Environmentally friendly procedure for the aqueous oxidation of benzyl alcohols to aldehydes with dibromodimethylhydantoin (DBDMH) and cyclodextrin: Scope and mechanistic insights

Article abstract of DOI:10.1080/00397911.2016.1161801

Reported herein is an environmentally friendly procedure for the oxidation of benzyl alcohols to aldehydes using an inexpensive, commercially available reagent, 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), and a variety of cyclodextrin additives under fully aqueous solvent conditions. This reaction proceeds with moderate to good yields for a broad scope of benzyl alcohol substrates, with the cyclodextrin acting to enhance the desired reactivity and limit undesired aromatic bromination side products. The reported experiments provide substantial mechanistic insight that will drive further reaction optimization and have broad-reaching applications.

Full text of DOI:10.1080/00397911.2016.1161801

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
An Environmentally Friendly Procedure for
the Aqueous Oxidation of Benzyl Alcohols to
Aldehydes with Dibromodimethylhydantoin
(DBDMH) and Cyclodextrin – Scope and
Mechanistic Insights
Sauradip Chaudhuri, Hossam Zaki & Mindy Levine
To cite this article: Sauradip Chaudhuri, Hossam Zaki & Mindy Levine (2016): An
Environmentally Friendly Procedure for the Aqueous Oxidation of Benzyl Alcohols to
Aldehydes with Dibromodimethylhydantoin (DBDMH) and Cyclodextrin – Scope and
Mechanistic Insights, Synthetic Communications, DOI: 10.1080/00397911.2016.1161801
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1161801
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Date: 29 March 2016, At: 00:40

An Environmentally Friendly Procedure for the Aqueous Oxidation of Benzyl
Alcohols to Aldehydes with Dibromodimethylhydantoin (DBDMH) and
Cyclodextrin – Scope and Mechanistic Insights
Sauradip Chaudhuri1, Hossam Zaki1, Mindy Levine1
1Department of Chemistry, University of Rhode Island, Kingston, RI
Corresponding author to Mindy Levine: E-mail: mlevine@chm.uri.edu; 401-874-4243
Abstract
Reported herein is an environmentally friendly procedure for the oxidation of benzyl
alcohols to aldehydes using an inexpensive, commercially available reagent, 1,3-
dibromo-5,5-dimethylhydantoin (DBDMH) and a variety of cyclodextrin additives under
fully aqueous solvent conditions. This reaction proceeds with moderate to good yields for
a broad scope of benzyl alcohol substrates, with the cyclodextrin acting to enhance the
desired reactivity and limit undesired aromatic bromination side products. The reported
experiments provide substantial mechanistic insight that will drive further reaction
optimization and broad-reaching applications.
1

KEYWORDS: Cyclodextrins, dibromodimethylhydantoin, hydrophobic effect,
oxidation, supramolecular chemistry
INTRODUCTION
Cyclodextrins are well-studied supramolecular hosts[1–4] that have been used for a variety
of high impact applications,[5,6]] including the catalysis of organic reactions,[7] the
environmental remediation of anthropogenic disasters,[8] and the solubilization of active
pharmaceutical agents and food additives.[9,10] Cyclodextrin-promoted reactions usually
occur under aqueous solvent conditions,[11] which has significant benefit in limiting the
use of organic solvents and minimizing the generation of hazardous waste.[12]
One example of an organic transformation with significant impact in synthetic research is
the oxidation of primary alcohols to aldehydes, and some examples of cyclodextrin-
promoted oxidation have been reported.[13] Other cyclodextrin-promoted oxidation
reactions have been reported in the literature, and include the use of N-
bromosuccinimide,[14] sodium hypochlorite,[15,16] hydrogen peroxide,[17,18] and o-
iodoxybenzoic acid[19] as reagents in combination with cyclodextrin. These reactions
have some additional drawbacks, including the potential toxicity of the reagents[20] as
well as the use of a compound that is a significant explosion hazard.[21]
Reagents with polarized N-halogen bonds such as 1,3-dibromo-5,5-dimethylhydantoin
(DBDMH, compound 3, Equation 1) have been shown to effect oxidation reactions on a
variety of substrates,[22,23] and have significant operational advantages including
2

