Catalyst-free, efficient and one pot protocol for synthesis of nitriles from aldehydes using glycerol as green solvent

Article abstract of DOI:10.1016/j.tetlet.2017.11.032

We described herein the novel, efficient and one-pot catalyst free protocol for the synthesis of nitriles from aldehydes by using hydroxyl amine hydrochlorides in glycerol as a green solvent. This protocol was efficiently used for transformation of aromatic aldehydes bearing electron-withdrawing and electron-donating groups into a aryl nitriles in good to excellent yields. The methodology offers a very simple, efficient and environmentally benign procedure.

Full text of DOI:10.1016/j.tetlet.2017.11.032

Accepted Manuscript
“Catalyst-free, efficient and one pot protocol for synthesis of nitriles from al-
dehydes using glycerol as green solvent”
Ajit P. Ingale, Shripad M. Patil, Sandeep V. Shinde
PII:
S0040-4039(17)31446-6
https://doi.org/10.1016/j.tetlet.2017.11.032
TETL 49475
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 October 2017
13 November 2017
14 November 2017
Please cite this article as: Ingale, A.P., Patil, S.M., Shinde, S.V., “Catalyst-free, efficient and one pot protocol for
synthesis of nitriles from aldehydes using glycerol as green solvent”, Tetrahedron Letters (2017), doi:https://doi.org/
10.1016/j.tetlet.2017.11.032
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Catalyst-free, efficient and one pot protocol
for synthesis of nitriles from aldehydes using
glycerol as green solvent
Leave this area blank for abstract info.
Ajit P Ingale, Shripad M Patil and Sandeep V Shinde

1
Tetrahedron Letters
"Catalyst-free, efficient and one pot protocol for synthesis of nitriles from aldehydes
using glycerol as green solvent"
Ajit P Ingalea, Shripad M Patilb and Sandeep V Shindea*
aDepartment of Chemistry, Pratibha Niketan College, Swami Ramanand Teerth Marathwada University, Nanded, Maharashtra, 431 606, India.
bDepartment of Chemistry, Dada Patil College, Savitribai Phule Pune University, Karjat, Ahmednagar, Maharashtra, 414 402, India.
ARTICLE INFO
ABSTRACT
We described herein the novel, efficient and one-pot catalyst free protocol for the synthesis of
nitriles from aldehydes by using hydroxyl amine hydrochlorides in glycerol as a green solvent.
This protocol was efficiently used for transformation of aromatic aldehydes bearing electron-
withdrawing and electron-donating groups into a aryl nitriles in good to excellent yields. The
methodology offers a very simple, efficient and environmentally benign procedure.
Keywords:
Glycerol
aldehydes
Nitriles
Nitriles are versatile synthetic precursors for the preparation
of agricultural chemicals, polymers, pigments, dyes and
pharmaceuticals.1 In addition, they are used for preparation of
amines, amidines, amides, aldehydes and carboxylic acid and
nitrogen containing heterocyclic systems.2 More-over, the cyano
group itself is present in biologically active compound, such as
Letrazole (used in the treatment of breast cancer), Periciazine (an
antipsychotic drug), Citalopram (an antidepressant drug), HIV
protease inhibitors, and 5-lipoxygenase inhibitors.3 Numerous
methods are reported in the literature for the synthesis of aryl
nitriles using various reagents. Sandmeyer and Rosenmund -von
Braun reactions are classic methods for the synthesis of aryl
nitriles, but both methods require stoichiometric amounts of
Copper(I)cyanide reagents and prefunctionlized starting
materials.4 The well developed transition-metal catalysed
cyanation of aryl halides5 and C-H cyanation reactions6 also used
for synthesis of aryl nitriles. Metal cyanide has been commonly
used in direct cyanation reactions, such as KCN, NaCN, CuCN,
AgCN, and TMSCN. The ammoxidation of toluene derivatives is
an industrial scale method for nitrile synthesis.7 The
ammoxidation is applicable only to a limited number of
substituted toluene derivatives and it is also requires high
temperature and high pressure besides the use of excess ammonia
restricts its application. Many methods have been reported that
aldehydes can be directly converted into nitriles without isolation
of aldoxime intermediates upon the one-pot treatment with
hydroxylamine in the presence of various dehydrating reagents.8
The main disadvantages of these methods are limited scope of
substrates, corrosive, toxic, expensive, or commercial unavailable
reagents, no reusability of reagents, drastic reaction conditions,
tedious workup, and unsatisfactory yields. Therefore, new
methods for this transformation are still desirable.
In this context, the development of protocols using recyclable
and environmentally friendly solvent has gained much interest
recently because of the extensive uses of solvents in almost all of
the chemical industries, and of the predicted disappearance of
fossil oil.9 It has also observed that the catalysts employed are not
always ecofriendly and because of this, serious environmental
pollution often results. Therefore, the design of catalyst-free
reactions is a crucial goal for chemist. In this regard, the use of
glycerol as a promoting medium for organic reaction was
recently demostrated.10 Glycerol due to its unique combination of
physical and chemical properties such as polarity, low toxicity,
no flammability, high boiling point, biodegradability, and easy
availability from renewable feed stocks prompted us to extend its
use as green solvent in organic synthesis.11 In this sense, we
describe here the catalyst-free, efficient, one-pot green protocol
for synthesis of nitriles from aldehydes using glycerol as green
solvents (Scheme 1).
Scheme 1. General scheme of reaction
In order to investigate the scope and limitations of catalyst-
free green protocol, we have chosen benzaldehyde as our model
compound for the desired transformations. Initially, we reacted
benzaldehyde 1a (1.0 mmol) with
a
hydroxylamine
hydrochloride (1.0 mmol) using glycerol (5 mL) as solvent at
different temperatures to optimize the reaction conditions to
access benzonitrile 2a (Table 1). When reaction was performed at
room temperature, product 2a was not formed, the benzaldehyde

