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«s^ Chapter-II Synthesis Of Selenol Esters Of
Benzoic Acid And Its Derivatives
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 29
2.1 INTRODUCTION
It is evident that selenium plays a very important role in human as well as animal health.
The selenium supplements are needed for the consumers living in the areas that are
deficient of selenium. Though sodium selenite is widely used in feeds, several studies
have demonstrated that organic source of selenium is more bioavailable when compared
to inorganic source . Several efforts of synthesizing organoselenium compounds have
been made by many researchers^"'*.
Many methods have been followed to introduce selenium into organic compounds. As
discussed in chapter I, selenium exhibits both electrophilic and nucleophilic nature. Here
we have considered the introduction of selenium as a nucleophile. Many methods are in
practice to introduce selenide ion into the organic compounds. Phosphorous
pentaselenide is one of the important starting materials to prepare organoselenium
compounds and the existence of phosphorous pentaselenide was reported by Berzelius^
as early as year 1834. Phosphorous pentaselenide was used for converting the carbonyl
group to selenocarbonyl groups ' (Scheme-1).
PzSes
Scheme-1
Jensen et al. converted urea into selenourea by using phosphorous pentaselenide .
Phosphorous pentaselenide was also used to prepare selenophosphoric amides^. In
another publication the synthesis of Se-alkynyl selenocarboxylates was reported^''
(Scheme-2).
„ ! _ „ _ „ _ „ - RCOC1,0°C 1 K L - C 5>e ^ R _ C ^ C _ S e
Li Etp \ ^ C—R
// O
Scheme- 2
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 30
These were further used as precursors of o-alkyl selenocarboxylates (Scheme-3) and
selenamides.
R
R - C = C - S e ^ IT, dark
C-CH3 + 2 R 0 H 60-8(yc,2hours
Scheme-3 o" Se
Alkali metal borohydrides like sodium borohydrides react with chalcogen elements by
direct ftision^' and also in aprotoic solvents like ether'^, dioxane^^, tetrahydrofuran^''''^and
diglyme. But the selenium reacts with sodiumborohydride in aprotoic solvents to yield
the product which is difficult to isolate and has been found to be NaBH2Se3. Synthesis of
Se-alkyl selenoformates was reported by the reaction of aluminum selenolates with
formates'^ (Scheme-4).
Hexane, 20°C, 1h ^ ^
O K
Se H 20°C, 10min.
Scheme-4
Additional care needs to be taken while working with dibutylaluminium hydride due to
the flammability hazard involved with this potential reducing agent. Hydrogen selenide is
a good nucleophile and also a good reducing agent'^ and is used to synthesize various
organoselenium compounds. It is produced in situ by the reaction of elemental selenium
with reducing agents like sodium formaldehyde sulfaxylate (Na^HOCH2S02', Rongalite)
in aqueous sodium hydroxide solution, sodium in liquid ammonia, sodium borohydride in
water or ethanol and lithium trialkylborohydride in tetrahydrofuran.
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 31
Klayman'^has reported the formation of sodium hydrogen selenide by the reaction of
selenium metal with sodium borohydride in aqueous medium or in protoic solvent like
ethanol (Scheme-5). This is an instantaneous reaction which proceeds at atmospheric
pressure and at room temperature.
4NaBH4 + 2Se + VHjO *• 2NaHSe+ Na2B407 + HHj
Scheme-5
He converted the benzyl chloride to benzylselenol by using ethanolic solution of sodium
hydrogen selenide'*.
Sodium diselenides are also synthesized based on the mole ratios. Diselenides are
obtained easily by adding another one mole of selenium to sodium hydrogen selenide
(Scheme-6).
2NaHSe + Na2B407 + 2Se + SHjO *- ZNajSej + 4H3BO3
Scheme-6
Excess of sodium borohydride is required when methanol is adopted as solvent media
due to faster decomposition of sodium borohydride in methanol. EthanoUc solution of
sodium hydrogen selenide is more useful for nucleophilic displacement reactions, in
particular insoluble and hydrolysis sensitive organic compounds. Here removal of sodium
selenide gas formed during the reaction is very much necessary to take the reaction to
completion. Alcoholic solutions are not preferred for the preparation of sodium hydrogen
selenide when acid chloride is used in the reaction since formation of ester is more
favorable (Scheme-7) than the selenium product.
