Transformation of tertiary benzyl alcohols into the vicinal halo-substituted derivatives using N-Halosuccinimides

Article abstract of DOI:10.3390/molecules21101325

The efficiency of direct conversion of tertiary alcohols bearing a-hydrogen atom to vicinal halohydrins-chlorohydrins and bromohydrins-under green reaction conditions was tested preliminarily on modeltertiary benzyl alcohols. Tertiary alcohols were successfully directly halogenated to vicinal halohydrins with N-halosuccinimide in aqueous media. The efficiency of the reaction in water was significantly improved in the presence of sodium dodecyl sulphate as the surfactant.

Full text of DOI:10.3390/molecules21101325

molecules
Article
Transformation of Tertiary Benzyl Alcohols
into the Vicinal Halo-Substituted Derivatives
Using N-Halosuccinimides
Njomza Ajvazi 1,2 and Stojan Stavber 1,2,3,
*
1
Department of Physical and Organic Chemistry, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia;
njomzaajvazi@hotmail.com
Jožef Stefan International Postgraduate School, Jamova 39, 1000 Ljubljana, Slovenia
Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins CIPKeBiP
(Seat at Jožef Stefan Institute), Jamova 39, 1000 Ljubljana, Slovenia
2
3
*
Correspondence: stojan.stavber@ijs.si; Tel.: +386-1-477-3660; Fax: +386-1-423-5400
Academic Editors: Joaquín García Álvarez and Jonathan Sperry
Received: 31 August 2016; Accepted: 27 September 2016; Published: 2 October 2016
Abstract: The efficiency of direct conversion of tertiary alcohols bearing a
β-hydrogen atom
to vicinal halohydrins—chlorohydrins and bromohydrins—under green reaction conditions was
tested preliminarily on model tertiary benzyl alcohols. Tertiary alcohols were successfully directly
halogenated to vicinal halohydrins with N-halosuccinimide in aqueous media. The efficiency of
the reaction in water was significantly improved in the presence of sodium dodecyl sulphate as
the surfactant.
Keywords: halohydrins; halogenation; water; tertiary alcohols; N-halosuccinimides
1. Introduction
Green chemistry, defined as “the invention, design, and application of chemical products and
processes to reduce or to eliminate the use and generation of hazardous substances”, was founded
by 12 basic principles nearly 20 years ago [
chemistry in particular, and has also had significant implementation in the pharmaceutical industry [
1
]. It became the general trend in chemistry, organic
].
2
As organic solvents used in synthesis, isolation or purification protocols have had considerable impact
on the green profile of particular processes, looking for alternatives for most applied solvents and
evaluating their green characteristics is of great interest to academics as well as the industrial chemistry
community [3–7]. Water is one of the most attractive alternatives for these tasks and the use of water as
the reaction medium is no longer an unknown approach. The incompatibility of organic substrates with
water as a result of hydrophobic interactions could represent a potential obstacle to performing organic
reactions in water. Reactions in micellar systems have considerably extended organic chemistry in
water and extraordinary selectivity and efficiency can be achieved through the addition of inexpensive
amphiphiles that self-associate into micelles, thus accommodating insoluble organic compounds within
hydrophobic cores and very often accelerating the rate of reaction. Investigation of organic reactions in
aqueous reaction media has thus been very intense in last two decades [8–12].
Halohydrins are versatile building blocks and target intermediates for the synthesis of many
bioactive molecules [13
Behind ring opening of epoxides by hydrogen halide (HX), aldol type condensations, and reduction
of -haloketones, electrophilic halo-addition to alkenes in the presence of water is the most common
–15]. Methods for their synthesis have been comprehensively reviewed [16–18].
α
approach to the preparation of these valuable compounds. In the last decade some attractive
approaches to this kind of transformation of alkenes have been reported, such as N-halosuccinimide
Molecules 2016, 21, 1325; doi:10.3390/molecules21101325
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mediated reactions in water in the presence of
β-cyclodextrin [19], ionic liquids [20], thiourea [21] or
ammonium acetate [22] and use of H2O2/HBr system in water [23]. In our continuing interest in the
green chemical approach to halotransformation of organic compounds, particularly those “in” or “on”
water [12,24–32] we now report a new method for the preparation of vicinal chloro- or bromohydrins
by N-halosuccinimide mediated halogenation of tertiary alcohols.
2. Results and Discussion
On the basis of our original discovery that fluorohydrins could be directly obtained by fluorination
of tertiary alcohols by SelectfluorTM F-TEDA-BF4 in MeCN solution [33], as well as by micellar
system-mediated conversion in water [34], we wondered if the related transformation could also be
realized for the synthesis of chloro- or bromohydrins. The basic thesis and the concept of its evaluation
are given in Scheme 1.
Scheme 1. Direct conversion of tertiary benzyl alcohols into chloro-, bromo- and iodohydrins. Thesis
and concept.
According to our experiences documented in reference [33], benzyl alcohols bearing at least one
vicinal hydrogen atom are the best choice for this transformation, we chose 1,1-diphenylethanol
and 2-phenyl-2-propanol as the basic model compounds. N-chloro- (NCS), N-bromo- (NBS)
and N-iodosuccinimide (NIS) were selected as halogen atom transfer reagents, while the list of
environmentally accepted solvents [
AcOH, and finally water was chosen as reaction medium candidates. According to our experiences
described in references [33 34] we assumed that secondary benzyl alcohols are not convenient
3–7
] from aprotic SolkaneTM 365 to Me-THF, protic MeOH and
,
candidates for this type of transformation. This assumption was confirmed also in the present case
since reactions of several secondary benzyl alcohols tested gave very complex reaction mixtures.
From the data collected in Table 1, it can be seen that aprotic reaction media seems to be
inconvenient for the halo-transformation of target tertiary alcohol
(SolkaneTM 365) or ethyl acetate none or low transformation of starting material
(entries 1–4). On the onther hand, when the reactions were performed in a mixture of EtOAc/H2O
we observed quantitative conversion of starting material into the eliminated product as the sole
) took
1, since in 1,1,1,3,3-pentafluorobutane
1
was observed
6
4
product (entries 5 and 6). In 2-methyltetrahydrofuran only dehydration to 1,1-diphenylethene (
place (entries 7 and 8).
4
In the case of performing the reactions in acetic acid, the quantitative conversion of
1 was
observed using NCS (entries 9 and 11), and the formation of 2-chloro-1,1-diphenylethene (3a) was
established as the main product, accompanied with a small amount of the eliminated product
4,
whilst in the case of reaction using NBS, the formation of the addition-elimination product 3b was
observed as the sole product, also after the shorter reaction time (entries 10 and 12). The decrease of

