A catalyst system for the reaction of carboxylic acids with aliphatic isocyanates

Article abstract of DOI:10.1016/j.tetlet.2004.02.012

Catalysts have been found for the selective reaction of aliphatic isocyanates with carboxylic acids giving amides after carbon dioxide extrusion. Magnesium and calcium salts lead to a dramatic increase in reaction rates while improving the selectivity when sterically hindered isocyanates and/or carboxylic acids are used.

Full text of DOI:10.1016/j.tetlet.2004.02.012

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2515–2521
A catalyst system for the reaction of carboxylic acids with
aliphatic isocyanates
*
€
C. Gurtler and K. Danielmeier
Bayer MaterialScience AG, Innovation Coatings, Adhesives and Sealants, D 51368 Leverkusen, Germany
Received 17 November 2003; revised 27 January 2004; accepted 4 February 2004
In memoriam Professor Dr. Eberhard Steckhan
Abstract—Catalysts have been found for the selective reaction of aliphatic isocyanates with carboxylic acids giving amides after
carbon dioxide extrusion. Magnesium and calcium salts lead to a dramatic increase in reaction rates while improving the selectivity
when sterically hindered isocyanates and/or carboxylic acids are used.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
of thermosensitive acids like acrylic acid possible. Very
often the prime way to lower reaction temperatures is to
make use of a catalytic system and this is the main goal
of the efforts described in this paper.
The reaction of isocyanates with carboxylic acids is one
of the lesser-utilised reactions in isocyanate chemistry.
Little has been published1;2 and these publications
almost exclusively deal with the reactions between aro-
matic isocyanates and acids. Furthermore no catalyst
system has been described. However, for the production
of raw coating materials the reaction between aliphatic
isocyanates and acids appears to be a viable tool that
should be further investigated due to the great variety of
readily available starting materials. In the production of
raw coating materials the starting materials need to
react completely because typically no final purification
step is involved. The results of this examination may be
interesting for a wider variety of applications.
Two reaction pathways are in competition in the reac-
tion of an acid and an isocyanate (Scheme 1). The actual
reaction pathways depend on the degree of substitution
of the a-carbon of the aliphatic carboxylic acid. For
higher substituted carboxylic acids (e.g., pivalic acids)
path B occurs almost exclusively, however, with the
sterically unhindered acetic acid, path A was found to be
preferred giving the corresponding amide. Depending
on the conditions and stoichiometry this amide can then
further react to form an acyl urea. Thus the catalyst
screening was focussed to find a catalyst system that
supports reaction path A.
Typically, for the reaction of aliphatic carboxylic acids
with aliphatic isocyanates, high reaction temperatures
(up to 140 °C) and long reaction times are required. By
lowering the reaction temperature and thus allowing
more controlled reactions a novel access to polyisocya-
nate building blocks for coatings could be opened up.
Lower temperature would lead to less colouration––
which is crucial for coating applications and raw mate-
rial manufacturing––and would make the incorporation
2. Catalyst screening
The catalyst screening was performed in a multiparallel
way in a minaturised fashion. Up to 10 reactions could
be run at a time on a 5 g scale. The small amounts of
catalysts employed made it difficult to reduce further the
size of these reactions, and no solvent was used. The
stoichiometry of acid to isocyanate was 1:1. Reactions
were run for 3 h at 70 °C, the amount of catalyst used
was 0.01 mol %. Reactions were repeated several times
to confirm the results obtained. The samples were
Keywords: Aliphatic isocyanates; Coatings; Catalyst screening; Acid–
isocyanate reaction.
* Corresponding author. Fax: +49-214-30-28564; e-mail: christoph.
guertler@bayermaterialscience.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.012

2516
C. G€urtler, K. Danielmeier / Tetrahedron Letters 45 (2004) 2515–2521
O
+
H
O
N
O
Path B (undesirable)
O
Path A (desirable)
O
O
O
O
O
N
H
O
Mixed anhydride
Anhydride
+
O
- CO2
H
N
O
H
N
H
NCO
R
- CO2
Amide
NCO
R
O
R
O
O
N
N
H
H
Biuret
N
R
Acyl urea
N
H
Scheme 1. Reaction pathways for the reaction of carboxylic acids with isocyanates.
investigated using SFC (supercritical fluid chromato-
graphy using supercritical CO2) directly after comple-
tion of the reaction to avoid follow up reactions.
