Exploring the influence of designer surfactant hydrophobicity in key C–C/C–N bond forming reactions

Article abstract of DOI:10.1016/j.mcat.2019.01.006

Designer micellar medium was explored for the transformation of diverse anilines to the corresponding densely substituted biologically relevant skatole derivatives in an aqueous medium via 5-exo-trig cyclization reaction. The scope of the reaction was extended to intermolecular Csp²-Csp² and Csp²-N bond forming reactions in water. Systematic investigations revealed that altering hydrophobicity of surfactant influences the yield of both C–C and C–N bond forming reactions in water.

Full text of DOI:10.1016/j.mcat.2019.01.006

Molecular Catalysis 465 (2019) 80–86
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Exploring the influence of designer surfactant hydrophobicity in key CeC/
CeN bond forming reactions
1
1
Singarajanahalli Mundarinti Krishna Reddy , Jagatheeswaran Kothandapani ,
⁎
⁎
Sengan Megarajan, Veerappan Anbazhagan , Subramaniapillai Selva Ganesan
Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, Tamil Nadu, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
Designer micellar medium was explored for the transformation of diverse anilines to the corresponding densely
Designer surfactant
Palladium catalysis
Green synthesis
Heck coupling
substituted biologically relevant skatole derivatives in an aqueous medium via 5-exo-trig cyclization reaction.
2
2
2
The scope of the reaction was extended to intermolecular Csp -Csp and Csp -N bond forming reactions in water.
Systematic investigations revealed that altering hydrophobicity of surfactant influences the yield of both CeC
and CeN bond forming reactions in water.
5
-Exo-trig cyclization
1. Introduction
Of late, (designer) micellar medium have been widely used to per-
form Suzuki-Miyaura cross-coupling reactions [6a-d], C2-arylation of
E factor [1a-b] categorises the industries based on the amount of
heterocycles and carboxylic acids [7a-b], phosphonation of arenes [8],
reduction of aromatic nitro groups and aromatic halides [9a-b] etc.
However, literature reports on investigations of lipophilicity of designer
micellar medium on the intramolecular/intermolecular CeC/CeN bond
forming reactions are scarce [10a-b]. Having known about the biolo-
gical activities of many nitrogen containing heterocyclic motifs [11–19]
(Fig. 1), we demonstrated a green surfactants medium to synthesize
diverse heterocyclic moieties through diverse CeC and CeN bond
forming reactions in the aqueous medium and also addressed the sig-
nificance of tuning hydrophobicity of the surfactant in obtaining high
yield.
waste produced by them. A higher E factor indicates that the industry
has a larger negative impact on the environment. Among the industries,
pharmaceutical industry secures the top of the list with the highest E-
factor (75–100). The soaring high E factor could be due to the re-
quirement of multiple synthetic steps for the production of higher
molecular complexity which in turn result in the formation of more
amounts of waste. In any synthetic transformation, the use of organic
solvent constitutes a major chunk of the waste produced [2a-b]. Re-
placement of traditional low boiling and/or toxic organic solvents with
water and green micellar medium would substantially reduce the
amount of waste produced in any pharmaceutical industries.
In micellar mediated organic transformations, it is believed that the
amphiphilic natures of the micelles are responsible for solubilizing the
lipophilic substrate thereby the desired organic transformations was
allowed in aqueous media. Tuning hydrophobicity affects the hydro-
philic-lipophilic balance (HLB) of surfactant and thereby improves the
water solubility of poorly soluble active organic ingredients [3]. There
are cases where the micelles are able to catalyze or inhibit organic re-
actions [4]. Thus, testing an organic reaction by varying hydro-
phobicity of surfactants may suggest a right designer micellar medium
for a specific organic transformation. Previously, we showed Stearyl
MethoxyPEGglycol Succinate (SMPS) micelles suitability in the synth-
esis of diverse aniline derivatives [5].
