Efficient and scaleable methods for ω-functionalized nonanoic acids: Development of a novel process for azelaic and 9-aminononanoic acids (nylon-6,9 and nylon-9 precursors)

Article abstract of DOI:10.1021/op000081j

A new, convergent synthesis and process of the title open-chain C-9 compounds, valuable monomers for preparation of polyamides with specific properties, are discussed. Starting from relatively inexpensive raw materials, for example, cyclohexanone and activated C-3 olefins, the method provides polymer grade co-functionalized nonanoic acids. An improved protocol for cyanoethylation or carbalkoxyethylation of cyclohexanone in the presence of a catalytic amount of primary or secondary amines gave 3-(2-oxo-cyclohexane) propanecarboxylic acid derivatives 1 in high yield. Cyclohexaneperoxycarboxylic acid (CHPCA) is introduced as highly efficient reagent in Baeyer-Villiger rearrangement of 1. Pyrolysis of 2 (EWG = CN) afforded under optimized conditions 3 in high yield and regioisomeric purity, otherwise a mixture of three unsaturated isomeric ω-cyano nonenoic acids is obtained. Partial hydrogenation of unsaturated acids 3 allowed isolation of saturated long-chain difunctionalized acids 4. Hydrolysis of 4 led to 1,9-nonanedicarboxylic acid (azelaic acid) 5, whereas its hydrogenation at elevated pressure gave 9-aminononanoic acid 6. Alternatively, a practical four-step syntehsis of 5 via isolable 7-substituted oxepan-2-one (EWG = COOMe) 2 has been designed and experimentated. The versatile position of 3-(2-oxo-cyclohexane) propanecarboxylic acid derivatives 1 as raw materials for Fine Chemicals is also discussed.

Full text of DOI:10.1021/op000081j

Organic Process Research & Development 2001, 5, 69−76
Efficient and Scaleable Methods for ω-Functionalized Nonanoic Acids:
Development of a Novel Process for Azelaic and 9-Aminononanoic Acids
(Nylon-6,9 and Nylon-9 Precursors)
Livius Cotarca,* Pietro Delogu, Alfonso Nardelli, Paolo Maggioni, Roberto Bianchini, Stefano Sguassero, Stefano Alini,†
Roberto Dario, Giuliano Clauti, Giorgio Pitta, Gianpaolo Duse, and Fabrizio Goffredi
CAFFARO SpA, 33050 TorViscosa (UD), Italy
Abstract:
The versatility of linear polyamides in the manufacture
of various products ranging from synthetic textiles to
electronic components, from packaging film to structural
elements induced a large and continuous interest for more
efficient synthesis of suitable monomers of their manufactur-
ing.2
The polyamides 6 and 6,6 are the most popular as well
as their monomers, caprolactam, adipic acid and hexameth-
ylenediamine, which are important products of the petro-
chemical industry.
Polyamides from long-chain amino acids in which the
polar groups are separated by at least four methylene groups
can yield materials that form fibers with superior properties.
Long-chain polyamides have found “niche” applications
requested by specific physicomechanical characteristics of
the polymer. The consumptions of long-chain polyamides
in the past decade were around 100 000 mt/year at the growth
rate of 8% per year. The past decade prices ranged from the
$7.3/kg of nylon-6,12 to the $10.6/kg of nylon-11.
Long-chain nylons are characterized by a ratio between
methylenic and amidic groups higher than nylon-6 and -6,6.
That enhances all polyethylene-like properties, as low water
absorption, dimensional stability under different conditions
of humidity, impact strengths, good behavior at low tem-
peratures, low density, low softening points, and lower
hydrolysis sensitivity, while some properties of polyamide
are maintained, like high melting points, good aesthetic
properties, good processability, and resistance to hydrocarbon
solvents.
A new, convergent synthesis and process of the title open-chain
C-9 compounds, valuable monomers for preparation of poly-
amides with specific properties, are discussed. Starting from
relatively inexpensive raw materials, for example, cyclohex-
anone and activated C-3 olefins, the method provides polymer
grade ω-functionalized nonanoic acids. An improved protocol
for cyanoethylation or carbalkoxyethylation of cyclohexanone
in the presence of a catalytic amount of primary or secondary
amines gave 3-(2-oxo-cyclohexane) propanecarboxylic acid
derivatives 1 in high yield. Cyclohexaneperoxycarboxylic acid
(CHPCA) is introduced as highly efficient reagent in Baeyer-
Villiger rearrangement of 1. Pyrolysis of 2 (EWG ) CN)
afforded under optimized conditions 3 in high yield and
regioisomeric purity, otherwise a mixture of three unsaturated
isomeric ω-cyano nonenoic acids is obtained. Partial hydrogen-
ation of unsaturated acids 3 allowed isolation of saturated long-
chain difunctionalized acids 4. Hydrolysis of 4 led to 1,9-
nonanedicarboxylic acid (azelaic acid) 5, whereas its hydrogen-
ation at elevated pressure gave 9-aminononanoic acid 6.
Alternatively, a practical four-step syntehsis of 5 via isolable
7-substituted oxepan-2-one (EWG ) COOMe) 2 has been
designed and experimentated. The versatile position of 3-(2-
oxo-cyclohexane) propanecarboxylic acid derivatives 1 as raw
materials for Fine Chemicals is also discussed.
Introduction
Altough polymer synthesis is almost completely atom-
efficient, monomer synthesis cannot be expected to be so
perfect. Because monomers are produced in such large
amounts, every effort has been made to maximize their yield
and purity. Remarkable success has been achieved in creating
high-purity, polymerization-grade monomers in enormous
volumes. The concept of atom economy for organic reactions
proposed by B. Trost teaches that, for economical and
ecological reasons, organic synthesis should be atom-
efficient; in other words, all reagents used should end up in
the final product. Ideally, there would be no waste streams,
and maximum use would be made of available resources.
