Effect of successive increase in alcohol chains on reaction with isocyanates and isothiocyanates

Article abstract of DOI:10.1080/14786410802270738

The reaction of isocyanates and isothiocyanates with long-chain alcohols, e.g. n-hexanol, n-heptanol and n-octanol, exclusively gave N-aryl-O-alkyl carbamates, while N-aryl-O-alkyl carbamates were formed along with symmetrical 1,3-disubstituted ureas and thioureas when the same reactions were carried out with small-chain alcohols at room temperature without using any solvent.

Full text of DOI:10.1080/14786410802270738

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Effect of successive increase in alcohol
chains on reaction with isocyanates and
isothiocyanates
Shahnaz Perveen a , Arfa Yasmin a & Khalid Mohammed Khan b
a PCSIR Laboratories Complex, Shahrah-e-Dr. Salimuzzaman
Siddiqui, Karachi, Pakistan
b H.E.J. Research Institute of Chemistry, International Center
for Chemical and Biological Sciences, University of Karachi,
Karachi–75270, Pakistan
Published online: 09 Dec 2009.
To cite this article: Shahnaz Perveen , Arfa Yasmin & Khalid Mohammed Khan (2010) Effect of
successive increase in alcohol chains on reaction with isocyanates and isothiocyanates, Natural
Product Research: Formerly Natural Product Letters, 24:1, 18-23, DOI: 10.1080/14786410802270738
To link to this article: http://dx.doi.org/10.1080/14786410802270738
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Natural Product Research
Vol. 24, No. 1, 10 January 2010, 18–23
Effect of successive increase in alcohol chains on reaction with isocyanates
and isothiocyanates
a
Shahnaz Perveen , Arfa Yasmin and Khalid Mohammed Khan
a
b
*
aPCSIR Laboratories Complex, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi, Pakistan;
bH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences,
University of Karachi, Karachi – 75270, Pakistan
(Received 10 April 2007; final version received 8 July 2008)
The reaction of isocyanates and isothiocyanates with long-chain alcohols, e.g.
n-hexanol, n-heptanol and n-octanol, exclusively gave N-aryl-O-alkyl carbamates,
while N-aryl-O-alkyl carbamates were formed along with symmetrical
1,3-disubstituted ureas and thioureas when the same reactions were carried out
with small-chain alcohols at room temperature without using any solvent.
Keywords: alcohols; isocyanates; isothiocyanates; N-aryl-O-alkyl carbamates;
symmetrical ureas
1. Introduction
Commercially, carbamates are used as agrochemicals (Dibenedetto, Aresta, Fragale,
& Narracci, 2002; Gupte, Shivarkar, & Chaudhari, 2001; Motolcsy, Nadasy, & Andriska,
1988; Thompson, 2002), for example: aldicarb, carbofuran, furadan, fenoxycarb, carbaryl,
sevin and 2-(1-methylpropyl) phenyl methyl carbamate. Some are used in human
pharmacotherapy, such as the cholinesterase inhibitors neostigmine and rivastigmine.
They are also used as an anaesthetic for animals (VCU, 2006). Formerly, cross-linking
agents for permanent press textile treatments were synthesised from urethane (NTP, 2005).
The formations of carbamates from isocyanates are fundamentally important for
polyurethane industries (Dibenedetto et al., 2002; Feldman & Barbalata, 1996; Gupte
et al., 2001). Carbamates are used as prodrugs (de Bont, Leenders, Haisima, van der
Meulen-Muileman, & Scheeren, 1997; Jose 1995; Jose, Robert, Judith, Barbara, &
Evamarie, 1991; Jose, Robyn, Stuart, & Harvey, 1988; Leenders et al., 1995; Syed et al.,
1999; Zhong, Panayota, Stanley, & Yang, 1997) in the pharmaceuticals industry and also
as drug intermediates (Dibenedetto et al., 2002; Gupte et al., 2001). The polyurethane
industries point out that the most common medical use of polyurethane is in short-term
implants, and polyurethanes are used in hospital bedding, surgical drapes, wound
dressings and injection moulded devices. Good ‘biocompatibility, excellent physical
properties and relative ease of process ability’ are some of the reasons that thermoplastic
polyurethanes are used in medical devices (Aine, 2004).
*Corresponding author. Email: dr_shahnaz_perveen@yahoo.com
ISSN 1478–6419 print/ISSN 1029–2349 online
ß 2010 Taylor & Francis
DOI: 10.1080/14786410802270738
http://www.informaworld.com