+ ROH
Scheme-7
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 32
Hence aqueous solution of sodium hydrogen selenide is a reagent of choice to prepare
some of the organoselenium compounds.
2.2 PRESENT WORK
Present work is based on the reaction of sodium hydrogen selenide in aqueous media with
benzoyl chloride followed by reaction with chloroacetic or chloropropionic acid. Selenol
esters obtained by this method are further converted to esters and amides via acid
chloride (Scheme-8).
2 NaHSe
O
Chloroacetic acid f l l [ ^ ^
kAySe , O
o
• I P J ^ " 25-30°C
Na, Se
water
SOCl, R-OH ^ ^ o j ,
SOCI2 Toluene
SOCI2 Toluene
RjNH
SOCl,, R-OH
0 ^ , 0 H
3-chloropropanoic acid^=^^^j^^^
O
4-11
NHR, Se
O 12 and 13
NR, Se
O 14 and IS
O^ ,0R
Se
16-23 O O^ ,NHR
SOClj Toluene
Se
24 abd 25
SOCl, Toluene
RjNH
O ^ N R ^
Se
O 26 and 27
Scheme-8
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 33
The present work has been divided into following subclasses.
2.2.1 Synthesis of sodium benzoyl selenide (1)
2.2.2 Preparation of benzoylselenoglycolic acid (2)
2.2.3 Synthesis of 3-[(phenyl carbonyl)selenyl]propanoic acid (3)
2.2.4 Construction of esters of benzoylselenoglycoUc acids (4-11)
2.2.5 Construction of amides of benzoylselenoglycoUc acids (12-15)
2.2.6 Synthesis of ester and amide derivatives of 3-[(phenyl
carbonyl)selenyl]propanoic acid (16-27)
2.2.7 Experimental section
2.2.8 Physical properties of the newly synthesized compounds
2.2.1 Synthesis of sodium benzoyl selenide (1)
Athayde-Filho'^ et al have reported one pot synthesis of benzoylselenoglycoUc acid by
using sodium hydrogen selenide in water. This is a very useful method to synthesize
organoselenium compounds. This method is adopted here to prepare several
organoselenium compounds. In the reported method purification is done using
chloroform as solvent and the recoveries are low. Here purification was done via sodium
salt.
In the first step of synthesis, sodium borohydride is made to react with metallic selenium
in aqueous medium as per Scheme-5. In the second step freshly prepared benzoyl
chloride is reacted with sodium hydrogen selenide to give sodium benzoylselenides
(Scheme-9).
cuo o Water, 25-30°C^ f T ^ r ^ S e + NaCl + HjSe
2NaHSe + ,, , n , XT Na
1
Scheme-9
Sodium benzoylselenide obtained by this method was used in the next step without
isolation.
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 34
2.2.2 Preparation of benzoylselenoglycolic acid (2)
In the third step it is further made to react with chloroacetic acid to yield benzoylseleno
glycolic acid (Scheme-10).
H
J/ O
H-
Cl OH
Scheme-10
Benzoylselenoglycolic acid (2) was prepared by the above mentioned method. A non
polar impurity identified as dibenzoyldiselenide (Ila) was formed during the reaction.
This impurity formation is due to the formation of disodium diselenide during the
reaction (Scheme-11).
O
^ 0
Na2Se2
+ 2NaCl
Scheme-11 Dibenzoyl diselenide (Ila)
This impurity was not soluble in sodium bicarbonate solution wherein product is soluble
fi-eely and the impurity remains with organic layer during purification.
Formation of benzoylselenoglycolic aicd was confmned by IR spectrum. A peak at
1696cm' was corresponding to characteristic carbonyl stretching fi-equency of-COOH
group. Stretching vibration frequency at 1674cm"' was corresponding to the carbonyl
group of -CO-Se bond. A broad peak between 3000-3300cm"' was corresponding to the
vibration fi-equency of-OH group (Figure-1). Further proof to the structure was obtained
by NMR spectra of the molecule dissolved in CDCI3. A smglet peak at 8 3.88 was
corresponding to Se-CH2 protons. Peaks between 6 7.26-8.0 were corresponding to 5
protons in the aromatic ring, -OH proton of the carboxylic acid moiety appeared at 5
10.46 (Figure-2).