Addition and cycloaddition reactions of organic molecules
are the most representative pathways to realize this concept.1
This set of properties allows the use of long-chain nylons
in applications forbidden for nylon-6 and -6,6 types, despite
their higher prices. As a consequence, nylon-11 and -12 are
particularly attractive as engineering polymers, and for
special technical applications, where the improved mechan-
ical properties, such as toughness, flexional strengths,
abrasion resistance, and dimensional stability are highly
desirable for the manufacture of precision engineering
components.
Looking to the long-chain polyamides, those based on
the C-9 chain seem to have interesting properties. The ratio
between methylene groups, conferring hydrophobicity to the
polymer and amide groups, giving hydrophilic properties,
* Corresponding author. Present address: Zambon Group SpA, 36045
Almisano di Lonigo (VI), Italy. Telephone: +39 0444 726 222. E-mail:
livius.cotarca@zambongroup.com.
(1) (a) Trost, B. Science 1991, 54, 1471. (b) Hall, H. K., Jr. CHEMTECH
1997, 27, 6.
(2) Kohan, M. I. Polyamides. In Ullmann’s Encyclopedia of Industrial
Chemistry, 5th ed.; VCH: Weinheim, 1985; Vol. A 21; p 180.
† Present address: Radici Chimica SpA, Via Fauser 50, 28100 Novara, Italy.
10.1021/op000081j CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Published on Web 12/14/2000
Vol. 5, No. 1, 2001 / Organic Process Research & Development
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is still high, and therefore water is absorbed in moderate
amounts. Their melting points, depending on the chain length,
are still too high to afford high operation temperature of
derived polymer. The above physical properties induce a
dimensional stability and use in the manufacturing of
precision components.
Nylon-9 was commercialized in the former Soviet Union.
It was made there by the polycondensation of 9-amino-
nopelargonic acid and went under the trade name “Pelar-
gon”.
The most important monomers of long-chain polyamides
are the ω-amino acids, their corresponding lactams, or the
ω-dicarboxylic acids and ω-diamines. Industrial applications
have found for example, 11-aminoundecanoic acid for nylon-
11, laurolactam for nylon-12, hexamethylenediamine and
azelaic or sebacic acids as comonomers for nylon-6,9 and
nylon-6,10, respectively.
The main C-9 monomers are 1,9-nonanedioic acid (azelaic
acid) and 9-aminononanoic acids (9-aminopelargonic acid).
ω-Functionalized nonanoic acids have been the subject of
active preparative investigations as they are important
monomers and comonomers for polyamides with specific
properties and applications2 and are also used as raw
materials for complex ester oils and lubricants4 as principal
components in alkyd resin preparation5 or as pharmaceutical
intermediates.6
Synthetic Approaches to Acid Monomers. Odd-
numbered carbon acids are rare in nature and in industrial
chemistry. Azelaic and pelargonic are the most accessible.
As an interesting characteristic it appears that odd-numbered
carbon acids are more surface active than are those with an
even number.
Even the most simple non-R-amino carboxylic acids, for
example, (3-amino propanoic acid-â-alanine-4-amino-
butanoic acid, also known as γ-aminobutyric acid (GABA),
5-aminopentanoic acid, known as δ-aminovaleric acid
(DAVA), are important compounds. The synthetic ap-
proaches to non-R-amino acids basically relay on functional
group exchange strategy and substituent refunctionalization
of cyclic precursors3
The commercial-scale manufacture of the above ω-amino
or alkanoic acids falls into two logical approaches.
The first one is of fragmentation type: long-chain
compounds can be fragmented and simultaneously function-
alized to difunctionalized compounds. The raw materials are
generally derived from agriculture. Synthesis of 11-amino-
undecanoic and sebacic acids from castor oil and the
synthesis of azelaic acid from tallow oil via oleic acid by
ozonolysis are examples of this approach.
The second approach is of convergent type: the alkane
chain is built up from low molecular weight fragments
starting from inexpensive petrochemical raw materials.
Synthesis of laurolactam starting from cyclododecatriene
obtained by the butadiene trimerization is a good example
of this approach.
Azelaic Acid. The class representative, 1,9-nonanedioic
acid is produced commercially by the ozone oxidation of
oleic acid (Henkel-Emery process),7 and it is the preferred
aliphatic dicarboxylic acid for preparation and modification
of high molecular weight polymers.4 Oleic acid may be
cleaved at the double bond by treatment with ozone from
an electrical discharge. Ozonolysis gives a mixture of crude
8-carboxyoctanealdehyde and pelargonic aldehyde. The next
step is the oxidation of aldehydes to pelargonic and azelaic
acids as well as other oxidation products. The process ends
with several clean up operations.
Reported Routes to 9-Aminononanoic Acid (and Nylon-
9). Although 9-aminononanoic acid is a compound which
has been known for a century,8 very few routes were
available (and only at high cost) until now for its commercial
production. On a laboratory scale, the preparation and
purification of 9-aminononanoic acid is complicated and
difficult.11 Laboratory methods starting either from ω-
halogenated9a or from ω-nitro derivatives9b have been studied;
however, neither precursor is easily available. Flaschen-
trager12 prepared 9-aminononanoic acid by performing the
Hoffmann degradation reaction on sebacic acid. Reductive
ozonolysis, reductive ammination, and ammonolysis of
olefins from soybean oil10a-f,19 (Scheme 1) and methods that
(7) (a) Goebel, C. G. U.S. Patent 2,813,113, 1957; Chem. Abstr. 1958, 52,
2431i. (b) Bogdanova, N. A.; Kolesov, M. L. Zh. Khim. Promisl. 1978, 4,
49, Chem. Abstr. 1978, 88, 191525. (c) Heins, A.; Withaus, M. Henkel-
Referate 1984, 20, 42.