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the reaction temperature to 70–75 ◦C, in the case of using NCS, provided efficiently and selectively
2-chloro-1,1-diphenylethene (3a) in quantitative yield (entry 13), while in the case of using NBS,
it afforded 2-bromo-1,1-diphenylethene (3b) in lower yield accompanied ◦with the formation of
1,1-diphenylethene (4) (entry 14). When the reaction was carried out at 40 C, using NCS or NBS,
no conversion of starting material (6) occurred (entries 15 and 16).
On the contrary, in the case of reactions using NIS, the formation of complex reaction mixtures
was observed.
Table 1. Transformation of 1,1-diphenylethanol 1 with N-chlorosuccinimide (NCS) and N-bromosuccinimide
(NBS) in organic solvents a.
Relative Distribution of Products b (%)
Conversion b
(%) of 1
Reaction
Conditions
Entry
X
Solvent
2a–b
3a–b
4
1 c
2 c
3
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
reflux, 18 h
reflux, 18 h
reflux, 18 h
reflux, 18 h
75–80 ◦C, 18 h
75–80 ◦C, 18 h
reflux, 18 h
reflux, 18 h
reflux, 24 h
reflux, 24 h
reflux, 4 h
/
/
/
/
/
/
3
/
/
2
/
/
/
5
/
/
1
/
98
100
96
100
100
60
/
/
/
/
24
100
100
78
82
2
/
4
/
/
SolkaneTM 365
SolkaneTM 365
EtOAc
4
EtOAc
32
5 d
6 d
7
EtOAc/H2O
EtOAc/H2O
2-MeTHF
2-MeTHF
AcOH
100
100
81
8
9
89
7
100
100
100
100
100
100
/
/
/
/
/
/
/
/
/
10
11
12
13
14
15
16
a
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
reflux, 4 h
70–75 ◦C, 4 h
70–75 ◦C, 4 h
40 ◦C, 4 h
40
/
/
40 ◦C, 4 h
/
/
Reaction conditions: 1,1-diphenylethanol (1) (0.5–1 mmol), N-halosuccinimide (NXS) (0.55–1.1 mmol), solvent
(5 mL); b determined from 1H-NMR spectra of isolated crude reaction mixtures; c reaction components were not
d
completely soluble. EtOAc (4 mL)/H2O (1 mL).
In the case of reactions in pure methanol (Table 2) we found quantitative conversion of starting
material
using NCS, while in the case of the reaction using NBS, the related product 5b was found as the
minor product and alkene as the main one (entry 2). The addition of water to the reaction media
considerably decreased the selectivity of the transformation (entries 3–6).
When we treated 2-phenyl-2-propanol ( ) with NCS or NBS in the above-mentioned solvents,
1 and the formation of the vicinal halomethoxy derivative 5a (entry 1) as the main product
4
6
the formation of very complex reaction mixtures took place in all cases, whilst using an AcOH/H2O
mixture as solvent, the efficient and selective conversion to 2-halo-2-phenylpropan-2-oles could be
achieved (entries 7 and 8, Table 2).
Water is one of the best alternatives to organic solvents [35]. It is naturally occurring, abundantly
available, nontoxic, nonflammable and inexpensive. Although all natural processes occur in aqueous
media, using water in the synthetic organic chemistry has never been popular. The reasons for this are
the limited solubility of organic molecules in water which leads to lower rates or/and yields, and the
hydrolytic instability of some reagents, products and catalysts. The major breakthrough in using
water as a medium for organic reactions occurred with the studies on the Diels-Alder reaction done