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SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 37
2.2.3 Synthesis of 3-[(phenyIcarbonyl)selenyI]propanoic acid (3)
The intermediate sodium selenobenzoate was a very reactive species and was made to
react with chloropropionic acid (Scheme-12). Reaction with chloropropionic acid was
incomplete at 25-30*'C and proceeded smoothly at 60-70*'C. This is due to the reduced
nucleophilicity of the p carbon atom.
2NaHSe +
Na Se
At IS-^O^C in water
1
At 60 - 70°C water
O + NaCl + HjSe
O OH
NaCl
1 3 O
Scheme-12
Formation of the compoimd 3 was confirmed by IR spectrum.
A peak at 1697cm'' was corresponding to the carbonyl stretching frequency of -COOH
group. Carbonyl stretching frequency of-Se-CO bond appeared at 1665cm'' (Figure-3).
Further evidence to the structure was obtained by ' H N M R spectrum. Methylene groups a
and p to the carboxylic acid group appeared as triplets at 8 2.95 and 3.28 respectively.
Signal corresponding to aromatic protons appeared between 8 values of 7.42-7.9. The
signal due to -OH proton of-COOH group was not visible (Figure-4). However presence
of carboxylic acid group was confirmed by its reaction with sodiiun bicarbonate. Further
evidence was obtained by recording the mass spectrum of the molecule. Mass spectra
gave m/z peak at 257 (Figure-5). Esterification of compound 3 with various alcohols
confirmed the formation of the product.
38
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SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 40
l U U -
O OH
0Ase-Ao
189 53 63 81 91 "" 115 128 147 165 171 203 221 233 245 ji
-;-TT-r,-r''Tr'nii;;!' ;••; T—r-vr tTr rcM' ; ' i ' t't:.ii i—; i;:nT!MMT-ir?i:rri—s T ' in i ' ; : M'II H'!—i iiii; : i . ' ; i ' ! r i i ' i Hiil.]! i')T-n]!rri-n'';-i-rrrr'-;-rrTrTn'-*^rn—rrk-H-rrTTi;-
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MS Peak Table Pealrf R.Time [Time F.Time Area Height A/H Mark %Total Name Base m/z Base Int.
1 0.708 0.527 0.9431214463250 93360795 13.00 100.00 257.0010682599 1214463250 93360795 100.00
Figure-5
2.2.4 Construction of esters of benzoylselenoglycolic acid (4-11)
Several esters were prepared from compound 2 to study the effect of substitution on the
biological activity and also to enhance the stability of the molecule. Esterification can be
brought about in many ways. In one of the common methods followed, acid is made to
react with alcohol in presence of H2SO4 or PTSA as catalyst. In this method it is
necessary to remove the byproduct water either through azeotropic distillation or by using
a dehydrating agent like molecular sieve. On the other hand HCl gas can also be used as
catalyst to bring about the esterification. Alternatively, acid anhydrides are made to react,
with alcohols to yield esters. This method does not hold good for those acids which are
likely to undergo degradation during anhydride preparation. When the esterification
reactions were carried out using sulfuric acid as catalyst at high temperature, impurity
formation was observed. Hence esters were synthesized via acid chloride (Scheme-13,
Table-1). Esters 4-7 were more stable. Few esters (8-11) were unstable and underwent
degradation very quickly.
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 41
R-OH, SOCL
Comp. No
50-60°C
Scheme-13
Table-1
R
-CH3
-C2H5
-C3H7
-C4H9
Comp. No
10
11
R
H . C ^ ^ C H
As an example compound 5 was prepared by adding thionyl chloride to the ethanolic
solution of compound 2 at 50-60°C. The Formation of ethyl ester was preliminarily
confirmed by recording the IR spectrum. The carbonyl frequency of -COOH group of
compound 2 was shifted to 1731cm"' from 1696cm"\ Vibrational frequency of-Se-CO
group remained unaltered. Broad peak at 3000cm'' disappeared (Figure-6). Further proof
to the product was obtained by ' H N M R spectra. A triplet at 6 1.28 was corresponding to
the methyl proton and protons of-O-CH2 group gave a quartet at 5 4.19. A singlet at 5
3.84 was corresponding to -Se-CH2- protons. Aromatic protons appeared at 8 7.27-7.92
accounting for 5 protons (Figure-7). Mass spectrum gave m+2 peak at m/z:273 (Figure-
8). Complete spectral data of the remaining ester molecules along with compounds 2 and
3 are depicted in Table-2.