2. Results and discussion
2.1. Synthesis and characterization of designer surfactant
Micelles are considered as an alternate to the widely used organic
solvents to perform important organic transformations especially,
greener micelles are highly appreciated for reducing the E factor.
Recently, we described
a
facile method to prepare Stearyl
MethoxyPEGglycol Succinate and demonstrated their ability to form
micelles and reported their appropriateness as greener medium for the
reduction of lipophilic nitroarenes and for the syntheses of aniline
tethered indole derivatives [5]. In this work, we intend to investigate
⁎
Corresponding authors.
E-mail addresses: anbazhagan@scbt.sastra.edu (A. Veerappan), selva@biotech.sastra.edu (S. Selva Ganesan).
Both authors have equal contribution to the work.
1
https://doi.org/10.1016/j.mcat.2019.01.006
Received 3 September 2018; Received in revised form 31 December 2018; Accepted 4 January 2019
2468-8231/ © 2019 Elsevier B.V. All rights reserved.

S.M.K. Reddy et al.
Molecular Catalysis 465 (2019) 80–86
Fig. 1. Representative examples of bioactive nitrogen heterocycles.
display weak fluorescence in water but increases more steeply beyond a
certain concentration of the amphiphile. The microenvironment of the
probe also changed drastically as evidenced from the blue shift (nearly
25 nm) in the emission maxima (Fig. 3A), which is the characteristic
fluorescence of ANS in non-polar media [21]. Fig. 3B shows the plots of
fluorescence intensity versus AMPS concentration.
It is note that the fluorescence intensity of the probe increases lin-
early up to a certain concentration of AMPS, and then breaks, which
indicate the change in the aggregation state of AMPS and noted as
critical micelle concentration. Qualitatively similar data were obtained
with all AMPS for C = 8–18 and the obtained CMC were listed in
Table 1. The CMC decreases with increasing tail length because the
lipophilic character increases. When log(CMC) values were plotted
versus the alkyl chain length, a linear dependence was observed, which
is in agreement with the previous observation of the chain length de-
pendence of CMCs for a variety of surfactants [22]. The CMC de-
termined for SMPS (23.25 μM) was slightly higher than the previous
study because the CMC was determined in water [5]. In addition to
ANS, CMC determination was verified with 1-N-phenylnaphthylamine
as a fluorescence probe. Both the probes yield comparable CMC and
values are given in Table 1. Having learned that the CMC of SMPS was
very low as compared with other AMPS, we initiated SMPS assisted
skatole derivatives synthesis in aqueous medium via 5-exo-trig cycli-
zation.
Fig. 2. Description of the synthesized designer surfactants.
the importance of the lipophilic part of micelles for obtaining products
in high yield. The hydrophilic and lipophilic moieties in the amphi-
philic molecules is an important factor to determine the physical
properties of micelles such as the size of micelles, the critical micelle
concentration (CMC), and the critical micelle temperature [20]. Ac-
cordingly, the lipophilic length and hydrophilic ratios always need to be
taken into consideration in designing the amphiphilic media. Hence, a
series of alkyl methoxyPEGglycol succinate (AMPS) with varying alkyl
chain length (C8-C18) were synthesized (Fig. 2).
The lipophilic section of octyl methoxyPEGglycol succinate (OMPS),
decyl methoxyPEGglycol succinate (DMPS), lauryl methoxyPEGglycol
succinate (LMPS), myristyl methoxyPEGglycol succinate (MMPS), pal-
mityl
methoxyPEGglycol
succinate
(PMPS),
and
stearyl
2.2. Designer micellar medium assisted Csp -Csp2 bond forming reactions
2
methoxyPEGglycol succinate (SMPS) were synthesized using readily
available inexpensive aliphatic lipophilic alcohol and succinic anhy-
dride. The obtained lipophilic acids were tethered with hydrophilic
polyethylene glycol monomethyl ether (Mn = 550) in a high yielding
reaction.