(8) Baruch, J. Chem. Ber. 1894, 27, 175
(9) (a) Asahi Chem. Ind., Belg. Pat. 627,723, 1963; Chem. Abstr. 1964, 60,
9154c. (b) Jegorow, A. J. Prakt. Chem. 1932, 86, 530.
(10) (a) Pollart, K. A.; Miller, R. E. J. Am. Chem. Soc. 1962, 27, 2392. (b)
Miller, W. R.; Pryde, E. H.; Moore, D. J.; Awl, R. A. Am. Chem. Soc.,
DiV. Org. Coat. Plast. Chem. Prepr. 1967, 27, 160. (c) W. L. Kohlhase,
Pryde, E. H.; Cowan, J. C. J. Am. Oil Chem. Soc. 1970, 47, 183. (d) W. L.
Kohlhase, Pryde, E. H.; Cowan, J. C. J. Am. Oil Chem. Soc. 1971, 48,
265. (e) Miller, W. R.; Pryde, E. H.; Awl, R. A.; Kohlhase, W. L.; Moore,
D. J. Ind. Eng. Chem. Prod. Res. DeV. 1971, 4, 442. (f) Perkins, R. B.;
Roden, J. J.; Pryde, E. H. J. Am. Oil Chem. Soc. 1975, 52, 473. (g) Pied,
J.-P. Ann. Chim. 1960, 469. (h) Anders, D. E.; Pryde, E. H.; Cowan, J. C.
J. Am. Oil Chem. Soc. 1965, 42, 824. (i) Miller, W. R.; Pryde, E. H.; Moore,
D. J.; Awl, R. A. Am. Chem. Soc., DiV. Org. Coat. Plast. Prepr. 1967,
27(2), 160. (j) Baoren, W.; Yuhuai, W.; Youxiong, W. Gaofenzi Tongxun
1984, 1, 27; Chem. Abstr. 1984, 101, 8575r.
(3) Smith, M. B. Methods of Non-R-amino Acid Synthesis; Marcel Dekker:
New York, 1995; p 1
(11) Aharoni, S. M. n-Nylons: Their Synthesis, Structure and Properties; John
Wiley & Sons: New York, 1997; p 381.
(4) (a) Cornils, B.; Lappe, P. Dicarboxylic Acids, Aliphatic. In Ullmann’s
Encyclopedia of Industrial Chemistry, 5th ed.; VCH: Weinheim, 1985;
Vol. A 8; p 523. (b) Brockmann, R.; Demmering, G.; Kreutzer, U.;
Lindemann, M.; Plachenka. J.; Steinberner, U. Fatty Acids. In Ullmann’s
Encyclopedia of Industrial Chemistry, 5th ed.; VCH: Weinheim, 1985;
Vol. A 10; p 271. (c) Klamann, D. Lubricants and Related Products. In
Ullmann’s Encyclopedia of Industrial Chemistry, 5th ed.; VCH: Weinheim,
1985; Vol. A 15; p 438.
(5) Lin, K. F. Alkyd Resins. In Kirk-Othmer Encyclopedia of Chemical
Technology, 4th ed.; John Wiley & Sons: New York, 1992; Vol.2, p 57.
(6) (a) Matsumoto, I.; Hidaka, H.; Ito, Y.; Aoki, N. Br. Patent 1,498,996, 1978;
Chem. Abstr. 1978, 89, 108193s. (b) Kaplan, J.-P. German Patent DE
3,242,442, 1983; Chem. Abstr. 1983, 99, 104980e.
(12) Flaschentrager, B. Z. Physiol. Chem. 1926, 159, 297.
(13) Coffman, D. D.; Cox, N. L.; Martin, E. L.; Mochel, W. E.; Van Natta, F.
J. J. Polymer Sci. 1948, 3, 85.
(14) Hill, J. W.; Carothers, W. H. J. Am. Chem. Soc. 1932, 54, 1570.
(15) Flaschentrager, B.; Gebhardt, F. Z. Physiol. Chem, 1930, 192, 250.
(16) Pryde, E. H.; Cowan, J. C. J. Am. Oil Chem. Soc. 39, 496, 1962.
(17) (a) Nesmeyanov, A. N.; Stepikheev, A. A. Chem. Technol. 1957, 9, 139.
(b) Nesmeyanov, A. N.; Freidlina, R. K. J. Gen. Chem. USSR 1957, 27, 9,
2418. (c) Nesmeyanov, A. N.; Freidlina, R. K. Tetrahedron 1962, 17, 65.
(18) Vofsi, M.; Ascher, E.; Levy, H.; Rosin, H.; Vofsi, D. Ind. Eng. Chem.
Prod. Res. DeV. 1963, 55(2), 121.
(19) Ravve, A. Organic Chemistry of Macromolecules; Marcel Dekker, New
York, 1967; p 278.
70
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Scheme 1. Ozonolysis and reductive amination route to
Scheme 3. Nylon-9 and nylon-9,9 monomers
nylon-9
Scheme 2. Redox-radicalic route to 9-aminononanoic acid
Scheme 4. Chemistry of the new process
imply either elongation (e.g., telomerization17,18 or shortening
of the chain length have been also published.10g,13-16
We now report the five-step synthesis of two ω-func-
tionalized derivatives of nonanoic acid, starting from easily
available C-6 and C-3 synthons (Scheme 4).
Starting from an isolable and pure cyclic precursor, the
corresponding lactone, we were able to find a route to the
difunctionalized saturated linear compounds. The lactone
cyclic precursor was easily accessible by a convergent
process, for example, by a coupled Stork addition and
Baeyer-Villiger rearrangement. The initial steps are notably
improved as compared to the described procedures, and the
whole method is operable on the large scale.
Cyclohexanone Alkylation by Electophilic Olefins.