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 42
Table-2: Spectral analysis data of compounds (2-11)
Comp. No ' H N M R values in 5 ppm. IRYmax in cm"' Mass :m/z 2 3.88(s, 2H,Se-CH2),
7.26-8.02(5,m, Ar-H). 1700(-COOH), 1674(-Se-CO-).
243
3 2.92 (t, 2H, -CH2-CO), 3.28 (t,2H, -Se-CH2), 7.42 -7.9 (m, 5H, Ar-H). •
1697 (-COOH)' 1665 (-Se-CO-).
257
4 3.74 (s,3H,-OCH3), 3.85 (s, 2H,Se-CH2), 7.4-7.9 (m, 5H).
1722 (-C00-), 1672 (-Se-CO-).
259
5 1.28(t,3H,-CH3), 3.84 (s, 2H, Se-CH2), 4.19(q,2H,-OCH2), 7.26 -7.92 (m, 5H, Ar-H).
1731 (-C00-), 1678 (-Se-CO-).
273
6 1.12(d,6H,-C(CH3)2), 3.83(s,2H,Se-CH2), 5.078 (m, IH, -OCH), 7.39-8.06 (m, 5H, Ar-H).
1725 (-C00-), 1677 (-Se-CO-).
287
7 0.92 (t, 3H, -CH3), 1.4(m,2H, -CH2), 1.56(p,2H,-CH2), 3.84 (s, 2H, Se-CHz), 4.14(t,2H,-OCH2), 7.43-7.91 (m,5H, Ar-H).
1730(-COO-), 1677 (-Se-CO-).
301
8 1.2(d,6H,-C(CH3)2 2.34 (s, 3H, Ph-CHj) 3.1(m, 1H,-CH) 3.88 (s, 2H, Se-CH2), 7.06 -7.9 (8H, Ar-H).
1730(-COO-), 1677 (-Se-CO-).
377
9 3.88 (s,2H,Se-CH2), 7.26-8.72 ( l l , m , Ar-H).
1757(-COO-), 1667(-Se-CO-).
372
10 3.72(s, 2H, Se-CH2), 7.26-9.02 (10, m, Ar-H)
1748(-COO-), 1672(-Se-CO-).
406
11 3.78(s,2H, Se-CH2), 7.26-8.82(9 m, Ar-H).
1745(-COO-), 1672(-Se-CO-).
441
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SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERTVATIVES 45
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Figure-8
2.2.5 Construction of amides of benzoylselenoglycolic acid (12-15)
Several amide derivatives were prepared to study the effect of substitution on the
biological activity. Compound 2 was converted to acid chloride and further it was made
to react with different amines to get corresponding amides (Scheme-14, Table-3).
O
, ^ OH Se
O
i) Toluene /SOCl^ at 55-60"C ii)Ri-NH2at5-10"C *"
i) Toluene /SOCI2 at SS-eO^C
ii)R,-NHat5-10T
O
NHR, ,Se
O
12 and 13
O
NRn ,Se
O
14 and 15
Scheme-14
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 46
Table-3
Comp. No. NHRi NR2
12 ^ N H , ^ ^ ^ ^ - ^
~
13 HN''
V CH3
14
•^0 15 -0
Formation of the amide was confirmed by spectral analysis of the newly synthesized
compounds. IR spectrum of the compound 12 gave a peak at 1654cm" corresponding to the
amide peak (Figure-9). Disappearance of broad peak corresponding to -OH group provided
further evidence to the amide formation. A sharp peak was observed at 3293cm'
corresponding to -NH stretching vibration of the amide bond. Further proof to the structure was
obtained by ' H N M R spectrum (Figure-10). Mass spectrum of the product confirmed the
formation of the product. M+ 2 peak was observed at m/z value of 320 (Figure-11). Spectral
analysis data of the amides (12-15) has been tabulated in Table-4.
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SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 49
Table-4: Spectral analysis data of compounds 12-15
Comp ' H N M R values in 6 ppm. IR Ymax in cm"' Mass :m/z
12 3.78 (s, 2H, Se-CH2 ), 1672 (-Se-CO-), 320
7.054 -8.322 (m, 1IH, 10 ArH+ 1654(-CO-NH-)
1 -NHCO). 3293 (Ph-NH-
CO).