The CMC of alkyl methoxyPEGglycol succinate was determined by
fluorescence spectroscopy using 8-anilinonapthalene-1-sulfonate (ANS)
as the fluorescent probe. Measurements were performed with samples
hydrated in distilled water. In these studies, the fluorescence intensity
of the probe was monitored as a function of AMPS concentration. ANS
2
2
Among CeC bond forming reactions, intramolecular Csp -Csp bond
formation via 5-exo-trig cyclization is valuable since it transforms
structurally simpler N-allylaniline to densely substituted biologically
relevant 3-alkylindole derivatives. Skatole, a representative 3-alky-
lindole is used in perfumes at low concentrations and in military
weaponry as malodorant at higher concentration [14]. Skatole is also
used in the concise synthesis of physostigmine, a bioactive molecule
used in the treatment of Alzheimer’s disease [15]. Hence, it is of interest
to investigate the designer surfactant assisted green synthesis of skatole
81

S.M.K. Reddy et al.
Molecular Catalysis 465 (2019) 80–86
found to be more productive and the product 11 was obtained in 85%
yield (Entry 5). To our surprise, the reaction carried out in the absence
of phosphine ligand didn’t deter the yield of the product (Entry 6).
3 2 2
Hence, it was decided to carry out the reaction with Pd(PPh ) Cl in the
absence of any external ligands. Under optimized reaction conditions,
the scope of the reaction was also extended to intermolecular cross-
coupling reactions (Table 2(ii)).
Unlike intramolecular cyclization, intermolecular cross-coupling
reaction requires accommodation of both lipophilic olefin (phenyl ac-
rylate) and aryl halide in the micellar core. The phenyl acrylate was
used in excess since it led to the corresponding hydrolyzed product
under basic reaction conditions. Similar to intramolecular cyclization,
intermolecular cross-coupling also proceeded well with Pd(PPh
3 2 2
) Cl
(
Table 2, Entry 8). Change of inorganic base to organic triethylamine
base enhanced the yield of the product (Entry 9 vs 10). Increasing the
reaction temperature above 100 °C led to an unclean reaction. Simi-
larly, stirring of the reaction mixture for 18 h is required to achieve
optimum yield (Table 2, Footnote e). The limitation of substrates and
role of leaving groups was investigated in both intra/intermolecular
2
2
Csp -Csp bond forming reactions with diverse electron donating and
electron withdrawing substrates.
The nature of halogen leaving group does not play a significant role
in the intramolecular cyclization reaction. Both bromo and iodo deri-
vatives gave the products in appreciable yields (Fig. 4, 11a vs 11b).
Interestingly, the nature of substituent on the aromatic ring sub-
stantially controls the yield of the product. Electron donating methyl
substituent gave the corresponding indole product in good yields whilst
the use of inductively electron withdrawing chloro substituent affected
the yield of the product (11a vs 11 g). The nature of substituent on the
nitrogen atom controls the course of the reaction. Unlike N-acetyl-N-
allylanilines 10, the reaction performed with free (NH)-N-allylaniline
gave unclean reaction (11a-c vs 11d). Lowering the reaction tempera-
ture, or changing the base also didn’t yield the desired product. Inter-
estingly, in the case of fluoro substituted aniline derivatives, the reac-
tion performed under optimized reaction conditions (at 90 °C) gave the
corresponding deacylated product 11f. Similar deacylation of the N-
acetylanilines were previously reported in the literature [23a-b].
Hence, to avoid deacylation, the reaction was carried out at 50 °C to
obtain the desired indole derivative 11e. The use of N-alkylanilines
instead of N-acetylanilines also gave the corresponding product 11g–h
albeit in moderate yields.