2
remains unreacted. To our satisfaction, by increasing the
Table 2
Synthesis of organic nitriles 2a-2q using glycerol as solventa
temperature, the reaction proceeds smoothly, and at 900C
benzonitrile 2a was obtained in 90% yield (Table 1, entry 3). It is
observed that an optimum yield of nitrile was obtained in
glycerol at 90OC (Table 1, entry 3). No there is no significant
improvement in reaction time and yield of product was observed
above that temperature (Table 1, entry 6), so 90OC was chosen as
the reaction temperature. It is also important to mention that
when the reaction was performed without glycerol no product
was obtained (Table 1, entry 4). When we performed the reaction
using other alcoholic solvents such as ethanol, methanol, no
product 2a was obtained (Table 1, entry 5). In an optimized
reaction12, benzaldehyde 1a (1.0 mmol) and hydroxylamine
hydrochloride (1.0 mmol) was dissolved in glycerol (5 ml) and
stir at 900C for 7.5 hours to obtained benzonitrile 2a in 96% yield
(Table1, entry 3).
Entry
Aldehyde (1)
Time (h)
Product (2)
Yieldb (%)
1
7.0
90%
1a
2a
2b
2
7.0
91%
90%
1b
3
4
5
6
7
7.0
6.5
6.5
6.5
7.0
Table 1
Reaction conditions optimizationa
1c
2c
92%
93%
93%
89%
1d
2d
Entry
Temperature (oC)
Time (h)
24
Yield 2ab (%)
1e
1f
2e
2f
1
2
3
4
5
6
rt
60
90
90
90
120
-
12
7.0
24
24
43
90
-
-
90
7.0
aReactions are performed using benzaldehyde 1a (1.0 mmol),
hydroxylamine hydrochloride (1.0 mmol) in glycerol (5 mL).
b Yields are given for isolated product.
1g
1h
2g
2h
c Reaction performed without glycerol.
d Reaction performed in ethanol, methanol.
8
9
7.0
8.5
86%
85%
With the optimized reaction conditions in hand, the scope and
limitations of functionalized aldehydes were studied, as shown
Table 2. Generally, substrate bearing electron-donating groups as
well as 1-formyl naphthalenes provided the nitriles product in
good to excellent yields (Table 2, entry 2b-2h). However, for
the substrates possessing electron-withdrawing groups, moderate
yields were obtained (Table 2, entry 2i-2o). Next, the scope of
heteroaromatic substrate was investigated and they are also
suitable for reaction and did not show any remarkable difference
in the yields (Table 2, entry 2p-2q). However, aliphatic
aldehydes were unable to provide the desired product in
acceptable yield.
2i
1i
10
11
12
13
8.5
9.0
9.5
9.5
85%
83%
81%
80%
1j
2j
After reaction optimization, a study regarding the use of
glycerol was performed. After the completion of reactions, the
reaction mixture was diluted and extracted with mixture of
hexane/ethyl aceate (95:5) (5 x 5). The upper phase was dried
and the solvent evaporated. The glycerol phase was dried under
vacuum and directly reused. Glycerol maintained its good level
of efficiency even after being reused three times. The product 2a
was obtained in 89%, 89% and 88% yields after the successive
cycles.
1k
2k
1l
2l
1m
2m