Nitrobenzene was used as an external standard. For this
screening we investigated a representative selection of
metals from the periodic table and in a few promising
cases we used different salts of the specific metal cation.
The first model system investigated was the reaction of
hexyl isocyanate with hexanoic acid.
With some catalysts, large amounts of urea are formed
as a side product. This is not desirable for further
applications.
Big, highly charged cations (e.g., Bi3þ) and salts of the
first group of the periodic table (lithium, sodium and
potassium) and group III salts as well as amine bases
and ionic liquids showed only limited catalytic activity.
This was also true for catalysts, which are used in the
coatings area such as DBTL (dibutyltin dilaurate) or
zinc 2-ethylhexanoate. Some of the catalysts under
investigation led to colouration of the reaction mixture,
which is also prohibitive for use in coatings applications.
These included acetylacetonates such as zirconium(IV)
acetylacetonate and catalysts containing titanium and
copper. We suppose that in situ reduction from Ti(IV)
to Ti(III) or Zr(III) takes place; these d1-species are
known to be coloured.
3. Results
By using the correct catalyst, the reaction of linear ali-
phatic isocyanates with aliphatic carboxylic acids could
be dramatically accelerated.
The ranking was made depending on the sum of the
yield of amide and acyl urea (the follow up product from
the reaction of an isocyanate with an amide). Magne-
sium salts exhibit the highest catalytic activity, followed
by lanthanum, ytterbium and calcium salts. Some of the
most active catalysts led to complete turnover after
30 min. Surprisingly, we found that magnesium and
ytterbium catalysed reactions were complete within less
than 10 min. The reaction could be initiated even at
room temperature. After completion the reaction was
quenched by diluting the reaction mixture with solvent
(THF) and immediate analysis by SFC. The yields for
some of the catalysts can be found in Table 2. The
selectivities obtained after a reaction time of 30 min may
differ from those after 3 h (compare Table 1).
All of the tested catalysts activate the carboxylic acid as
proved by the increased formation of carboxylic acid
anhydride in comparison to the noncatalysed reactions.
The most active catalysts promote the extrusion of CO2
from the addition product of the isocyanate and car-
boxylic acid. We have performed NMR studies to prove
this (Scheme 2). The extrusion of CO2 seems to be the
rate determining step in the overall reaction, as can be
shown with 13C labelled carboxylic acids. The carbon
dioxide stems from the isocyanate group.
4. Investigation of the reaction of a sterically hindered
isocyanate (cyclohexyl isocyanate) with an aliphatic
carboxylic acid