commercial availability,[24] air- and moisture-stability,[25] and general high reactivity.[26]
Initial reports of DBDMH-promoted oxidation of benzyl alcohols only demonstrated
efficacy in the conversion of secondary alcohols to ketones[27] likely because of the
higher sensitivity of primary alcohols to over-oxidation and other side reactions, or
require the use of organic solvents such as methanol and dichloromethane.[28]
The use of cyclodextrin in combination with DBDMH for accomplishing the oxidation of
primary alcohols to aldehydes has not been reported to date, despite the fact that this
combination is expected to demonstrate numerous operational advantages including all
advantages of using cyclodextrin (aqueous solvent system, mild reaction conditions) and
DBDMH (air- and moisture-insensitivity, commercial availability, limited human
toxicity) to accomplish a synthetically useful transformation. Reported herein is the
cyclodextrin-promoted DBDMH oxidation of a variety of benzyl alcohols 1 to
benzaldehydes 2 (Equation 1), which proceeds under fully aqueous conditions, with
limited generation of byproducts, and in moderate to high reaction yields. Detailed
mechanistic investigations provide substantial insight that will guide further reaction
development and applications.
DISCUSSION
A variety of benzyl alcohol substrates 1 (Figure 1) were converted into their respective
aldehydes 2, using mild heating in aqueous media to achieve moderate to high
conversions. The amount of cyclodextrin varied from 0.33 equivalents relative to the
benzyl alcohol up to 1.5 equivalents, with the amount used independently optimized for
3

each substrate. Table 1 summarizes the results of these experiments, and includes results
obtained using the highest performing cyclodextrin host and the optimal amount of
cyclodextrin, which depended strongly on the substrate structure. For example, the
reaction with the smallest substrate 1a was accelerated most strongly with the smallest
cyclodextrin host α-cyclodextrin. As the size of the para substituent on the benzyl
alcohol increased, the optimal cyclodextrin host size increased as well, with substrate 1d
(p-chloro) optimally catalyzed by β-cyclodextrin, substrate 1g (p-bromo) by methyl-β-
cyclodextrin, and substrate 1j (p-iodo) by γ-cyclodextrin. Moving the same substituent
from the para position to the ortho or meta position required a slightly larger
cyclodextrin host to accommodate this geometry and achieve optimal reactivity (compare
for example 1b vs. 1c; 1f vs. 1g; 1h vs. 1i).
In general, electron-deficient and electron-neutral substrates displayed markedly higher
conversions compared to the electron-rich substrates (see for example 1d and 1g
compared to 1b), which is a consequence both of their higher reactivity as well as the
lower amounts of side products resulting from bromination of the aromatic ring. These
reaction conditions were not effective in oxidizing aliphatic primary alcohols to
aldehydes, which confirms the importance of aromatic ring-cyclodextrin interactions in
the reaction mechanism, nor did other N-halogenated reagents such as 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH) or 1,3-diiodo-5,5-dimethylhydantoin (DIDMH) effect the
desired transformation. In all cases, the conversions obtained in the absence of
cyclodextrin were markedly lower than those obtained in the presence of cyclodextrin,
4

highlighting the crucial role for this supramolecular scaffold in promoting the desired
reactivity.
A plausible reaction mechanism is shown in Scheme 1, and involves the formation of a
key intermediate 5 from alcohol 1 and HOBr as the rate-determining step, followed by
fast elimination of HBr to form the desired product. This mechanism also highlights the
possibility of obtaining acyl bromides 6 from the same reaction, via the transfer of two
bromine atoms to form intermediate 5’ followed by elimination of HBr to give product 6.
The mechanistic hypothesis is supported by (a) the negative free energy of formation of
the intermediate 5, calculated based on DFT calculations;[29] and (b) a strong primary
kinetic isotope effect (KIE) of 3.2 on replacing benzyl alcohol 1a with deuterated benzyl
alcohol d2-1a (Equation 2), which implicates the involvement of C-H bond cleavage in
the rate determining step, likely to be the conversion of starting material 1 to intermediate
5.
The general trend observed is that the conversions of electron deficient substrates is
lower than benzyl alcohol and electron rich substrates (1h or 1i < 1a < 1b). This supports
the plausible formation of intermediate 5 via activation of the benzylic protons. On the
contrary, an alternate mechanism leading to the formation of a hypobromite followed by
HBr elimination would have favored electron deficient substrates as they make the
benzylic protons more acidic. Furthermore, the KIE experiments done by replacing the
benzylic protons with deuterium concur with the fact that benzylic deprotonation is
involved in the rate determining step of the reaction.
5