3
Struck, E. Chem. Ber. 1919, 52, 1749; (d) von Braun, J.; Manz,
G. Liebigs Ann. Chem. 1931, 488, 111; (e) Connor, J. A.;
Leeming, S. W.; Price, R. J. Chem Soc., Perkin Trans. 1990,
1127; (f) Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987,
87, 779.
Table 2 (continued)
5.
6.
(a) Schareina, T.; Beller, M. Copper-catalysed cyanations of aryl
halides and related compounds, ed. Evano, G.; Blanchard, N.
Wiley, 2014, pp 313-334; (b) Wen, Q. D.; Jin, J. S.; Zhang, L. P.;
Luo, Y.; Lu, P.; Wang, Y. G. Tetrahedron Lett. 2014, 55, 1271;
(c) Kim, J. H.; Kim, H. J.; Chang, S, Angew. Chem. Int. Ed. 2012,
51, 11948; (d) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc.
Rev. 2011, 40, 5049.
(a) Wang, T.; Jiao, N. Acc. Chem. Res. 2014, 47, 1137; (b) Ding,
S. T.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374; (c) Kim, J.;
Chang, S. J. Am. Chem. Soc. 2010, 132, 10272; (d) Gong, T. J.;
Xiao, B.; Cheng, W. M.; Su, W.; Liu, Z. J.; Fu, Y. J. Am. Chem.
Soc. 2013, 135, 10630; (e) Yu, D. G.; Gensch, T.; Azambuja, F.
D.; Vasquez-Cespedes, S.; Glorius, F. J. Am. Chem. Soc. 2014,
136,17722; (f) Yang, Y.; Buchwald, S. L. Angew. Chem. Int. Ed.
2014, 53, 8677; (g) Shu, Z. B.; Ji, W. Z.; Wang, X.; Zhou, Y. J.;
Zhang, Y.; Wang, J. B. Angew. Chem. Int. Ed. 2014, 53, 2186.
Martin, A.; Kalevaru, N. V.; Lucke, B.; Sans, J. Green Chem.
2002, 4, 481.
(a) Yang, S. H.; Chang, S. Org. Lett. 2001, 3, 4209; (b) Lai, G.;
Bhamare, N. K.; Anderson, W. K. Synlett. 2001, 230; (c) Sharghi,
H.; Saravari, M. H. Tetrahedron. 2002, 58, 10323; (d) Bandgar, B.
P.; Makone, S. S. Synlett. 2003, 262; (e) Ballini, R.; Fiorini, D.;
Palmieri, A. Synlett, 2003, 1841; (f) Movassagh, B.; Shokri, S.
Tetrahedron Lett. 2005, 46, 6923; (g) Zhu, J. L.; Lee, F. Y.; Wu, J.
D.; Kuo, C. W.; Shia, K. S. Synlett. 2007, 1317; (h) Khezri, S. H.;
Azimi, N.; Mohammed-Vali, M.; Eftekhari-Sis, B.; Hashemi, M.
M.; Baniasadi, M. H.; Teimouric, F. Arkivoc. 2007, 162; (i)Yam-
aguchi, K.; Fujiwara, H.; Ogasawara, Y.; Kotani, M.; Mizuno, N.
Angew. Chem. Int. Ed. 2007, 46, 3922; (j) Telvekar, V. N.; Patel,
K. N.; Kundaikar, H. S.; Chaudhari, H. K. Tetrahedron Lett.
2008. 49, 2213; (k) Reddy, K. R.; Maheswari, C. U.; Venkatesh-
war, M.; Prashanati, S.; Kantam, M. L. Tetrahedron Lett. 2009.
50, 2050; (l) Singh, M. K.; Lakshman, M. K. J. Org. Chem. 2009,
74, 3079; (m) Zhu, C. J.; Ji, L.; Wei, Y. Y. Synthesis. 2010, 3121;
(n) Augustine, J. K.; Bombraun, A.; Atta, R. N. Synlett. 2011,
2223.
14
9.5
8.0
83%
83%
1n
2n
2o
15
1o
16
7.0
7.0
86%
86%
1p
2p
2q
7.
8.
17
1q
aReactions are performed using aryl aldehydes 1a-1q (1.0 mmol),
hydroxylamine hydrochloride (1.0 mmol) in glycerol (5 mL).
b Yields are given for isolated product.
The role of glycerol in this one pot protocol was established
by the fact that in the absence of glycerol the formation of nitrile
does not take place. Obviously, glycerol is an essential
component of reaction. In addition, we performed the reaction
using other alcoholic solvents such as ethanol, methanol, no
product was obtained. The role of glycerol in this reaction is
obscure at this stage. We suggest that hydrogen of hydroxyl
group of glycerol through the formation of hydrogen bonding
activated the aldehyde carbonyl to form the aldoxime associated
with HCl in glycerol. After that the glycerol and HCl in glycerol
help for dehydration of aldoxime formed to afford the desired
nitrile at 90OC. It is very well known that it has three hydroxyl
groups which may provide hydrogen bonding to the Cl- counter
anion and helps acid in dehydration of aldoxime.
9.
(a) Lenardao, E. J.; Trencha, D. O.; Ferreira, P. C.; Jacob, R. G.;