Interestingly, in the case of magnesium there was only a
small dependence on the anion. However, we obtained
different ratios of carboxylic anhydride versus product
and dihexyl urea versus product, respectively. We found
this for calcium salts as well.
In order to widen the application we had a closer look at
the reaction of a cyclic aliphatic isocyanate with a linear

Table 1. Catalyst (selection) screening for the reaction of hexyl isocyanate with hexanoic acid
Catalyst
Hexyl
isocyanate
Hexanoic
acid
Carboxylic
acid anhy-
dride
Amide
Dihexyl
urea
Acyl
urea
Sum amide
plus acyl urea based on hexyl dride/product product
isocyanate [%] [%] [%]
Turnover
Ratio anhy-
Ratio urea/ Total selec-
tivity [%]
Triethyl borate
26.6
21.3
32.0
25.9
4.9
6.2
23.4
31.9
0.7
1.0
7.5
9.0
30.9
40.9
73.4
78.7
15.9
15.1
2.1
2.4
82.0
82.5
Tetraethylammonium tetrafluoro-
borate
Tin(II)-laurate
21.8
20.5
20.2
25.2
25.9
26.6
26.3
24.0
25.3
23.5
25.0
6.3
6.2
6.2
5.4
5.4
5.3
5.3
5.6
31.9
32.8
32.9
32.4
32.9
33.4
33.5
33.7
0.9
1.0
1.0
1.1
1.3
1.3
1.0
1.2
9.3
9.1
9.1
9.7
9.3
9.2
9.9
9.8
41.2
41.9
42.0
42.1
42.2
42.6
43.5
43.5
78.2
79.5
79.8
76.3
77.2
78.8
78.9
77.3
15.3
14.8
14.7
12.8
12.9
12.5
12.3
12.8
2.2
2.4
2.4
2.7
3.1
3.0
2.3
2.8
82.6
82.8
83.0
84.5
84.0
84.6
85.4
84.5
HMDS (hexamethyldisilazane)
Without catalyst
Butylpyridinium tetrafluoroborate 23.7
Aluminium acetylacetonate
Sodium chloride
22.8
21.2
21.1
22.7
Aluminum triethylate
Butyl-pyridinium-hexafluorophos-
phate
Triethylamine
Methyl-butyl-imidazolium-tetra-
fluoroborate
21.8
17.5
24.4
27.9
5.6
5.2
34.4
35.6
1.2
1.2
9.7
8.6
44.1
44.2
78.2
82.5
12.6
11.7
2.6
2.7
84.8
85.6
DBTL (dibutyltin dilaurate)
Bismuth(III) 2-ethylhexanoate
DBN (1,5-diazabicyclo[4.3.0]non-
5-ene)
19.5
20.5
18.7
22.9
20.8
25.5
5.5
5.5
5.4
35.7
37.2
37.4
1.1
1.5
1.3
9.7
9.4
9.6
45.4
46.5
47.0
80.5
79.5
81.3
12.2
11.8
11.6
2.5
3.2
2.7
85.4
84.9
85.8
Lithium hexafluorophosphate
Cesium methylsulfonate
Potassium triflate
21.7
19.8
19.6
20.1
21.5
22.5
23.1
22.6
6.2
5.8
5.8
5.9
35.9
37.1
37.5
37.2
1.0
1.1
1.4
1.4
11.2
10.0
9.8
47.1
47.2
47.3
47.3
78.3
80.2
80.4
79.9
13.1
12.3
12.2
12.5
2.1
2.4
2.9
2.9
84.8
85.3
84.9
84.6
Methyl-butyl-imidazolium-hexa-
fluorophosphate
10.1
Bismuth(III) acetate
Sodium methylsulfonate
Zinc 2-ethylhexanoate
Lithium tetrafluoroborate
Pyridinium triflate
17.4
18.6
18.2
18.5
19.0
18.4
17.5
16.2
16.1
15.6
12.2
16.9
13.5
14.2
16.0
21.5
23.4
22.5
21.8
22.7
22.7
21.3
21.3
21.1
20.4
20.8
18.5
18.8
18.0
14.9
5.5
5.8
5.8
6.1
5.9
6.0
6.0
5.6
6.1
6.1
6.9
4.3
6.5
7.0
6.7
37.4
38.0
38.0
38.1
38.4
39.1
40.0
40.7
41.3
42.4
44.2
44.0
43.0
42.9
44.0
1.1
1.2
1.2
1.3
1.2
1.2
1.2
1.2
1.4
1.3
1.5
1.4
2.0
1.8
1.7
10.0
10.2
10.5
10.4
10.3
10.6
10.4
10.4
10.7
11.1
9.5
47.4
48.1
48.4
48.5
48.7
49.7
50.4
51.1
51.9
53.5
53.7
54.0
54.2
54.6
56.1
82.6
81.4
81.8
81.5
81.0
81.6
82.5
83.8
83.9