Fig. 3. Determination of CMC of AMPS in water. (A) ANS fluorescence spectra
in the increasing concentration of lauryl methoxyPEGglycol succinate (LMPS),
2
2
Aryl-alkenyl Csp -Csp cross-coupling reaction gave the corre-
sponding E isomer in good yields (Fig. 4). Change of leaving group from
iodo to bromo did not affect the yield of the product (14b vs 14c). The
reaction performed with heterocyclic substrates also gave the corre-
sponding product 14c in good yields. The scope of aryl-alkenyl cross-
(B) plot of LMPS concentration versus ANS fluorescence at 490 nm, and (C) plot
of log(CMC) vs lipophilic tail length of AMPS.
Table 1
2
2
coupling reaction was extended to aryl-aryl Csp -Csp cross-coupling
reaction. Both lipophilic indole and heterocyclic quinoline derivative
gave the corresponding product 14i and 14f/14 h in excellent yields. A
plausible mechanism was proposed for palladium mediated in-
tramolecular cyclization and intermolecular cross-coupling reaction
(Scheme 1) [24]
CMC of AMPS.
Hydrophobic
alkyl chain length
HLB
CMC determined with
ANS (μM)
NPN (μM)
8
14.43
13.91
13.44
12.99
12.57
12.18
290.79 ± 7.54
218.45 ± 4.33
152.76 ± 6.53
82.09 ± 3.64
41.22 ± 5.22
23.25 ± 2.32
292.17 ± 4.82
220.12 ± 8.13
150.62 ± 4.77
84.15 ± 4.41
42.42 ± 3.37
23.10 ± 3.82
1
1
1
1
1
0
2
4
6
8
We presume the intramolecular cyclization goes via oxidative ad-
dition of Pd(0) to the aryl halide leading to the formation of inter-
mediate A which on 5-exo-trig cyclization followed by β-hydride
elimination could result in the formation of C which on aromatization
via double bond migration led to the desired indole product 11. In in-
2
2
termolecular Csp -Csp cross-coupling reaction, syn addition of orga-
nopalladium species followed by β-hydride elimination gave the cor-
responding product 14. It is of further interest to extend the scope of the
derivatives in water (Table 2(i)). After optimizing the reaction condi-
tions, the scope of the reaction was also extended to intermolecular
2
2
Csp -Csp bond forming reactions (Table 2(ii)).
2
designer micellar medium to intermolecular Csp -N bond forming re-
2
The preliminary screening of the reaction with Pd(dppf)Cl gave the
desired product only in moderate yields (Table 2, Entry 1). Increasing
the catalyst load to 20 mol% or change of base from triethylamine to
actions.
2
2
.3. Surfactant assisted intermolecular Csp -N bond forming reactions
K
2
CO
3
gave only a marginal improvement in the yield of the product
Cl instead of Pd(dppf)Cl with K CO
3
(
Entry 2–3). Use of Pd(PPh
3
)
2
2
2
2
Among the diverse CeN bond forming reactions, aromatic
82

S.M.K. Reddy et al.
Molecular Catalysis 465 (2019) 80–86
Table 2
Optimization of reaction conditions for Csp -Csp bond forming reactionsa.
2
2
o
Yield (%)b
S.No
Rxn
Catalyst
Ligand
Base
Temp ( C)
Time (h)
1
2
Ic
I
Pd(dppf)Cl
Pd(dppf)Cl
2
2
P(OPh)
P(OPh)
3
TEA
TEA
60
60
12
11
50
55
(20 mol%)
3
(
10 mol%)
3
4
5
I
I
I
Pd(dppf)Cl
2
P(OPh)
P(OPh)
P(OPh)
3
3
3
K
2
CO
TEA
CO
3
3
60
60
90
10
7
6
60
67
85
Pd(PPh
Pd(PPh
3
)
)
2
Cl
Cl
2
2
3
2
K
2
(
10 mol%)
6
7
8
9
I
II
II
II
II
Pd(PPh
Pd(dppf)Cl
3
)
2
Cl
2
—
—
—
—
—
K
2
CO
3
90
60
60
90
90
6
87
60
70
75
d
2
K
2
K
2
K
2
CO
CO
CO
3
3
3
24
24
17
18
Pd(PPh
Pd(PPh
3
3
)
)
2
Cl
Cl
2
2
2
e
1
0
Pd(PPh
)
3 2
Cl
2
TEA
90
a
Unless otherwise mentioned, all the reactions were performed with 40 mg of SMPS in 3 mL of water and 10 mol% of catalyst and 20 mol% of ligand.