Perin, G. J. Braz.Chem. Soc. 2009, 20, 93; (b) Lenardao, E. J.;
Silva, M. S.; Sachini, M.; Lara, R. G.; Jacob, R. G.; Perin, G.
Arkivoc. 2009, 11, 221; (c) Perin, G. L. G.; Mello, C. S.; Radatz,
L.; Savegnago, D.; Alves, R. G.; Jacob, E. J. Tetrahedron Lett.
2010, 51, 4354.
In conclusion, we have developed here a green and catalyst-
free protocol for the synthesis of nitriles from aldehydes by using
glycerol as green solvent. Excellent yield, catalyst-free, cost
efficient, environmentally benign, and simple work-up
procedures are the advantages of this protocol.
10. Radatz, C. S.; Silva, R. B.; Perin, G.; Lenardao, E. J.; Jacob, R.
G.; Alves, D. Tetrahedron Lett. 2011, 52, 4132; (b) Perin, G.;
Mello, L. G.; Radatz, C. S.; Savegnago, L.; Alves, D.; Jacob, R.
G.; Lenardao, E. J. Tetrahedron Lett. 2010, 51, 4354; (c) Gonca-
lves, L. C.; Fiss, G. F.; Perin, G.; Alves, Diego.; Jacob, R. G.;
Lenardao, E. J. Tetrahedron Lett. 2010, 51, 6772. (d) Nascime-
ment, J. E. R.; Barcellos, A. M.; Sachini, M.; Perin, G.; Lenardao,
E. J.; Alves, D.; Jacob, R. G.; Missau, F. Tetrahedron Lett. 2011,
52, 2571; (e) Bachhav, H. M.; Bhagat, S. B.; Telvekar, V. N.
Tetrahedron Lett. 2011, 52, 5697; (f) Wolfson, A.; Litvak, G.;
Dlugy, C.; Shotland, Y.; Tavor, D. Ind. Crop Prod. 2009, 30, 78.
11. (a) Nelson, W. M. In green Solvents for Chemistry: Perspectives
and practice; Oxford University Press: Oxford, 2003; (b)
Pagliarao, M; Rossi, M. In future of Glycerol: New Usages for a
Versatile Raw Material; Clark, J. H., Kraus, G. A., Eds.; RSC
Green Chemistry Series: Cambridge, 2008.
12. General procedure for synthesis of nitriles: To a round bottom
flask aldehydes (1a-1q) (1.0 mmol) and hydroxylamine
hydrochloride (1.0 mmol) was added in glycerol (5 ml). The
reaction mixture was allowed to stir at 900C for the time indicated
in table 2. After the completion of reaction, the reaction mixture
was washed with a mixture of hexane/Ethyl acetate (95:5) (3 x 3
mL) and the organic phase were separated from glycerol, dried
with MgSO4, and evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel using
hexane/ethyl acetate as eluent. All the compounds were
characterized by comparison with mp and 1H NMR, 13C NMR
spectra with literature. Selected spectral data for: Benzonitrile
(2a): Colorless Oil; b.p 191-192oC; FT-IR (υ, cm-1): 3097, 3050,
Acknowledgments
We thank the UGC, New Delhi and BCUD, SPPU, Pune for
financial support.
References and notes
1.
(a) Murdoch, D.; Keam, S. J. Drugs, 2005, 65, 2379; (b) Larock,
R.C. Comprehensive Organic Transformations: VCH: New York:
1989; pp 819-995; (c) Grundnann C. Houben-Wiley: Methodender
Organischen Chemie. Falbe; J. Ed. Georg Thieme Verlag:
Stuttgart; 1985, E5; PP 1313-1527.
(a) Fatiadi, A. J. In preparation and synthetic application of cyano
compounds; Patai, S., Rappoport, Z., Wiley-VCH; New York, NY,
1983; (b) Rappoport, Z., In Chemistry of the cyano group; John
Wiley & Sons; London, UK, 1970; PP 121-312.
(a) Jones, L. H.; Summerhill, N. W.; Swain, N. A.; Mills, J. E.
Med Chem. Commun. 2010, 1, 309; (b) Janakirman, M. N.;
Watenpaugh, K. D.; Chong, K. T.; Turner, S. R.; Tommasi, R. A.;
Thaisrivongs, S.; Strohbach, J. W. Bioorg. Med. Chem. Lett. 1998,
8, 1237; (c) Dube, D.; Blouin, M.; Brideau, C.; Chan, C. C.;
Desmarais, S.; Ethier, D.; Falgueyret, J. P.; Friesen, R. W.; Girard,
M.; Girard, Y.; Guay, J.; Riendeau, D.; Tagari, P.; Young, R. N.
Bioorg. Med. Chem. Lett. 1998, 8, 1255.
2.
3.
1
2231, 1502, 1401, 1276, 1198, 844; H NMR (400 MHz, CDCl3,
TMS, ppm): δ 7.65 (s, 3H), 7.45 (s, 2H); 13C NMR (100 MHz,
4.
(a) Sandmeyer, T.; Ber. Dtsch. Chem. Ges. 1884, 17, 1633; (b)
Galli, C. Chem. Rev. 1988, 88, 765; (c) Rosenmund, K. W.;