The roles of cyclodextrin in the proposed mechanism shown in Scheme 1 are two-fold:
(1) Acceleration of the C-H bond cleavage in the rate-determining first step; and (2)
shielding of the aromatic ring from undesired aromatic bromination. Both of these roles
are enabled through binding of the aromatic guests in the cyclodextrin cavity in a
geometry such as that shown in Figure 2. This complexation activates the benzyl protons
through interactions between the cyclodextrin rim and the benzyl position, leading to
markedly faster C-H bond cleavage, and protects the aromatic core of the substrate from
electrophilic aromatic bromination through hydrophobic interactions between the
aromatic ring and the cyclodextrin cavity.[30]
In addition to interactions between the cyclodextrin host and alcohol substrates 1,
cyclodextrin can also interact directly with compound 3. Literature precedent indicates
that cyclodextrins interact with hydantoins, and such interaction is used for efficient
chromatographic separation of hydantoin enantiomers.[31,32] In this system, 1H NMR
analysis of DBDMH-cyclodextrin mixtures indicates that complexation of DBDMH in
cyclodextrin leads to marked decreases in the rate of N-Br bond dissociation (Table 2).
The addition of substrate 1a to the reaction mixture markedly increases the formation of
compound 4 in the presence α-cyclodextrin, β-cyclodextrin, and methyl-β-cyclodextrin.
γ-Cyclodextrin showed no real change in the amount of compound 4 formed in the
presence and absence of substrate 1a, and in the absence of any cyclodextrin the addition
of compound 1a led to a decrease in the formation of compound 4. These results can be
explained by a weak, hydrophobically-driven interaction between 1a and 3, which has
some stabilizing effect in the absence of cyclodextrin. Introduction of the cyclodextrin
6

hosts results in the selective binding of the substrate 1a, in turn rendering compound 3
more reactive.
Aliphatic alcohols cyclohexanol and 4-methylcyclohexylmethanol (4-MCHM)[33] were
investigated as substrates, and no reaction was observed. The fact that these aliphatic
alcohols were not competent substrates under these reaction conditions provides further
evidence for the crucial role of the aromatic ring in ensuring favorable host-guest
complexation, and argues against literature reports that the role of cyclodextrin in organic
reactions is merely as a phase-transfer catalyst.[34,35] Moreover, the fact that aliphatic
alcohols are inert to oxidation allows for the recycling and re-use of the aliphatic alcohol-
rich cyclodextrin host without concerns about interfering reactivity (vide infra).
Investigation of the effect of electron density of the aromatic ring on its reactivity reveals
a strong effect on the substrate reactivity, with strongly electron donating substrates such
as p-methoxy benzyl alcohol 1m yielded none of the desired aldehyde 2m, with complete
conversion to the acid bromide 6 observed at 25 oC (Equation 3) (see ESI for spectral
characterization of compound 6). This is likely because the highly electron-rich aromatic
ring facilitates the formation of the dibromo intermediate 5’ (Scheme 1). Other somewhat
less electron rich substrates, such as 1b, proceeded to give the product in high yields in
the presence of the cyclodextrin host, whereas in the absence of the host aromatic
bromination products were observed (Table 1). Electron-deficient substrates such as 1h
and 1i were inert in the absence of the cyclodextrin, but underwent efficient reaction in
the presence of the cyclodextrin. In summary, electron deficient substrates required
7