Numerous investigators have found that the base-catalyzed
Michael addition of acrylonitrile to active hydrogen com-
pounds leads to the formation of polycyanoethylated deriva-
tives as the main reaction products. The requirement for a
strongly basic catalyst (such as sodium methoxide) precludes
the use of reactants having base-sensitive functional groups
and can result in side reaction such as aldol condensations.
The reactions are, moreover, strongly exothermic, thus
necessitating special precautions for removing the reaction
heat when the reactions are carried out on a technical scale.
Excellent alternatives to base-catalyzed condensation of
electrophilic olefins with cyclanones having active hydrogen
atoms are: (a) Stork’s procedure using tertiary enamines,22
and (b) Michael-type R-alkylation using imine derivatives
reacting as their secondary enamine tautomers23
Results and Discussion
Minisci and co-workers proposed a convergent route to
azelaic and 9-aminononanoic acid, starting from cyclohex-
anone and acrylonitrile.21 The intermediate addition product,
3-(2-oxocyclohexane)propionitrile can be oxidized by hy-
drogen peroxide and Fe2+/Cu2+ salts as catalyst to give
8-cyanooctenoic acid (Scheme 2). Further conversion of
nitrile group by hydogenation or hydrolysis led to the desired
product. The above reaction sequence presents important
economical advantages and easy access to the raw materials.
This “discovery method” has been extensively examined in
our laboratory to find a scalable route to the amino acid.
Unfortunately, the method as originally reported failed to
be developed as: (i) the hydrogen peroxide oxidation was
not selective, and a complex mixture of hydroxy acids was
formed from hydroperoxide intermediates; (ii) the work up
to isolate the oxidation intermediate was complicated, and
we did not succeed to recover it from the aqueous medium;
(iii) a high amount of catalyst salts was necessary, and
therefore much work had to be done to solve mixing
problems.
Improving the selectivity of the oxidation step was
therefore the entrance key to a scalable process. This new
versatile process is able to produce both monomers of
nylon-9 and nylon-6,9, for example, azelaic acid (or its
esters) and 9-aminononanoic acid (or its esters), through the
new key intermediate 8-cyanooctanoic acid (Scheme 3).
However, until now, literature concerning the one-step
catalytic enamine alkylation of cycloalkanones is still
limited.24 The reported methods,25a-f required a two-step
(22) (a) Stork, G.; Terrell, R.; Szmuszkovitz, J. J. Am. Chem. Soc. 1954, 76,
2029. (b) Stork, G.; Landesman, H. K. J. Am. Chem. Soc. 1956, 78, 5129.
(c) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovitz, J.; Terrell, R.
J. Am. Chem. Soc. 1963, 85, 207.
(23) Pfau, M.; Ughetto-Monfrin, J. Tetrahedron,1979, 35, 1899; Pfau, M.;
Tomas, A.; Lim, S.; Revial, G. J. Org. Chem. 1995, 60, 1143.
(24) Krimm, H. U.S. Patent 2,850,519, 1958; Chem. Abstr. 1960, 53, 14026a.
(20) (a) Pryde, E. H.; Cowan, J. C. J. Am. Oil Chem. Soc. 1962, 39, 496. (b)
Anders, D. E.; Pryde, E. H.; Cowan, J. C. J. Am. Oil Chem. Soc. 1965, 42,
824. (c) Miller, W. R.; Pryde, E. H.; Moore, D. J.; Awl, R. A. Am. Chem.
Soc., DiV. Org. Coat. Plast. Prepr. 1967, 27(2), 160.
(21) Minisci, F.; Maggioni, P.; Citterio, A. U.S. Patent 4,322,547, 1982 and
German Patent DE 3,027,111, 1981, Chem. Abstr. 1981, 94, 191709.
Vol. 5, No. 1, 2001 / Organic Process Research & Development
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71

Scheme 5. Michael-type monoalkylation of cyclohexanone
by distillation in a vacuum, and the fraction containing water,
cyclohexanone, and N-alkylated pyrrolidine was recycled.
Development of the process involved significant improve-
ments regarding suppression of cyclohexanone self-aldol
condensation, olefin polymerization, and amine alkylation
by the olefin.
The catalytic variant of Michael-type imine alkylation has
the advantage that it can also be performed in continuous
mode, which comprises running the reaction in two stages,
first at 70-80°, then at 130 °C. Cyclohexanone, acrylonitrile,
and the catalyst (molar ratio 2:1:0.15) were simultaneously
fed into the first reactor at 70-80 °C. Then the reaction
mixture was continuously transferred into a continuous stirred
tank reactor, preheated at 130°, residence time of 2 h, thus
allowing nearly quantitative conversion of the olefin and
yield of isolated δ-keto nitrile 1 of 92%. Continuous
distillation of the reaction mixture afforded separation of the
main product stream, a recycle stream containing the catalyst,
and the purge.
Scheme 6. Catalytic alkylation of cyclohexanone by methyl
acrylate in the presence of pyrrolidine
Baeyer-Villiger Oxidation. Regioselective Baeyer-
Villiger rearrangement of 1 was best performed using an
n-hexane solution of cyclohexaneperoxycarboxylic acid
(CHPCA).
CHPCA is an oxidising agent recently developed in our
laboratory.26a,d It has the advantage over short-chain aliphatic
peracids to be substantially immiscible with water, less
shock-sensitive, and nondeflagrating. CHPCA can be pro-
duced more cheaply than many other known peracids that
already have wide applications in preparative and industrial
organic chemistry. Organic solutions of CHPCA are safer
on both small- and large-scale operations. We prepared
solutions of CHPCA in n-hexane, cyclohexane, or cyclo-
hexanecarboxylic acid (CHCA) by a modified Swern
procedure26d,27 avoiding dangerous isolation of the solid
product. The loss of available oxygen content of a 1 M
solution of CHPCA in cyclohexanecarboxylic acid was less
than 2% after 48 h at 50 °C.