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by Breslow in 1980 [36]. These studies concluded that organic reactions proceed well, or even better,
in aqueous media, in comparison with organic solvents.
Table 2. Transformation of 1,1-diphenylethanol (
1) or 2-phenyl-2-propanol (6) with NCS and NBS in
methanol, acetic acid, aqueous media and their mixtures a.
Relative Distribution b of Products (%)
Conversion b
Entry
R
X
Solvent/Co-Solvent
(%) of 1
5a–b
4 or 8
2a–b or 7a–b
c
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Me Cl
Me Br
Ph
Ph
Cl
Br
Cl
Br
Cl
Br
MeOH (5 mL)
MeOH (5 mL)
100
100
98
100
100
100
100
100
14
73
40
60
13
43
9
/
/
/
/
23
60
30
84
25
74
/
/
/
/
/
/
/
MeOH (5 mL)/H2O (20 mmol)
MeOH (5 mL)/H2O (20 mmol)
MeOH (2.5 mL)/H2O (2.5 mL)
MeOH (2.5 mL)/H2O (2.5 mL)
AcOH (2.5 mL)/H2O (2.5 mL)
AcOH (2.5 mL)/H2O (2.5 mL)
H2O (5 mL)
5 c
3
29
7 c
93 d
95 e
14
Cl
Br
54 f
100
52
10
11
12
H2O (5 mL)
H2O (5 mL)
H2O (5 mL)
72
100
96
Me Cl
Me Br
/
/
44
a
Reaction conditions: alcohol 1 or 6
(1 mmol), NXS (1.1 mmol), solvent, under reflux, 4–22 h; b determined from
1H-NMR spectra of isolated crude reaction mixtures; c trace amounts of other products (3%–10%); d isolated
pure product; e isolated crude product; f 18% of 2,2-dibromo-1,1-diphenylethanol was also formed.
Initially, we checked the course of the reaction of 1,1-diphenylethanol (
(NXS) in pure water and the results are given in Table 2. Since 1,1-diphenylethanol (
are insoluble in water, the homogeneity of the reaction mixture was observed to be very low.
The conversion of starting material in the case of the reaction using NCS was thus found to be
1) with N-halosuccinimides
1) and NXS
1
low (entry 9), while the NBS-mediated transformation gave considerably higher efficiency (entry 10)
accompanied by 2,2-dichloro-1,1-diphenylethanol [37] or 2,2-dibromo-1,1-diphenylethanol [38] which
are known compounds based on 1H-NMR spectra of isolated crude reaction mixture, but we believe
that in both cases better results could be obtained. We further preliminarily investigated the reactions of
2-phenyl-2-propanol (
The conversion of starting material
resulting in the formation of the vicinal halohydrin 7a as the sole product (entry 11), while in the
reaction with NBS, quantitative conversion of starting material was observed, providing the vicinal
halohydrin 7b as the main product (due to the instability of the compound under chromatographic
6) with N-halosucinimides in pure water and the results are collected in Table 2.
6
in the case of the reaction with NCS was found to be quantitative,
6
conditions, purification was unsuccessful), accompanied by the formation of eliminated product
(entry 12).
8
In order to improve the efficiency of this transformation, in the continuation of our work we tested
if the addition of a surfactant had an effect on the course of the reaction. We chose sodium dodecyl
sulfate (SDS) as the amphiphilic surfactant and reactions were performed with different surfactant
concentrations in the aqueous media. Results are given in Table 3. The influence of the concentration
of amphiphile on conversion of 1,1-diphenylethanol (1) in water with NCS and NBS is graphically
presented in Figure 1 and it could be established that the catalytic effect of SDS amphiphile in the
case of NCS and NBS-mediated reaction, reached its maximum efficiency at a concentration of 3 mM