activation by the cyclodextrin (catalytic activation), whereas electron rich substrates need
protection from side reactions (chemoselective influence).
Moreover, decreasing the amount of N-halo reagent led to drastic decreases in the
conversion of compound 1m to acid bromide 6, in comparison to the less drastic
decreases observed for the conversion of 1a to 2a and 1h to 2h (Table 3). This result
supports the mechanism proposed in Scheme 1, wherein acid bromide 6 is formed via
dibromo intermediate 5’ and requires multiple equivalents of the N-halo reagent for the
reaction to proceed.
The methodology reported here is markedly more efficient in achieving the oxidation of
primary alcohols to aldehydes using cyclodextrin-based aqueous systems compared to
literature-reported results. Substantially higher conversions are reported within a three
hour reaction time frame, in comparison to previously-reported reaction times of eight
hours or more. A variety of commercially available cyclodextrins screened for this
purpose reveals their ability to outperform conventionally used β-cyclodextrin (the only
cyclodextrin employed in previous works), and provides substantial mechanistic insight
in the factors responsible for efficient cyclodextrin-promoted binding and cyclodextrin-
promoted reaction acceleration.
In summary, a novel aqueous oxidation procedure for the conversion of primary benzyl
alcohols to benzaldehydes is demonstrated, using DBDMH as an environmentally
friendly oxidant and cyclodextrins as supramolecular additives that promote the highly
8

efficient reaction and limit the formation of undesired side products. Importantly, the
cyclodextrin hosts are unaltered throughout the course of the reaction, and can be
recovered and reused (conversion of 1a to 2a: first run: 75%; second run: 74%; third run:
62%). This was accomplished simply by extracting the aldehyde products into an organic
solvent and then re-using the cyclodextrin-containing aqueous layer. The results indicate
that the aliphatic hydroxyl groups of the cyclodextrin are relatively stable to oxidation
under these reaction conditions, in accord with our previously reported results on inert
aliphatic alcohol substrates. This procedure has significant potential in environmentally
friendly reaction optimization and complex product synthesis. Efforts in these areas are
currently underway in our laboratory, and results of these and other investigations will be
reported in due course.
EXPERIMENTAL
Proton NMR spectra were recorded using a Bruker 300 MHz instrument, with the singlet
peak of HDO at 4.79 ppm as reference. All reagents, substrates, and solvents were
obtained from Sigma Aldrich. Four different cyclodextrin solutions were screened: α-
cyclodextrin, β-cyclodextrin, methyl β-cyclodextrin and γ-cyclodextrin dissolved in
deuterated water (D2O). A cyclodextrin-free D2O solution was used as the control.
To a clean and dry small vial, a solution of substrate 1 (15.0 μmol, 1.0 equivalent) was
made using an aqueous cyclodextrin solution (1.0 mL) of the specified concentration in
D2O. DBDMH 3 (4.3 mg, 15.0 μmol, 1.0 equivalent) was added to the reaction mixture
and sonicated to make sure that the reagents were well suspended. The reaction mixture
was heated at 60 oC with occasional shaking to maintain the homogeneity of the solution.
9

After the desired period of time, the 1H NMR spectrum of the reaction mixture was
recorded to determine the percent conversion.
The percent conversion of each reaction was calculated based on the following equation:
% Conversion = [(Integration of the product peak) / ((Integration of the product peak) +
(Integration of the starting material peak)/2)] x 100%
The starting material NMR peak used in this equation corresponds to 2 benzyl protons of
compound 1 and the product peak used for this equation corresponds to the 1 aldehyde
proton of the product 2 (Figure 3). The integrations of the NMR peaks were the relative
areas under the curve measured against a calibrated standard corresponding to the
anomeric protons of the cyclodextrin hosts.
ACKNOWLEDGEMENTS
Funding is acknowledged from the University of Rhode Island start-up funds and from
the Gulf of Mexico Research Initiative.
SUPPORTING INFORMATION
Standard experimental conditions, details of kinetic isotope effect experiments, table
demonstrating catalyst reusability, and 1H NMR spectra of all oxidation reactions.
10