84.4
87.8
83.1
86.5
85.8
84.0
11.6
12.0
11.9
12.6
12.1
12.0
11.9
11.0
11.7
11.4
12.9
8.0
2.4
2.5
2.5
2.6
2.5
2.4
2.4
2.3
2.7
2.4
2.7
2.5
3.8
3.2
3.0
86.1
85.5
85.6
84.8
85.5
85.5
85.7
86.7
85.6
86.2
84.3
89.5
84.2
83.9
85.0
Sodium triflate
Lithium chloride
Bismuth(III) neodecanoate
Zinc triflate
Lithium triflate
Calcium phosphate
Copper(II) triflate
9.9
Titanium(IV) isopropoxide
Titanium(IV) 2-ethylhexoxide
Zirconium(IV) trifluoroacetyl-
acetonate
11.2
11.7
12.1
12.0
12.9
12.0
Zirconium(IV) 2-ethylhexanoate
Zirconium(IV) acetylacetonate
Scandium(III) trifluoromethan-
sulfonate
11.7
8.1
14.1
12.8
8.9
7.2
7.0
7.1
49.3
55.0
59.8
2.6
2.3
4.6
10.5
11.2
7.9
59.9
66.2
67.8
88.3
91.9
90.8
12.0
10.7
10.5
4.3
3.4
6.7
83.7
85.9
82.7
9.2
Calcium chloride
5.2
11.9
7.6
60.5
3.1
10.4
70.8
94.8
10.7
4.4
84.9

Table 1 (continued)
Catalyst
Hexyl
isocyanate
Hexanoic
acid
Carboxylic
acid anhy-
dride
Amide
Dihexyl
urea
Acyl
urea
Sum amide
plus acyl urea based on hexyl dride/product product
isocyanate [%] [%] [%]
Turnover
Ratio anhy-
Ratio urea/ Total selec-
tivity [%]
Scandium(III) acetate hydrate
Calcium perchlorate
3.9
0.4
2.0
8.2
4.9
2.7
7.7
8.6
7.9
64.0
73.9
72.1
4.3
6.3
5.7
9.5
4.4
6.9
73.5
78.3
79.0
96.1
99.6
98.0
10.5
11.0
10.0
5.8
83.7
81.0
82.9
8.1
7.2
Calcium bis-(2,2,6,6-tetramethyl-
3,5-heptanedionate)
Calcium stearate
0.0
1.1
0.0
0.0
0.0
0.3
7.2
1.3
2.4
0.0
0.4
1.2
8.3
8.1
6.4
6.7
6.8
6.4
74.3
76.1
82.2
82.2
82.9
83.0
5.9
8.0
8.3
8.8
9.0
9.0
4.7
4.0
0.3
0.3
0.4
0.4
79.1
80.1
82.5
82.6
83.3
83.3
100.0
98.9
10.5
10.1
7.8
7.4
10.0
10.0
10.7
10.8
10.8
82.1
79.9
82.2
81.3
81.1
81.6
Lanthanum(III) acetate hydrate
Magnesium n-propoxide
Magnesium acetylacetonate
Magnesium stearate
100.0
100.0
100.0
99.7
8.1
8.2
Magnesium trifluoromethyl-
sulfonate
Magnesium chloride
7.6
0.0
1.7
0.8
2.7
6.4
6.0
83.8
82.8
8.4
6.7
0.3
2.4
84.1
85.2
100.0
98.3
7.6
7.1
10.0
7.9
82.5
85.0
Ytterbium(III) trifluoromethyl-
sulfonate
Magnesium perchlorate
0.0
2.3
5.3
85.4
6.8
0.3
85.7
100.0
6.2
7.9
85.9
Table 2. Reaction within 30 min
Catalyst
Hexyl
isocyanate
Hexanoic
acid
Acid
anhydride
Amide Dihexyl urea Acyl urea Sum amide
plus acyl urea
Turnover
Ratio anhy-
based on hexyl dride/products products
Ratio urea/ Total selec-
tivity [%]
isocyanate [%]
[%]
[%]
Without catalyst
Butylpyridinium tetra-
fluoroborate
37.7
38.3
42.5
72.6
3
2.8
11.5
12.3
1.4
1.8
3.1
3.7
14.6
16
62.3
61.7
20.5
17.5
9.6
69.9
71.3
11.3
11.4
DBTL (dibutyltin
dilaurate)
37.3
39.5
3.1
13.7
2
4
17.6
62.7
17.6
71.0
Zinc 2-ethylhexanoate
Calcium stearate
Ytterbium trifluoro-
methylsulfonatea
Magnesium stearatea
36.1
15.3
1.6
40.5
13.1
18.5
3.1
8.6
6.3
13.8
51.3
64.5
2
4.1
5.3
1.7
17.9
56.5
66.3
63.9
84.7
98.4
17.3
15.2
9.5
11.2
9.4
71.5
75.4
80.1
5.3
6.9
10.4
2.9
1.9
9.7
74.1
9.3
0.7
74.9
97.1
13.0
12.4
74.6
a Reaction was complete after 10 min.