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or higher. It was found that the choice of surfactant had a significant influence on the yield and the
reaction time; namely, the addition of SDS increases the yields and reduces the reaction times.
Table 3. The course of the reaction of 1,1-diphenylethanol (
1) with N-halosuccinimide (NXS) in aqueous
media in the presence of sodium dodecyl sulphate (SDS) amphiphile a.
Relative Distribution of Products b (%)
Conversion b
(%) of 1
Entry
H2O/SDS
X
2a–b
3a–b
4
9a–b
1
2
3
4
5
6
7
8
9
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
SDS (c = 0.0008 M)
SDS (c = 0.0008 M)
SDS (c = 0.001 M)
SDS (c = 0.001 M)
SDS (c = 0.003 M)
SDS (c = 0.003 M)
SDS (c = 0.008 M)
SDS (c = 0.008 M)
SDS (c = 0.05 M)
SDS (c = 0.05 M)
82
95
95
47
53
47
49
72
56
86
67
89
70
11
12
10
10
8
5
7
5
4
/
24
24
32
27
20
28
7
17
7
23
/
6
6
10
/
12
/
11
/
7
96
100
100
100
100
100
100
10
a
Reaction conditions: 1,1-diphenylethanol (
1) (1 mmol), NXS (1.1 mmol), solvent (5 mL), under reflux, 7 h;
b
determined from 1H-NMR spectra of isolated crude reaction mixtures.
Moreover, we checked the impact of SDS as the amphiphilic surfactant on the course of the
reaction of 2-phenyl-2-propanol ( ) with NCS and NBS and no effect was observed in either case.
6
We further checked the reactions of both tested alcohols with NXS under solvent-free conditions but
only starting material was recovered after 24 h at 70–75 ◦C.
Figure 1. Effect of the added amount of sodium dodecyl sulphate (SDS) amphiphile on the efficiency
of the reaction of 1,1-diphenylethanol (1) with N-halosuccinimide (NXS).
On the basis of the presented results we could propose a plausible reaction pathway for
the transformation of phenyl-alkyl substituted tertiary alcohols to vicinal halohydrins using
N-halosuccinimides as the halogenating reagents (Scheme 2). We suppose that the first step
of the reaction is the dehydration of the alcohol under the described reaction conditions, thus
forming the corresponding alkene; in our case 1,1-diphenylethene (4) or 2-phenylpropyl-1-ene (8),