Yields are for the isolated products.
Unless otherwise mentioned, 0.3 mmol of aryl halide, 0.6 mmol of base and 10 mol% of catalyst were added.
b
c
d
e
2
mmol of phenyl acrylate, 0.5 mmol of 4-methoxyiodobenzene, 10 mol% of catalyst and 2 mmol of base were added.
Reaction performed less than 18 h showed unreacted starting materials.
nucleophilic substitution reaction (S
its vital role in preparing medicinally important anticancer molecules
gefitinib erlotinib) [25], antihyperglycemic [26] and
N
Ar) secured a unique place due to
immunosuppressive agents [27]. S
synthesis of biologically active 1,3,5-triazine derivatives (Fig. 1). Ex-
cept limited examples [28a-b], most of the S Ar reactions were
N
Ar reaction also facilitates the
(
&
N
2
2
Fig. 4. Substrate scope and limitations of Csp -Csp bond forming reactions.
83

S.M.K. Reddy et al.
Molecular Catalysis 465 (2019) 80–86
Scheme 1. Plausible mechanism for the intramolecular cyclization reaction.
performed in toxic and non-green polar solvents such as DMF, NMP etc
which pose serious environmental and health hazards. Hence, it is of
here that in the presence of two different nucleophiles, unsymmetrically
substituted 1,3,5-traizine derivative 16c were obtained in good yields.
Thus, the given method offers a facile route to access diverse un-
symmetrically substituted triazine derivatives. The α-amination of the
lipophilic benzophenone was also carried out in water medium at 50 °C
for 6 h. The products 16d-e were obtained in excellent yields. The
presence of strong electron withdrawing nitro group at the para posi-
interest to investigate the SMPS assisted S
medium.
N
Ar reaction in water
Mono substituted triazine derivatives are valuable intermediate for
the synthesis of unsymmetrically substituted triazine derivatives. SMPS
facilitate selective mono substitution of 2,4,6-trichloro-1,3,5-triazine in
water medium (Fig. 5, 16a, 16b
needs to be carried out at 0 °C to suppress the formation of undesired
symmetrical dimorpholine product 16b . It is imperative to mention
1
). Reaction performed with morpholine
tion is essential for the successful S
nitro group with hydrogen drastically affected the yield of the product
16f (R1 = H) which further suggest the operation of S
Ar mechanism.
N
Ar reaction (16f-g). Replacement of
2
N
Fig. 5. Designer micellar medium assisted diverse C–N bond forming reactions.
84

S.M.K. Reddy et al.
Molecular Catalysis 465 (2019) 80–86
Fig. 6. Effect of surfactant hydrophobicity on the CeC/CeN bond forming reactions.
In the case of nitro aromatics, the reaction proceeded well with
1
chloro, fluoro or bromo leaving groups (16d-e, 16f (with R = NO
The use of aromatic amine as nucleophile failed to yield the desired
product 16 h. SMPS assisted, one-pot S Ar reaction followed by nitro
group reduction with Zn/NH Cl reagent system was also performed and
the product 16i was obtained in 71% yield.
2
)).
N
4
2.4. Role of lipophilic tail in CeC and CeN bond formation
Increasing the lipophilicity of the designer micelles may improve
the solubility of the organic substrates in aqueous solution and pro-
motes the reaction in the forward direction. To test this hypothesis, we
carried out intermolecular CeC and CeN bond forming reaction in the
micellar medium where the hydrophobic core differs from 8 to 18
carbon (Fig. 6).