13 2.23 &2.3 ( s, 6H Ar-(CH3)2), 1669 (-Se-CO-), 348
3.75 (s, 2H, Se-CH2), 1652 (-CO-NH-),
7.02 -8.4 (m, 9H, 8ArH +1 3287 (Ph-NH-
NHCO). CO).
14 1.4 (m,6H, Ring-(CH2)3), 1674 (-Se-CO-), 312
3.55 (b,4H, Ring-N-CH2-),
4.0 (s, 2H, Se-CH2),
7.39 -7.922 (m, 5H, Ar-H).
1632 (-CO-N-).
15 1.95 (m, 4H, Ring -CH2 -CH2), 1673 (-Se-CO-), 298
3.55 (b, 4H, Ring -N-CH2),
3.933 (s, 2H, Se-CHz),
7.4 -7.9 (m, 5H, Ar-H).
1625 (-CO-N-).
Many impurities were formed during the reaction. One such impurity formed during the
reaction with aniline was N- phenylbenzamide (lib).
^ NH " ^
lib (N-phenylbenzamide)
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 50
2.2.5.1 Structural elucidation of N-phenylbenzamide
This type of reaction is generally observed when amines are made to react with esters and are
known as aminolysis of esters. Aminolysis of esters has been intensively investigated and their
mechanisms are well understood^"'^'. Koh et al ^ studied the aminolysis reaction of
cyclopropanecarboxylate with benzylamines in acetonitrile (Scheme-15).
OC6H4Z + 2 XC6H4CH2NH2
O MeCN
NHCH2C6H4X + 2 XC6H4CH2NH3^ "OC6H4Z
O
X= P-CH3O, P-CH3, m-Cl or p-Cl
X=m-CN, m-NOj, P-CH3CO, p-CN or P-NO2
Scheme-15
Aminolysis of thiol ester has been studied to a lesser extent than its oxygen analogue
(Scheme-16) 33-36
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 51
O
X .NH Ph
ArS O
,NH
R
NH = r z / HN.
R=H or CH3
^2
O
Ph" N H
ArS
R= CHj NH, NCH2CH2OH, O, NCHO, NHj
Scheme-16
Aniline makes nucleophilic attack at the carbonyl group of acid chloride moiety leading
to the formation of the desired product. Simultaneously the selenol ester carbonyl group
competes with the carbonyl group within the molecule leading to the formation of
A^-phenylbenzamide, which can be explained by the following mechanism (Scheme-17).
Toluene at 5-10''C O
NH O
12-desired product
Toluene at S-IO^C \ /
NH O
nb- impurity
Scheme-17
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 52
Formation of N-phenylbenzamide was confirmed by reacting benzoyl chloride and
aniline in toluene (Scheme-18).
CI HoN
+ O
Toluene at 25-30 "C
^ V N H o
Scheme-18 lib
Product was compared with the impurity obtained during desired amide preparation by
TLC and by recording the IR spectrum. It confirmed that, the product formed was N-
phenylbenzamide. Similarly impurity formation was also observed when piperidine and
pyrrolidine were used as sources of amine.
Further to confirm the aminolysis reaction, benzoylselenoglycolic acid was made to react
with various amines at room temperature (Scheme-19, Table-5).
^ 2 Toluene, 25-30°C
R3
NH R2
R3
Scheme-19
Table-5
Il(b-d)
Compound Ri R2 R3
lib H H H
lie CH3 H CH3
lid H CF3 H
The melting point of the products was matching with that of the standards obtained by
reacting respective amines with benzoyl chloride. Further formation of the aminolysis
product as impurity was confirmed by spectroscopic methods. For example IR spectrum
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 53
of lib gave a peak at 1650cm" corresponding to the -CO vibration frequency of the
amide group. A new peak at 3293.2cm"^ was observed due to aromatic -N-H stretching
frequency. ' H N M R spectrum showed the presence of 11 protons in the aromatic region
corresponding to 10 aromatic protons and a proton of -NH-CO group. A singlet due to
Se-CH2 protons which was present in compound 2 was disappeared in the NMR spectra
of l ib confirming the nucleophilic attack at carbonyl group of -CO-Se moiety as shown
in Scheme-19.
2.2.6 Synthesis of ester and amide
carbonyl)selenyl] propanoic acid (16-27)
derivatives of 3-[(phenyl
Similarly several ester derivatives of compound 3 were prepared (16-23, Scheme-20).
Impiirity formation was minimized may be due to the increased stability of 3-[(phenyl
carbonyl)selenyl]propanoic acid. Esters were purified using column chromatography.