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as observed among the products in the isolated crude reaction mixtures. A certain degree of protic
conditions are necessary for this first step, since in aprotic solvents no reaction was observed (Table 1,
entries 1–4), while the addition of water to aprotic EtOAc readily resulted in dehydration of the
alcohol (Table 1, entries 5 and 6). The second step should be the halogenation of the alkene with NXS
reagents, known as the halogene-transfer reagents, to electron-rich unsaturated organic compounds
following the electrophilic process which includes the formation of the most stable
carbocation intermediates. These intermediates could lose a proton and result in the formation of
halogen-substituted alkenes, or, in the presence of a sufficient concentration of hydroxy or methoxy
nucleophile, it could collapse with them, thus forming vicinal halohydrins, and or halomethoxy
analoques respectively. In the cases of performing reactions of 1,1-diphenyl ethanol in water,
the formation of vicinal dihalohydrins were also observed in approximately 10% relative yield.
β-halosubstituted
3
2
7
5
9
The formation of dihalohydins is the consequence of further halohydroxy transformation of the
addition-elimination product 3.
Scheme 2. Plausible reaction pathway for direct halogenation of phenyl-alkyl substituted tertiary
alcohols to vicinal halohydrins using N-halosuccinimides.
3. Materials and Methods
All alcohol substrates were commercially available and were used without further purification.
Reactions were carried out in 10 mL round-bottom flasks. All reactions were monitored by thin layer
chromatography (TLC) (using silica gel/TLC cards, DC-Alufolien-Kieselgel (Fluka, Sigma-Aldrich,
St. Louis, MO, USA). (mobile phase: hexane/ethyl acetate) and visualized by UV lamp (254 nm) and
KI (0.1 M) test. Column chromatography (CC) was performed using silica gel Kieselgel 60 (Fluka,
Sigma-Aldrich, particle size: 0.063–0.200 mm). Spectroscopic methods: nuclear magnetic resonance
Varian INOVA 300 NMR instrument, recorded at National Institute of Chemistry, Ljubljana, Slovenia
1H: at 303.0 MHz, 13C: at 76.2 MHz using CDCl3 as the solvent with SiMe4 (TMS) as an internal
reference and melting points (open capillary tube methodology; uncorrected, by Buchi 535 equipment
at the Jožef Stefan Institute, Ljubljana, Slovenia) were used for identification and structure elucidation.
General Procedure for Vicinal Halogenation of Tertiary Benzyl Alcohols Using NXS on mmol Scale
A solvent (5 mL) was placed in a 10 mL round bottom-flask equipped with a magnetic stirrer
under reflux, NXS (1.1 mmol) was then added and, after being dissolved, the substrate (1 mmol) was
added and the solution was stirred for 4–24 h. The progress of the reaction mixture was monitored

Molecules 2016, 21, 1325
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by TLC, whilst the consumption of NXS was tested by KI (0.1 M). Upon completion of the reaction,
the crude reaction mixture was cooled down at room temperature, diluted with EtOAc (15 mL), washed
with aqueous Na2S2O3 (6 mL), NaHCO3 (6 mL), and water (10 mL), and dried over anhydrous Na2SO4.
The solvent was evaporated under reduced pressure and the crude product obtained was analyzed by
1H-NMR. The pure final products were obtained after flash chromatography, column chromatography
or preparative thin layer chromatography. The characterization and NMR spectra of the isolated
products can be found in the Supplementary Materials.
4. Conclusions
The assumption that tertiary benzyl alcohols bearing at least one vicinal hydrogen atom could be
directly transformed to the vicinal halohydrins 2a
–
b
or 7a
–b using N-halosuccinimides was verified
on 1,1-diphenylethanol ( ) and 2-phenyl-2-propanol (
1
6) as the basic model compounds. In both
cases the efficient and selective one pot synthesis to the corresponding vicinal chlorohydrins 2a or
7a and bromohydrins 2b or 7b was achieved using NCS or NBS respectively, in aqueous reaction
media. However, in the case of the more hydrophobic 1,1-diphenylethanol (1), the addition of sodium
dodecyl sulphate in the amounts around its critical micelle concentration was found to be essential
in order to considerably enhance the yield of the transformation. When acetic acid was used as the
reaction media the addition-elimination process took place, resulting in the selective formation of
2-chloro-1-1-diphenylethene (3a) or 2-bromo-1-1-diphenylethene (3b), while under the same conditions
a complex reaction course took place in the case of treatment of 2-phenyl-2-propanol (6).
Supplementary Materials: The following are available online at www.mdpi.com/1420-3049/21/10/1325/s1,
S1. General information, S2. General procedure for vicinal halogenation of tertiary benzyl alcohols, S3.
1
Characterization data of isolated final products, S4. H-NMR and 13C-NMR spectra of isolated final products,
S5. References.
Acknowledgments: We are grateful to the Slovene Human Resources Development and Scholarship Fund
(contract: 11011-9/2011), Slovenian Research Agency (contracts: Programme P1-0134 at JS Institute and IO-0048
at CIPKeBiP) for the financial support. National NMR Centre at the National Institute of Chemistry, Ljubljana,
Slovenia, is acknowledged for the use of NMR instrumentation.
Author Contributions: Njomza Ajvazi co-designed and performed the experimental work; conceived and
designed the concept of the work; Njomza Ajvazi and Stojan Stavber analyzed the experimental results and wrote
the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 2a–b, 3a–b, 5a–b and 7a–b are available from the authors.
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