REFERENCES
[1] D'Souza, V. T.; Lipkowitz, K. B. Article title. Chem. Rev. 1998, 98, 1741-1742.
[2] Chen, G.; Jiang, M. Article title. Chem. Soc. Rev. 2011, 40, 2254-2266.
[3] Schneider, H.-J.; Hacket, F.; Ruediger, V.; Ikeda, H. Article title. Article title. Chem.
Rev. 1998, 98, 1755-1785.
[4] Szejtli, J. Article title. Chem. Rev. 1998, 98, 1743-1753.
[5] Harada, A.; Takashima, Y.; Nakahata, M. Article title. Acc. Chem. Res. 2014, 47,
2128-2140.
[6] Ghale, G.; Nau, W. M. Article title. Acc. Chem. Res. 2014, 47, 2150-2159.
[7] Chaudhuri, S.; Phelan, T.; Levine, M. Article title. Tetrahedron Lett. 2015, 56, 1619-
1623.
[8] Serio, N.; Chanthalyma, C.; Prignano, L.; Levine, M. Article title. ACS Appl. Mater.
Interfaces 2013, 5, 11951-11957.
[9] Akasha, A. A.; Elwahedi, M. A.; Eldeeb, A. M. Article title. PharmaTutor Magazine
2014, 2, 40-46.
[10] Laokuldilok, N.; Thakeow, P.; Kopermsub, P.; Utama-ang, N. Article title. Food
Chem. 2016, 194, 695-704.
[11] Breslow, R. Article title. Acc. Chem. Res. 1995, 28, 146-153.
[12] Kumar, A.; Dutt Shukla, R. Article title. Green Chem. 2015, 17, 848-851.
[13] Zhu, J.; Wang, P.-c.; Lu, M. Article title. J. Brazilian Chem. Soc. 2013, 24, 171-176.
[14] Krishnaveni, N. S.; Surendra, K.; Rao, K. R. Article title. Adv. Synth. Catal. 2004,
346, 346-350.
11

[15] Surendra, K.; Krishnaveni, N. S.; Rao, K. R. Article title. Canadian J. Chem. 2004,
82, 1230-1233.
[16] Chen, H.; Ji, H. Article title. Chinese J. Chem. Engineering 2011, 19, 972-977.
[17] Marinescu, L. G.; Bols, M. Article title. Angew. Chem. Int. Ed. 2006, 45, 4590-4593.
[18] Marinescu, L. G.; Doyagueez, E. G.; Petrillo, M.; Fernandez-Mayoralas, A.; Bols,
M. Article title. Eur. J. Org. Chem. 2010, 157-167.
[19] Surendra, K.; Krishnaveni, N. S.; Reddy, M. A.; Nageswar, Y. V. D.; Rao, K. R.
Article title. J. Org. Chem. 2003, 68, 2058-2059.
[20] Verma, A.; Vanguri, V. K.; Golla, V.; Rhyee, S.; Trainor, M.; Abramov, K. Article
title. J. Medical Toxicol. 2013, 9, 71-74.
[21] Oxley, J. C.; Brady, J.; Wilson, S. A.; Smith, J. L. Article title. J. Chem. Health
Safety 2012, 19, 27-33.
[22] Azarifar, D.; Zolfigol, M. A.; Maleki, B. Article title. Bull. Korean Chem. Soc. 2004,
25, 23-24.
[23] Alam, A.; Takaguchi, Y.; Tsuboi, S. Article title. Synth. Commun. 2005, 35, 1329-
1333.
[24] Suzuki, N.; Takahashi, A.; Mashiko, S.; Mizumoto, I.; Inaba, H. Article title.
Agricultural Biol. Chem. 1990, 54, 459-462.
[25] Hernandez-Torres, G.; Tan, B.; Barbas, C. F. Article title. Org. Lett. 2012, 14, 1858-
1861.
[26] Radaram, B.; Levine, M. Article title. Tetrahedron Lett. 2014, 55, 4905-4908.
[27] Liu, R.; Dong, C.; Liang, X.; Wang, X.; Hu, X. Article title. J. Org. Chem. 2005, 70,
729-731.
12