CHPCA offered significant advantages in the process
scale up. It can be produced in situ from the commercially
available parent acid, which is recycled, and hydrogen
peroxide, avoiding hazardous storage and handling (ship-
ment). CHPCA/CHCA couple shows interesting oxidation
behavior. The parent acid, CHCA, has melting point of 28
°C and is therefore liquid at temperatures slightly above
ambient; it can be simultaneously used as reagent and solvent
of peracid. It is immiscible with water, and consequently it
can be prepared in biphasic system, and the peracid can be
recovered in the organic phase by simple phase separation.
Azeotropic distillation at low temperature and pressure
affords the preparation of anhydrous peracid organic solution.
The peracid preparation has been scaled up in a continu-
ous process, and the peracid stream has the operating
concentration below 20%. The active oxygen content was
continuously monitored to ensure the reaction and processing
outside the detonable area.
reaction involving enamine formation with equimolecular
quantities of amine and hydrolysis of C-alkylated imine,
respectively.
By our method,26a-e the R-alkylation of cyclohexanone
by acrylonitrile was carried out in the presence of cyclo-
hexylamine/acetic acid as a catalytic system, at 130 °C. GC-
MS monitoring of reaction progress at 60-90 °C revealed
the very selective formation of 1 via intermediary imine
compounds 7 and 9 (Scheme 5). In the final stage formation
of N,N-di(â-cyanoethyl)cyclohexylamine has been also ob-
served.
High yields (92-95%) and selectivities of 3-(2-oxo-
cyclohexane)propanoic acid alkyl esters (1a, 1b) have been
obtained when pyrrolidine was used as catalyst and with
methyl or ethyl acrylate as the olefins (Scheme 6).
Moreover, we observed that using a recycled distillation
fraction containing controlled amount of water, cyclohex-
anone and N-alkylated pyrrolidine [e.g., alkyl (Me or Et)
3-(N-pyrrolidino) propionate], and neutral pH, high yields
(94%) of δ-ketoesters 1a or 1b were obtained. Pyrrolidine
or alkyl (Me or Et) 3-(N-pyrrolidino) propionates have been
used as catalysts to prepare compounds 1a or 1b, according
to the method described for 1. Crude product was isolated
(25) (a) Stork, G.; Terrell, R.; Szmuszkovitz, J. J. Am. Chem. Soc. 1954, 76,
2029. (b) Stork, G.; Landesman, H. K. J. Am. Chem. Soc. 1956, 78, 5129.
(c) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovitz, J.; Terrell, R.
J. Am. Chem. Soc. 1963, 85, 207. (d) Whitesell, J. K.; M. A. Whitesell.
Synthesis 1983, 517. (e) Hickmott, W. P.; Rae, B. S. Afr. J. Chem. 1988,
4 (13), 85. (f) Mammadi, M.; Villemin, D. Synth. Commun. 1996, 26(15),
2901.
(26) (a) Cotarca, L.; Bianchini, R. U.S. Patent 5,670,661, 1996 and PCT Int.
Appl. WO 94 29,294, 1994; Chem. Abstr. 1995, 122, 187420q. (b) Cotarca,
L.; Maggioni, P.; Nardelli, A.; Sguassero, S. U.S. Patent 5,917,067, 1996
and PCT Int. Appl. WO 94 29,258, 1994; Chem. Abstr. 1995, 122, 186960d.
(c) Cotarca, L.; Maggioni, P.; Nardelli, A. U.S. Patent 5,872,267, 1996.
(d) Cotarca, L.; Delogu, P.; Maggioni, P.; Nardelli, A.; Bianchini, R.;
Sguassero, S. Synthesis 1997, 328. (e) Cotarca, L.; Delogu, P.; Maggioni,
P.; Nardelli, A.; Bianchini, R.; Sguassero, S. Chim. Ind. 1996, 78, 845.
The main reaction product, 7-(â-cyanoethyl)oxepan-2-one,
2a (Scheme 7) is slightly soluble in an n-hexane solution of
(27) Swern, D.; Clements, A. H.; Luong, T. M. Anal. Chem. 1969, 41, 412.
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Scheme 8. Pyrolysis of 7-(â-cyanoethyl)oxepan-2-one
Scheme 9. Pyrolysis of 7-(â-cyanoethyl)oxepan-2-one at
lower temperature
hexandioic, pentandioic, and heptandioic acid, respectively
(Bayer test).
Figure 1. Liquid-liquid equilibrium of the n-hexane-
CHCA-7 cyanoethylcaprolactone at 50 °C.
As regarding the process, the three unsaturated acids are
all useful precursors of saturated chain carboxylic acid.
Increased selectivity with temperature can be explained by
prevalent ionic, surface-catalysed pyrolysis at lower tem-
peratures and pure gas-phase thermal pyrolysis at higher
temperatures. The lower-temperature conditions are known
to increase the surface-catalyzed carbocation formation that
rearranges into other structurally similar, more stable car-
bocations,28 whereas gas-phase pyrolysis follows a pericyclic
mechanism,29 and in our case leads to 3 as the only product.
Although the reaction is known, no preparative applica-
tions are reported according to our knowledge in the
caprolactone family.
The main difficulty of the scale-up was the cyanolactone
transfer in the gas phase. In fact heating the lactone at the
boiling point induced an extensive polymerization. To avoid
the lactone loss, the vaporization (nebulization) has to be
realized in very short time at pyrolytic temperature. This
stage of the process has been realized on pilot scale by “on-
column” feeding of the liquid lactone into the pyrolysis tube
reactor flushed by nitrogen flow through a suitably designed
dispersion system of dropping liquid into the gas phase. This
stage of reaction has been the determining step of the scale-
up.