4
CDCl3, ppm): δ 132.6, 132.0, 129.0, 118.6, 112.5. GC-MS m/z
(% relative intensity): 103 (M+, 100), 76 (40), 50 (11).
11
12
13
9.0
9.5
9.5
83%
81%
80%
1k
2k
Table 2
Synthesis of organic nitriles 2a-2q using glycerol as solventa
1l
2l
Entry
Aldehyde (1)
Time (h)
Product (2)
Yieldb (%)
1m
2m
1
7.0
90%
1a
14
9.5
83%
2a
2b
1n
1o
2n
2o
2
7.0
91%
1b
15
8.0
83%
90%
92%
3
4
7.0
6.5
1c
2c
16
17
7.0
7.0
86%
86%
1p
1q
2p
2q
1d
2d
aReactions are performed using aryl aldehydes 1a-1q (1.0 mmol),
hydroxylamine hydrochloride (1.0 mmol) in glycerol (5 mL).
bYields are given for isolated product.
5
6
7
6.5
6.5
7.0
93%
93%
89%
1e
1f
2e
2f
Research Highlights
 Catalyst-free protocol for the synthesis of
nitriles in glycerol as green solvent.
1g
1h
2g
2h
 Methods is suitable for aromatic aldehyde
and heteroaromatic aldehydes
8
7.0
86%
 Excellent
yield,
cost-efficient
and
environmentally benign are advantages of
protocol.
9
8.5
8.5
85%
85%
2
1i
1j
i
10
2j

5
Graphical Abstract
Catalyst-free, efficient and one pot protocol
for synthesis of nitriles from aldehydes using
glycerol as green solvent
Leave this area blank for abstract info.
Ajit P Ingale, Shripad M Patil and Sandeep V Shinde