C. G€urtler, K. Danielmeier / Tetrahedron Letters 45 (2004) 2515–2521
2519
Mg
O
O
O
13C
+
O
HO
N
H
O
N
- CO2
O
N
H
Scheme 2. The reaction of carboxylic acids with isocyanates.
aliphatic carboxylic acid using the approach described
above (Scheme 3).
towards the amide and its follow up product, the
acyl urea, was achieved with magnesium perchlorate
(or any of the other magnesium catalysts). Other
catalysts led to larger amounts of side products.
The formation of acyl ureas is unfavoured due
to steric hindrance and the stoichiometry used
(Table 3).
The order of catalytic activity as outlined in Table 1 is
about the same in this case. Interestingly, the selectivity
of the reaction increases strongly with higher reaction
rates. The fastest reaction and highest selectivity
O
O
O
+
N
N
O
+
N
H
- CO2
HO
O
Scheme 3. Reaction of cyclohexyl isocyanate with hexanoic acid.
Table 3. Reaction of a cyclic isocyanate with a linear aliphatic carboxylic acid
Catalyst
Cyclohexyl Hexanoic Acid
isocyanate acid anhydride
Amide Dicyclo-
hexyl urea
Acyl Sum amide + Ratio dicyclo- Ratio
urea acyl urea
Total
selectivity
hexyl urea/
product [%]
anhydride/
products [%]
Without
catalyst
35.9
34.1
34.3
25.2
26.6
25.9
5.7
6.2
6
16.7
17.2
17.6
5.8
5.6
5.6
3.4
3.5
3.7
22.5
22.9
23.2
25.8
24.7
24.1
25.3
26.9
25.9
48.9
48.4
50
Aluminum
triethylate
DBTL
(dibutyltin
dilaurate)
Bismuth(III) 33.6
acetate
26.8
30.5
30.2
29.9
23.1
17.3
6.6
5.9
6.7
17.7
18.5
17.9
20.9
24.4
30.7
62.1
65.1
79.4
83.5
5.6
5.4
6.6
6.4
7.6
8.1
8.2
8
3.7
2.8
3.1
2.9
3.3
2.8
1.7
1.6
0.5
0.2
23.3
23.9
24.5
27.3
32
24
25.3
27.8
25.6
24.6
22.5
21.6
16.1
14.8
10.6
6
50.7
49.6
47.4
51.9
53.7
57.5
72.2
74.2
81.8
86.2
Sodium
triflate
30
22.6
27
Potassium
triflate
31
6.3
Triethyl-
amine
27.2
26.8
6.7
23.5
23.8
20.9
11.6
10.9
7.6
Lithium
triflate
7.2
Zinc 2-ethyl- 24.7
hexanoate
8.4
38.8
70.2
73.1
86
Calcium
3.9
5.2
0
11.3
10.8
9.1
perchlorate
Calcium
stearate
0.6
Magnesium
stearate
0
6.6
7.1
Magnesium
perchlorate
0
4.1
5.4
90.6
7.9

2520
C. G€urtler, K. Danielmeier / Tetrahedron Letters 45 (2004) 2515–2521
5. Reaction of a sterically hindered aliphatic carboxylic
acid (cyclohexyl carboxylic acid) with an aliphatic iso-
cyanate
As in the reactions previously described, magnesium
salts showed the greatest catalytic activity, followed by
calcium salts. In addition, they contributed to a
remarkable increase in selectivity towards the formation
of the (desired) amide. However, the acylation reaction
of cyclohexyl butylamide with cyclohexane carboxylic
acid is also catalysed (Scheme 4).
From the previous investigations it is known, that ste-
rically crowded carboxylic acids substituted at the
a-carbon only react very reluctantly with isocyanates.
As a test reaction we chose the reaction of cyclohexane
carboxylic acid with butyl isocyanate.
A certain amount of cyclohexane carboxylic acid
anhydride is formed as a side product. As a background
reaction of the noncatalysed reaction, the reaction of
dibutyl urea with butyl isocyanate to give the corre-
sponding biuret takes place. Catalysts that had some
activity in the reaction between a linear aliphatic iso-
cyanate with a linear aliphatic carboxylic acid are
almost nonactive in the reaction outlined above.
