Efficient synthesis of glutaric acid from L-glutamic acid via diazoniation/hydrogenation sequence

Article abstract of DOI:10.1515/chempap-2015-0067

The practical synthetic preparation of glutaric acid has remained a major challenge to date. In the present study, glutaric acid was synthesised by way of one-pot diazoniation/hydrogenation of the readily available L-glutamic acid under aqueous conditions on a gram-scale with good yields. This is the first example of the deamination of the aliphatic primary amine via diazoniation and could afford a practical approach to the production of glutaric acid.

Full text of DOI:10.1515/chempap-2015-0067

Chemical Papers 69 (5) 716–721 (2015)
DOI: 10.1515/chempap-2015-0067
ORIGINAL PAPER
Efficient synthesis of glutaric acid from L-glutamic acid via
diazoniation/hydrogenation sequence
Wei Zhang, Meng-Yun Rao, Zhong-Jun Cheng, Xiao-Yan Zhu, Kai Gao,
Jian Yang, Bo Yang, Xia-Li Liao*
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China
Received 9 June 2014; Revised 29 August 2014; Accepted 23 September 2014
The practical synthetic preparation of glutaric acid has remained a major challenge to date. In
the present study, glutaric acid was synthesised by way of one-pot diazoniation/hydrogenation of
the readily available L-glutamic acid under aqueous conditions on a gram-scale with good yields.
This is the first example of the deamination of the aliphatic primary amine via diazoniation and
could afford a practical approach to the production of glutaric acid.
c
ꢀ 2014 Institute of Chemistry, Slovak Academy of Sciences
Keywords: glutaric acid, L-glutamic acid, diazoniation/hydrogenation, sodium nitrite, hypophos-
phorous acid
Introduction
Glutaric acid (I, Fig. 1) is among the substan-
tially important fine chemicals. It is widely used in
fine chemistry, agriculture, medicine and architecture
(Johnson et al., 1993). In the plastics industry, it is the
essential raw material for the production of polymeric
materials such as polyvinyl chloride (PVC), polyester,
polyamide, resin, synthetic rubber, etc. (Besson et al.,
2005). It has been reported that I exhibited some im-
portant physiological activities such as neurotoxicity
(K¨olker et al., 1999), inhibition of glutamate uptake
(Porciúncula et al., 2000; Rosa et al., 2007), inhibition
of energy production (Silva et al., 2000), inducing ox-
idative stress (Marques et al., 2003) and membrane
translocation (Mu¨hlhausen et al., 2008), etc.
Currently, the production of I is largely depen-
dent on the recovery of byproducts from the process
of manufacturing adipic acid (Castellan et al., 1991;
Tullo et al., 2002). However, this incurs significant
drawbacks such as complex process, purification diffi-
culty and high cost. In addition, the outcome is always
uncertain due to the yield being closely dependent
on the production process of adipic acid. With con-
tinuous improvements to the processing technique of
Fig. 1. Synthesis of glutaric acid (I) from L-glutamic acid (II).
Reaction conditions: i) NaNO2, mineral acid (H2SO4 or
HCl or H3PO4) and H3PO2 (see Table 1) or another
reductant (see Table 2), –5–0◦C, 10–12 h.
adipic acid, the I outputs obtained therefrom have de-
creased accordingly. Meanwhile, the chemical synthe-
sis of I has emerged as a further option, having been
synthesised by the catalytic oxidation of cyclopentene
(Orita et al., 1986; Choudary et al., 1991; Antonelli
et al., 1998; Griffith et al., 2000; Wang & Dai, 2002;
Griffith & Kwong, 2003; Chen et al., 2006a, 2006b;
Che et al., 2006; Shoair & Mahamed, 2006; Saedi et
al., 2012a, 2012b), 1,5-pentanediol (Iwahama et al.,
2000; Chen et al., 2007; Balaraman et al., 2013), 1,3-
cyclohexanedione (Yuan & Zhao, 2010; Tachikawa et
al., 2013), dihydropyran (English & Dayan, 1957),
tetrahydropyran (Smith & Scarborough, 1980), 2-
cyclohexenone (Travis et al., 2002), cyclopentane-1,2-
*Corresponding author, e-mail: xlliao@yahoo.com
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W. Zhang et al./Chemical Papers 69 (5) 716–721 (2015)
717
diol (Gao et al., 2009), or glutaraldehyde (Chu et
al., 2012), by the acidic hydrolysis of glutaronitrile