[28] Li, Z.; Zhu, W.; Bao, J.; Zou, X. Article title. Synth. Commun. 2014, 44, 1155-1164.
[29] Fan, J.-C.; Shang, Z.-C.; Liang, J.; Liu, X.-H.; Liu, Y. Article title. J. Phys. Org.
Chem. 2008, 21, 945-953.
[30] Schneider, H.-J. Article title. Acc. Chem. Res. 2015, 48, 1815-1822.
[31] Cabordery, A. C.; Toussaint, M.; Bonte, J. P.; Melnyk, P.; Vaccher, C.; Foulon, C.
Article title. J. Chromatography A 2010, 1217, 3871-3875.
[32] Maguire, J. H. Article title. J. Chromatography 1987, 387, 453-458.
[33] Sain, A. E.; Dietrich, A. M.; Smiley, E.; Gallagher, D. L. Article title. Sci. Total
Environ. 2015, 538, 298-305.
[34] Yang, Z.-J.; Jiang, H.-G.; Zhou, X.-T.; Fang, Y.-X.; Ji, H.-B. Article title. Supramol.
Chem. 2012, 24, 379-384.
[35] Yang, Z.; Zeng, H.; Zhou, X.; Ji, H. Article title. Tetrahedron 2012, 68, 5912-5919.
13

Table 1. Percent conversions of alcohol substrates 1 to aldehydes 2
Substrate Time
(hrs)
CD (eq.)
Conversion with
Conversion without
CDa
75
CD
1
α-CD (0.33)
β-CD (0.5)
3
1a
1b
1c
1d
1e
1f
3
60
40b (59)
3
mβ-CD (1.5) 33b (18)
11b (85)
3
β-CD (0.33)
β-CD (0.5)
γ-CD (0.33)
88
1
3
55
8
3
77b (23)
57b (43)
3
mβ-CD (0.33) 100
23
16
4
1g
1h
1i
1
α-CD (0.33)
β-CD (0.33)
γ-CD (0.5)
80c
33
3
0.5
3
100
40
15
6
1j
α-CD (0.33)
α-CD (0.33)
1k
1l
3
100
8
a Percent conversions were calculated based on the 1H NMR analysis of the reaction
mixture.
b Percentage in parentheses indicates the amount of aromatic brominated side product
formed.
c The reaction was run at elevated temperature (80 oC). No product formation was
observed at 60 oC.
14

Table 2. Percent formation of compound 4 in the presence of cyclodextrins and substrate
1aa
CD (eq.)
% of 4 (with 3)
% of 4 (with 3 and
Δ% of 4 (due to 1a)b
1a)
80
88
91
10
78
α-CD (0.33)
β-CD (0.33)
mβ-CD (0.33)
γ-CD (0.33)
No CDs
50
30
21
23
-1
67
68
11
100
-22
a Percent conversions were calculated based on 1H NMR analysis of the reaction.
b Δ% of 4 calculated as the change in % conversion on the introduction of 1.0 equivalent
of substrate 1a
15

Table 3. Percent conversions to aldehydes with different N-halo reagents and
equivalentsa
Substrate
1a
1.0 eq. 3
63
0.5 eq. 3
48
Δ% Conversionb
15
13
42
80
67
1h
1mc
100
58
a Percent conversions were calculated based on the NMR analysis of the reaction.
b Δ% Conversion calculated as the change in % conversion on going from 1.0 equivalent
of reagent 3 to 0.5 equivalents of reagent 3
c Percent conversion to acid bromide, calculated based on the 1H NMR analysis of the
reaction mixture.
16

Scheme 1. Plausible reaction mechanism for the synthesis of aldehydes 2 from alcohols 1
17

Figure 1. Benzyl alcohol substrates
18

Figure 2. Illustration of the complexation of benzyl alcohols in cyclodextrin
Figure 3. 1H NMR peaks of protons (marked in red) integrated for the starting material 1
and product 2
19

Equation 1. Oxidation reaction of primary benzyl alcohols to benzaldehydes
20

Equation 2. Illustration of the primary kinetic isotope effect observed
21

Equation 3. Alternate reaction pathway for highly electron rich substrates
22