This reaction was also investigated using a multiparallel
approach. No additional solvent was added. The reac-
tion was performed at 75 °C for 2 h. The higher tem-
perature was necessary to start the reaction and the
results are summarised in Table 4.
Table 4. Reaction of cyclohexane carboxylic acid with butyl isocyanate
Catalyst
Butyl iso-
cyanate
Cyclohexane Amide Dibutyl Cyclohexane Dibutyl urea Acyl N-Butyl-di
Ratio anhy-
dride/product
[%]
carboxylic
acid
urea
carboxylic
acid anhy-
dride
biuret
urea cyclohexyl
imide
Butyl-pyridinium-
tetrafluoroboratea
Bismuth(III)
12.7
12.4
29.3
28.4
26.1
26.7
12.6
12.6
12.4
0.3
0.3
0.2
0.2
48.2
46.3
12.4
acetatea
Triethylaminea
DBTL (dibutyltin
dilaurate)a
13.1
12.3
28.7
28.9
27
27.1
12.6
12.3
12
12.9
0.3
0.3
0.2
0.2
46.6
45.5
DBUa
12.8
12
29.6
28.4
27.2
27.3
12.5
12.8
12.2
12.7
0.3
0.3
0.2
0.2
46.1
46.7
Zinc 2-ethylhexa-
noatea
Tin(II) lauratea
Aluminium
triethylatea
12.6
11.4
29.2
27.9
27.5
28.4
12.4
13.1
12.2
12.9
0.3
0.3
0.2
0.2
45.1
46.2
Without catalysta
Sodium triflatea
Potassium triflatea
Lithium triflatea
Calcium chloride
Ytterbium trifluoro-
methylsulfonate
Calcium perchlorate
Calcium stearate
Magnesium stearate
Magnesium
11
12
27.5
28
28.7
28.8
29.1
29.5
56.2
59.3
13.1
12.5
12.8
13
12.9
11.7
11.9
13.2
7.6
0.3
0.3
0.3
0.3
0.3
0.3
0.2
0.2
0.2
0.3
0.5
0.4
45.6
43.6
43.9
44.2
30
11.9
10.6
0.9
1.5
28
26.8
10.9
9.1
4.1
3.8
16.9
15.1
6.2
25.5
0.8
0.2
0
9.1
9
59.5
59.8
66.7
74.5
5.2
5.2
7.5
5.2
16.7
16.8
14.4
12.1
5.5
5.5
0.6
0.6
0.5
0.4
1.5
1.1
0.7
0.8
2.4
1.9
28
28
4.6
4.6
21.6
16.2
0
perchlorate
a In these cases a comprehensive interpretation of the experimental results was difficult since the amide and the dibutyl urea cannot be separated using
SFC. The figures are therefore approximate.
O
O
O
O
OH
+
O
N
+
N
N
H
- CO2
O
O
O
N
N
N
+
H
O
N
H
Scheme 4. Reaction of butyl isocyanate with cyclohexane carboxylic acid.

C. G€urtler, K. Danielmeier / Tetrahedron Letters 45 (2004) 2515–2521
2521
6. Conclusion
Acknowledgements
In an investigation of the reaction of isocyanates with
aliphatic carboxylic acids highly active catalysts could
be identified. In particular, magnesium and calcium salts
exhibited considerable catalytic activity. These catalysts
are equally active in the reaction of linear aliphatic
isocyanates with secondary aliphatic carboxylic acids
and in the reaction of secondary aliphatic isocyanates
with linear aliphatic carboxylic acids. In these cases a
remarkable increase in selectivity was observed. The
amount of side products produced by each catalyst for
each reaction also has to be taken into account.
We would like to thank our technicians Volker Marker
and Klaus Jagusch for their kind support in doing this
study.
References and notes
1. Babusiaux, P.; Longeray, R.; Dreux, J. Liebigs Ann. Chem.
1976, 487.
2. Schotmann, A. H. M.; Mijs, W. J. Recl. Trav. Chim. Pays
Bas 1992, 111, 88.