity of the nitrogen atom in the pyridine ring relative to the basicity (nucleophilicity)
of the carbonyl oxygen atom in the carboxyl group. The nitrogen atom in the pyridine ring could
therefore take a role of a Lewis base in a strong halogen bond interaction. [49] In net effect, it could
therefore act as a Br+ scavenger, preventing the activation of carboxylic acid toward the nucleophile
(alcohol) attack in the esterification reaction.
Table 7. Transesterification of cholesterol and epiandrosterone 1,2,3
.
Cholesteryl Acetate and Epiandrosteryl Acetate
1
Reaction conditions: steroidal alcohol (0.25–0.5 mmol), EtOAc (1 mL), DBDMH (0.018–0.035 mmol), 70 ◦C,
20 h. Conversions were determined by 1H-NMR spectroscopy. The values in brackets stand for yields of
2
3
isolated products.
The commercial importance of certain methyl esters in biodiesel production (FAME) and perfumery
(methyl benzoate) encouraged us to test the esterification of different types of alkyl carboxylic acids
with MeOH under optimal reaction conditions in the presence of DBDMH (Table 5). No limitations
were observed, and excellent yields were achieved, even in the case of polycarboxy derivatives.
In addition, the esterification of a selection of relevant bile acids was conducted to verify the
synthetic applicability of this method on larger and more complex structures (Table 6). Esterification
with methanol (a) and n-butanol (d) predominantly resulted in excellent yields, while the use of the
secondary alcohol isopropanol (c) resulted in fair conversion.
Moreover, the results regarding the acetylation of cholesterol and epiandrosterone are presented
in Table 7. Due to the high lipophilicity, and consequently, low solubility of these steroid alcohols in
acetic acid, no esterification took place, and ethyl acetate was used as a reaction medium to obtain
ester derivatives 34k and 34l in high yields. Using this approach, we also managed to demonstrate the
potential of DBDMH as mediator in transesterification reactions. Additionally, to confirm the synthetic
value of the presented methodology, scaled-up syntheses of methyl benzoate (1a), methyl stearate
(21a), methyl citrate (29a), and cholic acid methyl ester (30a) up to 30 mmol were performed with
excellent yields (93–100%).
The disinfection agency of DBDMH is known to originate from its ability to act as a source of Br+
in the presence of water through the release of hypobromous acid (HOBr), which further reacts as an
oxidant in the process of disinfection [34]. However, as the substoichiometric amounts of DBDMH
(7 mol%) used in the esterification method discussed herein were sufficient for high-yield, direct
esterification between carboxylic acid and alcohol, Br+ clearly acted as a catalytic species rather than
an oxidant.

Molecules 2019, 24, 2608
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Based on the results of the control experiments presented in Table 2 and Figure 3, the proposed
reaction pathway is presented in Scheme 1. In general, DBDMH in the presence of traces of water
decomposes to form HOBr (A1), which catalyses the esterification reaction and regenerates via path
A
(steps A2 A4, depicted in red colour). However, as the reaction yields 80% conversion even under
–
dry starting reaction conditions (Table 2, Entry 7), the initial DBDMH decomposition most probably
originates from its reaction with alcohol to form alkyl hypobromite [50], which further promotes the
esterification reaction via path
B (steps B2–B4, depicted in green colour). As a consequence of water
formation during the esterification reaction (step A3 or/and B5), the reaction can further proceed both
ways simultaneously, where the formation of HOBr acts as the ultimate driving force of the reaction.
As already mentioned, a considerable drop in pH from 4.0–4.5 to 0–0.5 was measured during the
reaction, which could not be attributed to the acidity of HOBr because of its relatively high pKa value
(pKa = 8.65). At the same time, the formation of a distinctive orange color and bromine odor was
observed during the reaction, which readily disappeared upon introduction of a sodium thiosulphate
solution, NaS2O3(aq), to the reaction mixture. All of this could be explained by the instability of
HOBr and its decomposition at pH below 4 to form bromine (Br2) and bromic acid (HOBr3) with a
considerably lower pKa of 2 (Scheme 1, Equation 1) [51]. Bromine is well-known to form HOBr and
−
HBr in reactions with water through an equilibrium reaction (Scheme 1, Equation 2), thereby allowing
the regeneration of HOBr for subsequent esterification catalysis. Therefore, the water formed through
the esterification reaction is more than only an inevitable side product, it is an assisting component
in catalysis, due to this equilibrium reaction according to Le Chatelier’s principle. The hypothesis of
water-assistance in the proposed mechanism is supported by the fact that only an 80% conversion to
the ester product was observed when the reaction was performed in the presence of a drying agent
(Na2SO4), which is in contrast to the general requirement for water removal for efficient transformation
in an acid-catalyzed Fischer esterification methodology (Table 2, Entry 7). However, if the reaction was
performed in water as a solvent, the hydrolysis of the ester product due to the carboxylic acid/ester
equilibrium dominated the beneficial increased concentration of HOBr and the reaction resulted in
no conversion. Furthermore, to eliminate the possibility of classic Brønsted acid catalysis acting as
the major driving force of the quantitative esterification reaction (by the in-situ formed HBrO3 and
HBr), the reaction was conducted in the presence of 7 mol% of hydrobromic acid (pKa = 9), and only
−
84 percent conversion to methyl benzoate was noticed (Table 1, Entry 9).