A purpose-built vertical furnace-reactor equipped with a
pyrolysis metal tube having an inner spinning-carrier device
was used. Nitrogen was passed through the lactone 2,
previously melted, and then the lactone was added dropwise
at the rate of 0.5 g/min through the pyrolysis tube preheated
at 600 °C. A pale-yellow pyrolysate was formed. To isolate
pure 3, pyrolysate was washed with base and acid, extracted
and fractionally distilled; 8-cyano-6-octenoic acid, 3 was
obtained in 92% yield, bp 155 °C/0.05 Torr; its titration
indicated the presence of 95% of titratable carboxylic acid
(mixture of cis/trans isomers).
Scheme 7. Regioselectivity of Baeyer-Villiger
rearrangement
cyclohexanecarboxylic acid. This behavior facilitated its
separation from the reaction mixture (Figure 1), affording
significant advantage, that is to use n-hexane solutions of
cyclohexaneperoxycarboxylic acid in Baeyer-Villiger reac-
tion.
The scaled Baeyer-Villiger step was carried out at 50
°C, that is the temperature of peracid synthesis. Therefore,
during the process, the peracid temperature and concentration
are kept constant, enhancing thus the plant safety operation.
Quantitative peracid conversion is achieved in a plug-flow
reactor and with residence time of a few hours.
As CHCA is completely soluble in n-hexane, separation
of lactone is possible by hexane counter-flow extraction,
applying mild separation conditions, without heating or
evaporation/concentration. The last operations would repre-
sent hazardous points in the process in the case of th wrong
operation of the Baeyer-Villiger reactor. All of these
considerations are incorporated in the plant process.
Lactone Pyrolytic Ring Opening. Synthesis of Unsat-
urated Acids. Unsaturated ω-functionalized nonanoic acids
are precursors of corresponding saturated chain carboxylic
acids. Their facile hydrogenation affords the synthesis of a
9-carbon atom straight-chain structure, difficult to build
through carbon-carbon homologation pathways or starting
from the common available organic synthons. Formation of
the open-chain C-9 intermediate was completed by pyrolytic
ring opening of lactone at 550-600 °C, and according to
the reaction thermodynamics, a residence time of a few
seconds is sufficient to cleanly and quantitatively convert
the lactone.26b-e
An alternative procedure for the lactone opening is the
nucleophilic cleavage by various methods and reagents
(Scheme 10). All of the methods above add new steps to
the process and increase the costs.
Surprisingly, the pyrolytic reaction proceeded with higher
regioselectivity at more elevated temperatures than at the
lower ones: at 600 °C, 92% of 8-cyano-6-octenoic acid was
formed, (Scheme 8), whereas at 550 °C, a mixture 2:1:1 of
three olefinic ω-cyanooctenoic acids was obtained (Scheme
9). This product distribution was revealed by GC-MS and
confirmed by oxidative cleavage of 3, 10, and 11 to
Lactone cleavage can be also performed batchwise, with
hydrogen gas and catalyst under pressure (Scheme 11). In
the case of lactone-ester a mixture of azelaic acid methyl
esters and acid itself is obtained in a very clean process which
has not been yet scaled up.
(28) Wertz, D. H.; Allinger, N. L. J. Org. Chem. 1977, 42, 698.
(29) Bailey, W. J.; Bird, C. N. J. Org. Chem. 1977, 42, 3895.
Vol. 5, No. 1, 2001 / Organic Process Research & Development
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73

Scheme 10. Nucleophilic cleavage of substituted
Scheme 12. Synthesis of 3,4-dihydro-2-pyridones
caprolactones
Scheme 11. Hydrogen cleavage of
7-(â-cyanoethyl)oxepan-2-one
Scheme 13. Synthesis of coumarin from
3-(2-oxocyclohexyl)propanoic acid methyl ester
Use of hydrogen as carrier gas and of a suitable
hydrogenation catalyst to directly obtain 8-cyanooctanoic
acid are the likely improvements in the nitrile-lactone
opening.
Experimental work on hydrogenation of unsaturated
cyanoacids has been carried out using traditional conditions,
for example, batch reactor and Pd-C as catalyst. Low-
pressure catalytic hydrogenation of unsaturated carboxylic
acid 3 yields 8-cyanoctanoic acid 4. Compound 3 was
hydrogenated with H2 at 50 °C and 8-at, using toluene as
solvent and 5% Pd-C as catalyst. After filtration and solvent
evaporation (90%) of pale yellow oil was recovered. It
contained 99% of titratable 8-cyanooctanoic acid. Pure 4 has
bp 150 °C/0.05 Torr.26b-e
In the final steps either hydrolysis to 5 or hydrogenation
to 6 was performed; under optimized conditions both
reactions proceed with ∼90% yield.26b-e Final hydrogenation
of saturated cyanoacid to obtain 9-aminononanoic acid was
performed as follows: compound 4 was hydrogenated at 55
°C and 80 atm in ammonia-saturated ethyl alcohol, over
Raney-Ni. Cooling, filtration, and recrystallization from hot
water afforded (90%) of 9-aminononanoic acid, mp 191-
192 °C. Polymer grade 9-aminonononanoic acid (mp 192-
193 °C) was obtained by recrystallization of amino acid
barium salt from hot water and then recovering the amino
acid by treatment with “dry ice” CO2.
1,9-Nonanedioic acid was obtained by hydrolysis of 4 at
100 °C in concentrated H2SO4. After the mixture cooled,
the solid product was separated by filtration. Washing and
recrystallization from water afforded (90%) of 1,9-nonandioic
acid 6, mp 107-108 °C.
Versatility of 3-(2-oxocyclohexane) Propanoic Acid
Derivatives. δ-Keto-derivatives of 3-substituted propanoic
acid are useful intermediates in the synthesis of fine
chemicals. Selective monoalkylation of cyclohexanone by
acrylic acid derivatives afforded the study of intramolecular
cyclization of the above compounds.