Various amide (24-27, Scheme-20) derivatives of compound 3 were also synthesized
(Table-6). Aminolysis of selenol esters was observed in these reactions also.
O^^OH
0-^OR
SQCl , R-QH
Se
O
i. SOCI2, Toluene
ii. R1NH2
16-23 O^NHRj
Se
O 24 abd 25
i. SOCI2, Toluene
ii. R^NH
OyNRj
Se
O 26 and 27
Scheme-20
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DEMVATIVES 54
Table-6
Comp. No. R NHRi NR2 Comp. No. R NHRi NR2
16 -CHj 22 60 CI
17 -C2H5 23
CI
18 -C3H7 24 '•0
19 -C4H9 25 jbf'^
20 26 ^0 21 l ^ ^ ^ N 27 -0
Esters 20 -23 were highly unstable and decomposed to acid and alcohol within a week.
All the compounds were characterized by mass, IR and proton NMR spectroscopic
methods and the data has been tabulated in Table-7.
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 55
Table-7: Characterization data of the compounds 16-27
Comp. No. ^H NMR values in 6 ppm. IR Ymax in cm'' Mass :in/z 16 2.86 (t, 2H, -CH2-C0),
3.29 (t, 2H, -Se-CH2), 3.71(s,3H,OCH3), 7.4 -7.9 (m, 5H, Ar-H).
1722 (-C00-), 1672 (-Se-CO-).
273
17 1.3(t,3H,-CH3), 2.84 (t, 2H, -CH2-CO), 3.29 (t, 2H, -Se-CH2), 4.15(q,2H,-OCH2), 7.4 -7.9 (m, 5H, Ar-H).
1731 (-C00-), 1669 (-Se-CO-).
287
18 1.26(d,6H,-C(CH3)2, 2.84 (t, 2H, -CH2-C0), 3.29 (t, 2H, -Se-CH2), 5 (m, IH, -OCH ), 7.4 -7.9 (m, 5H, Ar-H).
1727(-COO-), 1670 (-Se-CO-).
301
19 0.92 (t, 3H, -CH3), 1.393 (m,2H,CH2), 1.62 (p,2H,CH2), 2.84 (t, 2H, - CH2-CO), 3.29 (t, 2H, -Se-CH2), 4.03 (t, 2H, -OCH2)), 7.4 -7.9 (m 5H, Ar-H).
1735 (-C00-), 1673 (-Se-CO-).
315
20 1.2(d,6H,-C(CH3)2, 2.34 (s, 3H, Ph-CH3), 2.82 (t, 2H, -CH2-CO), 3.1(m, 1H,-CH), 3.31(t,2H, Se-CH2), 7.06 -7.9 (8H, Ar-H).
1727 (-C00-), 1659 (-Se-CO-)
389
21 2.9 (t-3H, -CH2-CO), 3.38 (t, 2H, Se-CHz), 7.26-8.22 ( l l , m , Ar-H).
1730(-COO-), 1677 (-Se-CO-).
384
22 2.9 (t-3H, -CH2-CO), 3.41(t,2H,Se-CH2), 7.26-8.22 (10, m, Ar-H).
1730(-COO-), 1677 (-Se-CO-).
418
23 2.9 (t-3H, -CH2-CO), 3.29 (t, 2H,Se-CH2), 7.26-8.22 (9, m, Ar-H).
1730(-COO-), 1677 (-Se-CO-).
453
24 2.85 (t, 2H, -CH2-CO), 3.28 (t, 2H, Se-CHz), 6.98-7.8(m, 1IH, Ar-H + Ar-NH).
1673 (-Se-CO-), 1653 (-CO-NH-).
334
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 56
25 2.8 (t, 2H, CH2-CO), 2.23 & 2.3 (m, 6H Ar-(CH3)2), 3.38 (s,2H,Se-CH2), 7.054-8.322 (m, lOH).
1613 (-Se-CO-), 1659 (-CO-NH-).
360
26 1.59(b,6H,Ring(CH2)3), 2.855 (t, 2H, CH2-CO), 3 .2-3.4 (b, 4H, Ring N(CH2)2, 3.54 (t, 2H, -Se-CH2), 7.39-7.911 (m, 5H, Ar-H).
1668 (-Se-CO-),
1635 (-CO-N-).