Natural Product Research
19
Alcohols and phenols react with isocyanates to yield carbamate esters (Saunders
& Slocombe, 1948). These derivatives are often used for the characterisation of hydroxyl-
containing compounds (Gaylord & O’Brien, 1955). Carbamate esters can be prepared
from primary, secondary and aromatic amines, CO2, and a variety of electrophiles
(Ken, 1994), as well as in the presence of dimethyl carbonate (Pietro, Salima, Alessandro,
& Gabriel, 2005). The bisalkyl and bisphenyl carbamates were prepared by the reaction
of the amino alcohols with the corresponding alkyl (Parcell, 1958a, 1958b) and phenyl
isocyanates. Carbamates can also be prepared by the reaction of alcohols with
trichloroacetic acid and sodium cyanate without using any solvent (Ali, Mohsen, &
Parisa, 2006), azides with chloroformates using indium metal (Jhillu, Basi, &
Garudammagari, 2000), amine with alcohol in the presence of one or more catalyst
(H. Kim, S.D. Lee, H.-J. Lee, Seo, & Y. Kim), oxidative alkoxycarbonylation of amines by
CO or O2, in the presence of palladium and iodide catalysts (Shinsuke, Masazumi, &
Masashi, 1984), and in alcohols using CO2, amines and Mitsunobu’s reagent (Devdutt,
Nisha, & Virendra, 2007). In haemoglobin, carbamate groups are formed when CO2
molecules bond with the amino termini of the globin chains. This helps to stabilise the
protein when it becomes deoxy haemoglobin and increase the likelihood of the release of
the remaining oxygen molecules bound to the protein. Ribulose 1,5-disphosphate
carboxylase/oxygenase (the enzyme required to fix a CO2 molecule at the start of the
Calvin cycle) also requires the formation of a carbamate to function.
2. Results and discussion
In this article, we wish to report a very simple, economical, efficient and one step synthesis
of N-aryl-O-alkyl carbamates. When isocyanates/isothiocyanates were treated with
alcohols, e.g. n-hexanol, n-heptanol and n-octanol (Scheme 1) in the absence of any
solvent, while monitoring through TLC, we found that a single product was formed, and
spectroscopic studies confirmed the formation of N-aryl-O-alkyl carbamates (100% yield,
1–8, i–k) (Table 1). When the same reactions were carried out with small-chain alcohols,
e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-amyl alcohol,
and isoamyl alcohol, two products were formed (Bickel & French, 1926; French & Wirtel,
1926; Neuberg & Kansky, 1909; Shoichiro, 1972): one of them had 30–60% yield, and
other had 40–70% yield. After spectroscopic studies, we came to know that one product
(30–60% yield) was an N-aryl-O-alkyl carbamate (1–8, a–h), while the other product was a
symmetrical 1,3-disubstituted ureas/thiourease (1–8). A seventy percent yield of 1,3-
disubstituted ureas/thiourease was formed when isocyanates/isothiocyanates were treated
with methanol.
The result gave very strong evidence that the alcohol was playing a dual role: both as
a catalyst and as a reactant. It acted like a tertiary amine, as a promoter (Shahnaz et al.,
X
H
R
N
C
X
R
N
C
O
R′
n-Hexanol/n-Heptanol/n-Octanol
R′= n-Hexyl, n-Heptyl, n-Octyl
R = Alkyl or aryl
X = O or S
RT, 60–120 min
1–8 (i–k)
Reagents and conditions: n-Hexanol/n-Heptanol/n-Octanol, RT; 60–120 min.
Scheme 1. Synthesis of N-aryl-O-alkyl carbamates.