Intramolecular cyclization of 3-(2-oxocyclohexyl)pro-
panoic acid esters to ene-lactones opened a very interesting
preparative route to coumarin and its hydrogenated precursor,
3,4-dihydrobenzopyran-2-one (dihydrocoumarin).31 A pilot-
scale process including alkylation of cyclohexanone by
methyl acrylate and dehydrogenation of ene-lactone under
catalytic hydrogen transfer conditions by various hydrogen
acceptors (e.g., dimethyl maleate) has been developed
(Scheme 13).
Conclusions
In summary, an efficient route to ω-functionalized deriva-
tives of nonanoic acid has been developed. The initial two
steps can be performed also in a continuous manner. The
first one is characterized by the catalytic variant of the
Michael-type imine alkylation of cyclohexanone, and the
second by the use of cyclohexaneperoxycarboxylic acid as
a new regioselective Baeyer-Villiger reagent. In the final
steps controlled pyrolysis of 7-(â-cyanoethyl)oxepan-2-one
affords unsaturated ω-cyanooctenoic acid, a key intermediate
which is converted to the saturated chain corresponding acid
and then to 9-aminononanoic and azelaic acids, both valuable
C-9 monomers.
Azelaic acid has a well-consolidated commercial position.
9-Aminononanoic acid, on the contrary, has not found until
now a suitable process to compete with other nylon
monomers. The comparative evaluation of the new manu-
facturing process would require a detailed cost-performance
3,4-Dihydro-2-pyridones (ene-lactams) are versatile in-
termediates for the synthesis of piperidine and hydroquinoline
ring system. Katritzky’s procedure for the oxidative hydration
of nitriles to amides by basic hydrogen peroxide in DMSO
may be efficiently applied to the synthesis of 3,4-dihydro-
2-pyridones (15a-f) from cyanoethylated ketones (12a-f)
(Scheme 12).30
(30) Citterio, A.; Carnevali, E.; Farina, A.; Meille, V.; Stefano, A.; Cotarca, L.
Org. Prep. Proced. Int. 1997, 29(4), 465.
(31) Alini, S.; Cotarca, L.; Delogu, P. U.S. Patent 5,872,265, 1997; Cotarca,
L.; Clauti, G.; Delogu, P.; Nardelli, A.; Nero, A. I.; Alini, S.; Bianchini,
R.; Sguassero, S. ICOS-12, 1998, Venice, Italy.
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Vol. 5, No. 1, 2001 / Organic Process Research & Development

analysis of the nylon-9 polymer versus other long-chain
polyamides. This is outside of the scope of this paper.
The new process uses easily available and stably priced
petrochemical raw materials. Cyclohexanone and acrylonitrile
are basic raw materials in the polymeric materials arena.
Hydrogen peroxide is becoming more and more a “com-
modity” with favorable and less hazardous industrial ap-
plications. Cyclohexanecarboxylic acid is the more prob-
lematic raw material being available only from only one
company even through it is manufactured at 20 thousand
mt/levels for many years. CHCA is continuously recycled
in the process, and therefore losses can be limited by a careful
plant design. The unit operations are all of standard type,
with liquid or gas flows and solid final products. Only the
pyrolysis reactor remains with outstanding design problems.
The new process has a high atom economy and produces
only a low volume of easily treated waste. The only
important byproduct is ammonia, which is, eliminated as
ammonium sulfate (∼0.7 kg/kg of azelaic acid) a common
large byproduct of petrochemical industry where a single
process (e.g., caprolactam manufacture) coproduces amounts
such as millions of mt/y.
The process starting from oleic acid has more unfavorable
mass balances. One ton of tallow oil produces an average
amount of 270 kg of long-chain acids, half of them being
represented by oleic acid. A small part of the other
coproducts are useful to agricultural or industrial applications;
the other one is treated.
In the oleic acid process, beside the pelargonic acid, a
huge amount of low molecular weight acids sludge and
water-soluble acids are produced. The synthesis starting from
natural raw materials looks much more problematic with
respect to the route starting from low-price petrochemical
raw materials, and the atom economy is very low.
Cyclohexaneperoxycarboxylic Acid. A. Batchwise Meth-
od. Cyclohexanecarboxylic acid (12.8 g, purified by crystal-
lization of commercial product, from n-hexane/diethyl ether,
mp 43-44 °C) was dissolved in methanesulphonic acid (64
g), and hydrogen peroxide (13 mL, 70% in water) was added
dropwise at -5 to 0 °C over 1 h. Stirring was continued for
additional 2.5 h at the same temperature, and then a water-
ice mixture (200 mL) was added at such a rate that the
temperature never exceeded +5 °C. The dilute reaction
mixture was rapidly extracted with cold ether (2 × 100 mL),
and extracts were washed with cold saturated ammonium
sulfate solution (3 × 50 mL) and then with 100 mL of cold
water. The ether solution was dried over anhydrous magne-
sium sulfate and kept in a refrigerator. Vacuum evaporation
of filtrate below 10 °C afforded an oily residue, which slowly
crystallized at 0 °C, to yield cyclohexaneperoxycarboxylic
acid (82%), white crystalline solid, 11.8 g, mp ∼0 °C;
peroxide oxygen: calcd 11.10%, found 11.25%. Purity of
peracid is >95% (0.1 N NaOH titration) when freshly
prepared. It quickly decomposed in the pure solid state, at
ambient temperature, but contrarywise, it was stable for
weeks when dissolved in organic solvents such as n-hexane,
cyclohexane, or cyclohexanecarboxylic acid, at room tem-
perature. We did not succeed in recrystallyzation of crude
product.
Warning! Violent decomposition occurred in our labora-
tory when the solid CHPCA was deposited at ambient
temperature.