326
27 1.89 (m,4H, Ring (CH2)2), 2.8 (t, 2H, CH2-CO), 3.3-3.65 (m, 6p, Se-CH2and ring N(CH2)2), 7.28 -7.9 (m, 5H, Ar-H).
1664 (-Se-CO-), 1634 (-CO-N-).
310
2.2.7 Experimental section
i. Syntliesis of benzoyl chloride
Benzoic acid (20 mmol) was dissolved in 100 ml of toluene in a 4 necked round bottom
flask and heated to SO C. Thionyl chloride (30mmol) was added to it slowly at 80-85V.
Reaction mass was refluxed for 3 hours at 100-110*^0 to complete the conversion. Solvent
was distilled at below 120°C. Benzoyl chloride was collected as a second fraction at 180-
190V. Product was transferred to an air tight container and stored under inert atmosphere
till it is used.
ii. Synthesis of Benzoylselenoglycolic acid (2)
Selenium metal (12.66 mmol) was suspended in 12 ml of water. Sodium borohydride
(26.5 mmole) was dissolved in 12 ml of water and added slowly to selenium metal.
Exothermic reaction with vigorous evolution of hydrogen gas was observed. Benzoyl
chloride (12.8 mmol) was added slowly at 30*'C. Sodium salt of selenobenzoate (1) was
obtained as a yellow colored solution and used without isolation to the next step.
Chloroacetic acid (12.8mmol) was added slowly at 25- 30^0, solid was precipitated at the
end of addition. Product was filtered and the residue was dissolved in 20 ml of
dichloromethane. Product was extracted with 5% sodium bicarbonate solution. pH of the
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 57
sodium bicarbonate layer was adjusted to 4-5 using 5% HCl. Product was extracted into
dichloromethane and concentrated under vacuum to get pure solid.
iii. Synthesis of 3-[(phenyl carbonyl)selenyI]propanoic acid (3)
Selenium metal (12.66 mmol) was suspended in 12 ml of water. Sodium borohydride
(26.5 mmoles) was dissolved in 12 ml of water and added slowly to selenium metal.
Exothermic reaction with vigorous evolution of hydrogen gas was observed. Benzoyl
chloride (12.8 mmol) was added slowly at SO^C. A yellow colored solution was obtained.
Chloropropanoic acid (13 mmol) was added slowly at 65-70*'C. Solid was precipitated at
the end of addition. Product was filtered and dissolved in 20 ml of dichloromethane and
extracted with 5% sodium bicarbonate solution. To the collected sodium bicarbonate
layer, pH was adjusted to 4-5 using 5% HCl. Product was extracted back into
dichloromethane, dried over anhydrous sodium sulfate and concentrated under vacuum to
get white solid.
iv. Methyl 2-(benzoyIselenyl)acetate (4)
Benzoyl selenoglycolic acid (4.1 mmol) was dissolved in 20 ml of methanol, 6 mmol of
thionyl chloride was added slowly at 50-55''C. Reaction mass was stirred for one hour.
Reaction mass was concentrated under vacuum at 35-40°C. The residue was dissolved in
10 ml of dichloromethane and washed with 5% sodium bicarbonate solution followed by
water wash. Organic layer was collected and dried over anhydrous sodium sulfate.
Product was obtained as yellow colored liquid which was purified using column
containing silica gel as stationary phase and using hexane and ethyl acetate as mobile
phase.
Esters 5-7 and 16-19 were also synthesized by the same method.
V. 2-Isopropyl-5-methylphenyl 2-(benzoylselenyI)acetate (8)
Benzoylselenoglycolic acid (4.1 mmol) was dissolved in 20 ml of toluene, thionyl
chloride (6 mmol) was added at 60-65^0. Reaction mass was stirred for one hour.
Excess of thionyl chloride was removed under vacuum at 40-45°C. Thymol (4mmol) was
dissolved in 10 ml of toluene and added to the acid chloride slowly at 50-60''C. After the
completion of the reaction, the reaction mass was poured into water and washed with
sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 58
and concentrated to get oily residue. The product obtained after the reaction had many
impurities including starting materials. Crude material was loaded on to the column and
product was isolated with 20% ethyl acetate in hexane. Column fractions were
concentrated to get product as pale yellow colored oil.