20
S. Perveen et al.
2005; Syed, Shahnaz, Rashid, Khalid, & Nighat, 2003) of reaction. Evidence showed that
the alcohol–isocyanate reaction indicated that isocyanates/isothiocyanates are highly
sensitive to the action of nucleophilic catalysts. The N-phenyl urethane, which was the
product of the combination of phenyl isocyanate with an alcohol, was a weak catalyst for
the reaction (Baker & Holdsworth, 1947; Smith, 1968). With a successive increase in
alcohol chains, the yield of 1,3-disubstituted ureas and thioureas decreased, and no
symmetrical 1,3-disubstituted ureas and thioureas were formed with n-hexanol, n-heptanol
Table 1. Results of syntheses of N-aryl-O-alkyl carbamates, 1,3-disubstituted ureas and
thioureas.
Sr.
no.
Substrate
Products
O
C
O
C
N=C=O
H
N
H
N
H
N
1.
OR′
OR′
1
1a–k
S
S
N=C=S
H
N
H
N
H
N
2.
C
C
2
2a–k
O
C
O
C
3.
4.
N=C=O
N=C=S
N=C=O
NH
NH
OR′
OR′
NH
3a–k
3
S
S
C
NH
NH C NH
4
4a–k
O
O
H
N
H
N
H
N
5.
OR′
C
C
HO
OH
HO
HO
5
5a–k
NO2
O
C
NO
2
O
C
NO
NO
2
2
H
N
H
N
H
6.
7.
OR′
N
N=C=O
N=C=O
6
6a–k
O
C
O
H
N
H
N
H
N
NO
2
OR′
C
NO
2
O N
2
NO
2
7
7a–k
O
C
O
C
N=C=O
H
N
H
N
H
8.
OR′
N
O N
2
O N
2
NO
2
O N
2
8
8a–k
Notes: R0 ¼ Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-amyl, isoamyl, n-hexyl,
n-heptyl and n-octyl.

Natural Product Research
21
X
H
X
C
Alcohols
H
H
N
X
R
N
C
O
R′
+
R
C
R
N
N
R
RT, 5–60 min
R = Alkyl or aryl
X = O or S
1,3-Disubstituted
ureas or thioureas
R′ = Alkyl
1–8(a–h)
1–8
Reagents and conditions: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,
n-amyl alcohol, iso amyl alcohol, RT; 5–60 min.
Scheme 2. Synthesis of symmentrical ureas, thioureas and N-aryl-O-alkyl carbamates.
O
R
R
O
Proposed mechanism:-
-
O
C
N
C
C
N
O
+
..
–R′OH
+
R–N=C=O
a
R
N
C
OR′
R
N
C
OR′
R–N=C=O + R′OH
H
H
N– R
O
-
I
II
-
O
R
O
R
N
C
C–OH
H
N
H
N
–OH
N
C
C
H O
2
R
R
O
N
R
N
-
O
..
1–8
O
R
1,3-Disubstituted ureas
-
O
O
C
O
H
N C OR′
+
+
-
R–N=C=O + R′OH
R
N
C
OR′
R
N
OR′
R
H
b
H
1–8(a–k)
N-aryl-O-alkyl carbamates
I
nor n-octanol (higher alcohols), but the reaction took place slowly and was completed after
60–120 min. This was due to the steric hindrance: the bulky group of alcohol did not allow
the attack of another molecule of isocyanate/isothiocyanate. Conversely, the reactions with
small-chain alcohols took place very rapidly and were completed in 5–60 min (Scheme 2),
without the application of heat. The mechanism of reaction indicated that both the
reactions (Schemes 1 and 2) took place by the same intermediate I. In the case of long-chain
alcohols, the intermediate I was directly converted into cabamate, while with the small-
chain alcohols, as soon as the intermediate I was formed it picked up another molecule of
isocyanate/isothiocyanate and symmetrical 1,3-disubstituted ureas/thioureas were formed
as a major product, with N-aryl-O-alkyl carbamates formed as a minor product. The
alcohols were used as they were obtained, without drying, and inheritent moisture present
in the alcohols was responsible for assisting the formation of ureas/thiourease.
The reactivity of 2-nitrophenyl isocyanate, 3-nitrophenyl isocyanate and 4-nitrophenyl
isocyanate were more likely due to the presence of electron-withdrawing groups, and
reactions took place very easily compared to p-hydroxy phenyl isocyanate, phenyl
isocyanate, phenyl isothiocyanates and benzyl isocyanate (Shoichiro, 1972).
3. Experimental
In a typical reaction, 0.3 moles of isocyanate and thioisocyanate were treated with 2 moles
of alcohol, e.g. n-hexanol, n-heptanol and n-octanol, in the absence of any solvent at room

22
S. Perveen et al.
temperature, and the progress of reaction was monitored by TLC. TLC showed the
formation of a single product. After completion of the reaction, the reaction mixture was
poured into ice cold water and continuously stirred. The solid obtained was filtered and
afforded the pure desired carbamate. With methanol, ethanol, n-propanol, isopropanol,
n-butanol, isobutanol, n-amyl alcohol and isoamyl alcohol, two products were formed,
and on purification by column chromatography afforded pure desired materials.
Acknowledgements
The authors are thankful to the Pakistan Science Foundation ‘PSF Grants for Active Scientists and
Technologists of Pakistan’ for funding for this research work.
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