B. Continuous Method. To produce solutions of “equi-
librium” concentration of CHPCA in a biphasic water-n-
hexane system, 1.75 mol/h of 50% hydrogen peroxide, 1.85
mol/h n-hexane solution of cyclohexanecarboxylic acid, and
385 mL of continuously recycled 45% sulfuric acid were
fed into a laboratory glass continuously stirred tank reactor
at 50-70 °C and slightly reduced pressure. The residence
time was 3 h. CHPCA content in the efluent organic solution
(usually 17-19%) was controlled by the rate of azeotropic
water removal. Conversion of hydrogen peroxide was of over
60%, and selectivity of CHPCA formation was 50-55%.
Anhydrification and acidity removal afforded a solution ready
for use in Baeyer-Villiger rearrangement.
7-(â-Cyanoethyl)oxepan-2-one (2). 3-(2-oxocyclohexyl)-
propanenitrile 1, (15.1 g, 100 mmol) was heated at 40 °C,
then cyclohexaneperoxycarboxylic acid (53 g of a hexane
solution containing 15.8 g (109 mmol) of peracid) was added
dropwise, under stirring, over 1.5 h. The reaction required
cooling during the addition of peracid to maintain the
temperature at 45-50 °C. After an additional 2 h of stirring,
determination of peracid indicated 96% conversion. After
the mixture cooled, two well-separated organic phases were
formed. The lower layer containing 7-(â-cyanoethyl)oxepan-
2-one, 2, was concentrated under reduced pressure to remove
n-hexane and cyclohexanecarboxylic acid. Lactone can be
isolated either by short-path distillation or by continuous
extraction of cyclohexanecarboxylic acid with n-hexane. On
crystallization from ethyl acetate and methyl-tert-butyl ether
15.3 g (yield of 92%) of pure 2, mp 34-36 °C, was obtained.
Experimental Section
3-(2-oxocyclohexyl) Propanenitrile (1). A mixture of
cyclohexanone (20.7 g, 210 mmol), cyclohexylamine (1.5
g, 15 mmol), acetic acid (0.16 g, 2.5 mmol), and 4-meth-
oxyphenol (0.17 g, 1.4 mmol) was heated at 70-80 °C.
Acrylonitrile (5.55 g, 105 mmol) was dropwise added,
heating the reaction mixture without reflux at 130 °C for 2
h. The product was then distilled in a vacuum. Obtained was
14 g of 3-(2-oxocyclohexyl)-propanenitrile, bp 114-115 °C/4
mmHg. The second crop (∼1 g) was obtained on heating
on a steam bath with dilute hydrochloric acid for 30 min,
followed by separation of the oil by extraction in benzene,
evaporation of the solvent, and distillation in a vacuum. The
yield of 1 thus amounts to 95%.
3-(2-oxocyclohexyl)-propanoic Acid Alkyl Esters (1a,
1b). Pyrrolidine or alkyl (Me or Et) 3-(N-pyrrolidino)
propionates have been used as catalysts to prepare com-
pounds 1a or 1b, according to the method described for 1.
Crude product was isolated by distillation in a vacuum, and
the fraction containing water, cyclohexanone, and N-alkylated
pyrrolidine was recycled. Obtained was 18.3 g (94%) of 3-(2-
oxocyclohexyl)-propanoic acid methyl ester (1a) or 19.7 g
(94%) of 3-(2-oxocyclohexyl)-propanoic acid ethyl ester 1b.
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75

8-Cyano-6-octenoic Acid (3). A purpose-built vertical
furnace equipped with a pyrolysis metal tube having an inner
spinning-carrier device was used. Nitrogen was bubbled for
a few minutes through the melted lactone 2 to be pyrolyzed,
and then 0.24 mol of lactone was added dropwise at the rate
of 0.5 g/min through the pyrolysis tube preheated at 600 °C.
A pale-yellow pyrolysate was formed. To isolate pure 3,
pyrolysate was base- and acid-washed, extracted, and
fractionally distilled; 8-cyano-6-octenoic acid, 3 was obtained
in 92% yield, bp 155 °C/0.05 Torr; its titration indicated
the presence of 95% of titrable carboxylic acid (mixture of
cis/trans isomers).
Working at temperatures of 500-550 °C, mixtures of
regioisomers 3, 10, and 11 were obtained in the ratio 2:1:1.
Their structures were assigned by oxidative cleavage of
double bond (Baeyer test)25 and by GC-MS identification
of the resulted dicarboxylic acids. Partial, low-pressure
hydrogenation of this mixture, as described below for 3,
afforded saturated acid 4 with >98% purity.
filtration and solvent evaporation 35 g (90%) of pale yellow
oil was recovered. It contained 99% of titratable 8-cyano-
octanoic acid. Pure 4 has bp 150 °C/0.05 Torr.
1,9-Nonanedioic Acid (5). Compound 4 (5.5 g, 32 mmol)
was hydrolyzed for 6 h at 100 °C in H2SO4 concentrated
(10 mL). After the mixture cooled, the solid product was
separated by filtration. Washing and recrystallization from
water afforded 5.5 g (90%) of 1,9-nonandioic acid (5), mp
107-108 °C.
9-Aminononanoic Acid (6). Compound 4 (23 g, 134.5
mmol) was hydrogenated at 55 °C and 80 atm in 380 mL of
ammonia saturated ethyl alcohol, over 2.2 g of Raney-Ni.
Cooling, then filtration, and recrystallization from hot water
afforded 21 g (90.2%) of 9-aminononanoic acid, mp 191-
192 °C. Polymer grade 9-aminonononanoic acid (mp 192-
193 °C) was obtained by recrystallization of amino acid
barium salt from hot water and then recovering the amino
acid by treatment with “dry ice” CO2.
8-Cyanooctanoic Acid (4). Compound 3 (38 g, 220
mmol) was hydrogenated in toluene (370 mL), at 50 °C and
8 atm of hydrogen, in the presence of 1.8 g Pd/C (5%). After
Received for review July 24, 2000.
OP000081J
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