To screen the efficiency of the surfactants with variable hydro-
phobicity, we have chosen lipophilic indole derivatives 14i and rigid
benzophenone derivative 16d as target molecules. The reaction time
and substrate concentration was kept constant for all micellar medium.
Fig. 7. Relationship between yield and CMC. Black bar - intermolecular CeC
bond reaction (14i); Gray bar – intermolecular CeN bond reaction (16d).
With micelles of variable chain length, S
at 50 °C for 6 h and Suzuki-Miyaura cross-coupling was carried out at
0 °C for 2 h. At a definite time point, the reactions were stopped and
N
Ar reactions were performed
amphiphile increases the hydrophobic core size by ˜ 2.5 Å [29]. From
this approximation, the hydrophobic core size formed by OMPS, DMPS,
LMPS, MMPS, PMPS, and SMPS as ˜20, 25, 30, 35 and 40 Å, respec-
tively. The higher hydrophobic core size of SMPS may easily draw the
lipophilic substrate from the aqueous environment, similar to enzymes,
and thereby brings the reactant to close proximity to proceed forward
[30]. In short, the present work clearly indicates that tuning hydro-
phobicity of the surfactant is critical for successful high yield inter-
molecular reaction.
9
product was purified by standard procedure and their yield was cal-
culated. In addition, we have also performed the synthesis of less li-
pophilic product 14d in the presence of C-8 and C-18 surfactants. The
yields obtained are 70% and 88% respectively, which indicates that the
yield of 14d is less sensitive to the surfactant hydrophobicity. We
presume that the sterically less bulky 4-methoxyiodobenzene substrate
is well accommodated by both C-8 and C-18 micellar core and hence
the yield obtained with OMPS (C-8) and SMPS (C-18) are comparable.
However, sterically bulky 5-bromo-1-dodecyl 1H-indole and (2-chloro-
3. Conclusions
5
-nitrophenyl)(phenyl)methanone substrates prefer a bigger C-18 mi-
In summary, a successful exploration of designer surfactant in the
cellar core rather than a smaller C-8 core. Hence, yields of 14i and 16d
are higher in SMPS (C-18) than in OMPS (C-8). In contrast to inter-
molecular cyclization, the yields obtained from the intramolecular 5-
exo-trig cyclization of N-allylaniline in C8 and C18 surfactants are
highly comparable. Fig. 7 showed the relationship between the yield
and micellation, which suggests that hydrophobicity of the surfactant
has a significant role in determining the forward reaction.
2
2
2
diverse Csp -Csp and Csp -N bond forming reactions was demon-
strated. More importantly, challenging intramolecular cyclization re-
actions were successfully carried out in an environmentally benign
water medium in good yield. The significance of tuning the hydro-
phobicity of surfactant in obtaining high yield from the reactions re-
presents a promising future for developing a greener medium to per-
form varieties of organic transformations.
These results can be interpreted by considering that all the reactants
are present in one hydrophobic shell and the reaction centres are co-
exist for complete transformations. Whereas in the case of inter-
molecular reaction, the smaller hydrophobic core size increases the HLB
ratio or decreases the hydrophobicity which may prevent the diffusion
of the reactants to enter the hydrophobic core and resulted in lesser
yield. When the hydrophobic core is bigger, it can accommodate more
lipophilic reactants and allows the reaction to good yield. It is well
known that the increase in one methylene unit in the acyl chain of an
Author contribution
S.S.G., designed surfactant synthesis and their application part of
the work; V.A., designed CMC determination of surfactants and studies;
S.M.K.R. and J.K. carried out surfactant synthesis and their applica-
tions. S.M performed CMC determination. S.S.G., and V.A. wrote the
manuscript.
85

S.M.K. Reddy et al.
Molecular Catalysis 465 (2019) 80–86
Acknowledgements
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