Esters 9-11 and 20-23 were also synthesized by the same methodology.
vi. Se-[2-oxo-2-(phenylaniino)ethyl]benzenecarboselenate(12)
Benzoylselenoglycolic acid (4.1 mmol) was dissolved in 20 ml toluene, 6 mmols of
thionyl chloride was added slowly at 50-55°C. Reaction mass was stirred for one hour.
Excess thionyl chloride was removed under vacuum at SO-SS^C. Fresh toluene was added
and the reaction mass was chilled to O-S C, 4 ramoles of aniline was dissolved in 5 ml of
toluene and added slowly at S-IO^C. Reaction mass was stirred for two hours at 5-10 C.
The reaction mass was washed using 10% HCl solution followed by 5% sodium
bicarbonate solution. Organic layer was collected and dried over anhydrous sodium
sulfate. Solvent was removed under reduced pressure at 45-50''C. Product obtained was
solid and recrystallized from isopropyl alcohol to get pure material.
Amides 13-15 and 24-27 were also synthesized by the same methodology.
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 59
2.2.8 Table-8: Physical properties of the newly synthesized compounds
Compd. No.
M.P. in "C Yield in %
Solubility Mol. Formula Se. content in% Found(calculated)
2 82-84 80 MeOH, CHCI3 CgHsOsSe 31.8(32.48)
3 84-86 80 MeOH, CHCI3 CioHioOaSe 29.9 (30.71)
4 Liquid 60 MeOH, CHCI3 CioHio03Se 29.32 (30.71)
5 Liquid 70 MeOH, CHCI3 CiiHi203Se 28.42 (29.1)
6 Liquid 70 MeOH, CHCI3 Ci2Hi403Se 27.9 (27.69)
7 Liquid 75 MeOH, CHCI3 Ci3Hi603Se 26.10(26.39)
8 Liquid 29 MeOH, CHCI3 Ci9H2o03Se 20.08(21.04)
9 Liquid 25 MeOH, CHCI3 C,8Hi3N03Se 21.78(21.33)
10 Liquid 15 MeOH, CHCI3 CigHisClNOsSe 18.6(19.51)
11 Liquid 15 MeOH, CHCI3 Ci8H,iCl2N03Se 16.92(17.98)
12 124 - 126 40 CHCI3 CisHnNOzSe 24.1 (24.8)
13 144 - 146 35 CHCI3 C,7H,7N02Se 22.54 (22.8)
14 Liquid 50 CHCI3 C,4Hi7N02Se 24.76(25.45)
15 Liquid 45 CHCI3 Ci3Hi5N02Se 25.75(26.66)
16 Liquid 75 MeOH, CHCI3 CiiHi203Se 28.9(29.1)
17 Liquid 75 MeOH, CHCI3 Ci2Hi403Se 26.56(27.69)
18 Liquid 85 MeOH, CHCI3 Ci3Hi603Se 26.05(26.39)
19 Liquid 87 MeOH, CHCI3 Ci4Hi803Se 25.8(25.2)
20 Liquid 30 MeOH, CHCI3 C2oH2203Se 18.05(20.2)
21 Semisolid 25 MeOH, CHCI3 CsHisNOsSe 17.95 (20.5)
22 Semisolid 20 MeOH, CHCI3 Ci9Hi4ClN03Se 15.68 (18.86)
23 Semisolid 20 MeOH, CHCI3 Ci9Hi3Cl2N03Se 16.23 (17.4)
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERFVATIVES 60
24 120-122 (Crude)
40 CHCI3 Ci6Hi5N02Se 21.84(23.76)
25 133-135 (Crude)
40 CHCI3 CigHigNOaSe 21.54(21.91)
26 Liquid 50 CHCI3 CisHigNOiSe 24.12(24.35)
27 Liquid 45 CHCI3 Ci4Hi7N02Se 24.1(25.45)
Among the compounds synthesized, the esters of compound 2 and 3 with 8-hydroxy
quinoline, 5-chIoro-8-hydroxy quinoline and 5,7-dichloro-8-hydroxy quinoline were
unstable and underwent quick degradation within a week. Hence the activity of these
compounds was not tested. Remaining newly synthesized compounds were screened for
their antimicrobial efficacy in vitro. Also they were screened for antioxidant efficacy by
DPPH fi-ee radical scavenging method and the details of the same is discussed in the
Chapter-VI.
SYNTHESIS OF SELENOL ESTERS OF BENZOIC ACD AND ITS DERIVATIVES 61
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