2.2. Aldol Condensation
To furtherly investigate possible DBDMH mediation in the activation of the carbonyl moiety, aldol
condensation as an additional reaction model was chosen. Aldol condensation remains one of the most
versatile, effective, and cheap methods for C–C bond formation in organic synthesis, widely employed
in industry for the preparation of indigo dye as well as in preclinical and clinical drug-discovery
research [52,53]. It also serves as a powerful tool in the fragrance industry for synthesising aromatic
compounds, such as 2-benzylideneheptanal (jasmine odor), 2-methyl-3-(4-isopropylphenyl)propanal
(cyclamen odor), and 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)butanol (sandalwood odor) [54].
To optimize the reaction conditions, hexanal was used as a model substrate for self-aldol condensation
of aldehydes, and the results of the optimization are presented in Table 8. The reaction proceeded
under neat reaction conditions and was found to be time sensitive, as prolonging the reaction time
resulted in the formation of polymeric material (Table 8, Entries 5–7). Furthermore, the optimal reaction
conditions were then applied in studies to examine the scope of the methodology (Table 9). Excellent
conversions and regioselectivity were obtained in the aldol condensation of alkyl aldehydes, and it was
observed that chain elongation did not exhibit a significant influence on reaction conversion. Finally,
the synthesis of the commercially-important product (E)-2-benzylideneheptanal (jasmine aldehyde,
Scheme 2) as an example of cross-aldol condensation was performed, with quantitative conversion,
yet with low yields, as a consequence of difficult separation resulting from the presence of excessive
amounts of benzaldehyde reagent (3:1).

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Table 8. Catalyst, catalyst loading, temperature, and time optimization for aldol condensation of
hexanal 1.
Conv. [%] 2
Entry
Catalyst
Loading [mol%]
Temperature [◦C]
Time
1
2
3
4
5
6
7
8
9
10
11
12
13
14
/
/
70
70
70
70
70
80
60
80
80
80
80
80
80
80
17 h
17 h
1 h
1 h
1 h
1 h
1 h
45 min
30 min
15 min
10 min
5 min
45 min
45 min
0
21
58
NCS
NBS
NIS
7
7
7
7
7
7
7
7
7
7
7
5
3
58
90 3
99 3
84 3
100
97
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
91
76
62
94
90
1
2
Reaction conditions: hexanal (2.0 mmol), DBDMH, T, t. Conversions were determined by 1H-NMR analysis of
3
the crude reaction mixtures. Considerable amounts of polymeric material were detected in the reaction mixture.
Table 9. Effect of chain elongation on aldol condensation efficiency 1,2,3
.
Product
n
Aldehyde
Product Structure
Conversion [%] (Yield [%])
35m
36m
37m
38m
39m
1
3
4
7
9
Butanal
Hexanal
Heptanal
Decanal
94 (90)
100 (94)
100 (95)
94 (90)
Dodecanal
97 (92)
1
2
Reaction conditions: aldehyde (2.0 mmol), DBDMH (7 mol%), neat, 80 ◦C, 45–90 min. Conversions were
determined by 1H-NMR spectroscopy. The values in brackets indicate yields of isolated products.
3
Scheme 2. Synthesis of (E)-2-benzylideneheptanal (jasmine aldehyde).
3. Materials and Methods
3.1. General Information
All reactions were performed in a Mettler-Toledo Easymax 102 Advanced Synthesis Workstation,
using closed 25 mL vials. NMR spectra were recorded on a Varian Inova 300 spectrometer (300 MHz
1H, 75 MHz 13C, 285 MHz 19F) at 25 ◦C. 1H-NMR spectra were obtained as solutions in CDCl3 with
TMS as an internal standard. 19F-NMR spectra were obtained as solutions in CDCl3 with CFCl3 as an

Molecules 2019, 24, 2608
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internal standard. pH was measured with Whatman Panpeha pH indicator strips (pH range 0–14).
All chemicals used for synthetic procedures were obtained from commercial sources and were of
reagent grade purity or better (Merck, Darmstadt, Germany; Sigma Aldrich, St. Louis, MO, USA; Carlo
Erba, Milano, Italy; Fluka, Seelze, Germany, Fisher Scientific, Waltham, MA, USA; Apollo Scientific,
Bredbury, United Kingdom; etc.). Reactions were monitored by thin layer chromatography (TLC)
with silica gel coated plates (Silica gel/TLC cards; DC-Alufolien-Kieselgel; with 60 Å medium pore
diameter; Sigma Aldrich), and detection was conducted by UV absorption (254 nm, Camag, Muttenz,
Switzerland). Purification of certain products was conducted on preparative silica gel glass plates
(PLC Kieselgel 60 F254 with 2 mm layer thickness). Density functional theory (DFT) calculations were
performed with the PWscf (Plain-Wave Self-Consistent Field) code from the Quantum ESPRESSO
distribution [55,56], using the generalized gradient approximation (GGA) of Perdew–Burke–Ernzerhof
(PBE) [57]. Bader charge analysis was performed by generating charge densities with single point
self-consistent-field calculations of Ultra-Soft Pseudopotential (US-PP) optimized [58] structures using
the PAW (projector-augmented-wave) potentials [59] and 1000 Ry kinetic energy cutoff for charge
density, and then computing the Bader charges using the Bader program [60,61].
3.2. Experimental Procedures
3.2.1. General Procedure for the Esterification between Carboxylic Acids and Alcohols
The mixture of carboxyli◦c acid, alcohol, and 1,3-dibromo-5,5-dimethylhydantoin was stirred
in a 25 mL reactor tube at 70 C for 2–40 h. After reaction completion, the mixture was cooled to
room temperature and the alcohol was evaporated under reduced pressure. The isolation procedure
was as follows, except where noted differently in the Supporting Information. The residue was
dissolved in 10 mL ethyl acetate and washed with a mixture of 1 mL saturated NaHCO3(aq), 1 mL
saturated Na2S2O3(aq), and 10 mL distilled water, and the water phase was extracted with ethyl acetate
(2 × 10 mL). The organic layers were combined, dried over Na2SO4, and the solvent was evaporated
under reduced pressure.
3.2.2. General Procedure for the Self-aldol Condensation of Aldehydes
The mixture of aldehyde (2.0 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (0.14 mmol, 40 mg)
was stirred in a 25 mL reactor tube at 80 ◦C for 45–90 min. After reaction completion, the mixture was
cooled to room temperature and dissolved in 10 mL EtOAc. The solution was washed with the mixture
of 1 mL saturated Na2S2O3(aq), 1 mL saturated NaHCO3(aq), and 10 mL distilled water. The water
phase was extracted with ethyl acetate (3
Na2SO4, and the solvent was evaporated under reduced pressure.
×
10 mL). The organic layers were combined, dried with
4. Conclusions
In summary, the precatalytic potential of cost-effective, accessible, and easily manipulable
1,3-dibromo-5,5-dimethylhydantoin as an air-tolerant mediator for the activation of carbonyl
moieties has been demonstrated by developing a metal-free methodology for direct dehydrative
esterification of carboxylic acids with alcohols, as well as for aldol condensation of aldehydes
(self- and cross-condensation). This approach allows neat reaction conditions and does not need
simultaneous water removal or stoichiometric amounts of activators. The esterification method using
1,3-dibromo-5,5-dimethylhydantoin provides good yields for a wide range of substrates. It was
also successfully applied to certain significant steroidal backbones, such as cholesterol, bile acids,
and epiandrosterone. Scaled-up synthesis of some commercially-interesting esters was successfully
accomplished with high-to-excellent yields, and an esterification mechanism has been proposed.
The effects of chain extension on self-aldol condensation products have been presented.

Molecules 2019, 24, 2608
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Supplementary Materials: The following are available online, detailed experimental data, 1H-NMR, 13C-NMR,
and 19F-NMR spectra of isolated final products.
ˇ
ˇ
Author Contributions: Conceptualization, S.S; Formal analysis, K.C., B.
Đ
.B. and S.S; Investigation, K.C., B.
Đ
.B.
ˇ
and S.S; Methodology, K.C., B.Đ.B. and S.S; Supervision, S.S; Writing–original draft, K.C. and B.Đ.B.; Writing–review
ˇ
ˇ
& editing, K.C, B.Đ.B. and S.S.
Funding: This research was funded by Slovenian Research Agency (grant number P1-0134 and Young Researcher
Programme—ARRS-SP-2990/17) and Serbian Ministry of Education, Science and Technological Development
grant number 173052.
Acknowledgments: The authors are grateful to the Slovenian NMR Centre at the National Institute of Chemistry
and to Matic Poberžnik for performing DFT calculations and Bader charge analysis.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data, in the writing of the manuscript, and in the decision to
publish the results.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).