(Marvel & Tuley, 1925), by γ-butyrolactone (Paris et
al., 1957) or by electrosynthesis (Lyalin & Petrosyan,
2009). However, all these methods entailed the use of
expensive substrates or catalysts, harsh conditions or
toxic reagents. Hence, the practical production of I by
chemical synthesis represents a challenge.
rity was used as received. Melting points (uncorrected)
were determined on an RY-1 instrument (Shanghai,
China). IR spectra were recorded on a Bio-Rad FTS-
40 FTIR spectrometer (Bio-Rad, USA). 1H NMR
spectra were measured on a Bruker Avance DRX
500 spectrometer (Bruker, Germany) at 298 K and
the HRESI-MS data were recorded on a Bruker Mi-
crOTOF Q-II mass spectrometer (Bruker, Germany).
L-Glutamic acid (II ) (Fig. 1) is one of the natural
essential amino acids. It is readily available and is used
extensively in the pharmaceutical and food industries.
Simple replacement of the amino group with hydro-
gen could readily transform II to glutaric acid (I ) due
to the similarity in their chemical structures. Diazo-
nium compounds, mostly aromatic diazonium salts,
are recognised as important intermediates in organic
synthesis because they can be expediently converted
to aryl halides, phenols, arenes, nitro arenes, cyano
arenes, etc. (Mo et al., 2013; He et al., 2014). Replace-
ment of the diazonium group with hydrogen usually
requires an appropriate reductant to afford the trans-
formation. To date, a number of reducing agents such
as ethanol (Clarke & Taylor, 1923; Bogert & Mandel-
baum 1923; Bigelow et al., 1926; Coleman & Talbot,
1933; Wallingford & Krueger, 1939; Roe & Graham,
1952; Baqi & Mu¨ller, 2012), alkaline formaldehyde
(Brewster & Poje, 1939), borohydride (Hendrickson,
1961; Rieker et al., 1969), thiophenol (Shono et al.,
1979), bisulphite (Shapiro et al., 1970; Geoffroy et al.,
2001), ethyl acetate (Bacherikov et al., 2004; Meng
& Cai, 2005), phosphorous acid (Kornblum et al.,
1952) and hypophosphorous acid (or hypophosphite)
(Kornblum, 1941; Adams & Kornblum, 1941; Robi-
son & Robison, 1956; Mitsuhashi et al., 2000) have
been developed. However, to the best of our knowl-
edge, the transformation of aliphatic amines has been
disclosed only rarely in comparison with the numerous
reports on aromatic amines. Nickon and Hill (1964)
and Doldouras and Kollonitsch (1978) conducted the
deamination of aliphatic amines with hydroxylamine-
O-sulphonic acid, whilst the preparation of α-hydroxy
acids by the diazoniation of natural amino acids was
disclosed by Kolitz et al. (2009); however, there has
been no report on the deamination via diazoniation of
aromatic amines. Furthermore, it was reported that,
in contrast with aromatic amines, aliphatic primary
amines did not react with nitrous acid below a pH
value of 3.0 (Kornblum & Iffland, 1949). Hypophos-
phorous acid (H3PO2) is a potent and readily avail-
able reducing reagent which is used ubiquitously in
chemical, pharmaceutical and dyestuff fields. Herein,
a new method for the preparation of I from II via a
diazoniation/hydrogenation sequence with H3PO2 is
presented.
Typical procedure of deamination with hy-
pophosphorous acid
A 500-mL three-necked round-bottom flask con-
taining water (150 mL) was cooled in an ice-salt bath
(–10◦C to –5◦C) for 10 min. H2SO4 (98 mass %,
32.5 mL, 598 mmol) was added carefully through a
dropping funnel with stirring. Following the addition,
an aqueous solution of NaNO2 (23.5 g of NaNO2,
30 mL of water, 340 mmol) was added drop-wise
through another dropping funnel and the solution
was stirred for a further 10 min, followed by the
drop-wise addition of precooled H3PO2 (50 mass %,
53.9 g, 408 mmol) over 10–15 min. L-Glutamic acid
(II ) (5 g, 34 mmol) was added carefully by stages
maintaining the reaction temperature at –5–0◦C. The
reaction mixture was stirred for 10–12 h (monitored
by TLC; developing solvent system: 1-butanol/acetic
acid/water (ϕr = 4 : 1 : 1); visualisation by ninhy-
drin and bromocresol green), the pH was adjusted to
approximately 5.0 with an aqueous solution of NaOH
(10 mass %) and the solvent was evaporated under
diminished pressure at 40◦C to a volume of about
200 mL. The thick liquid was extracted with hot ethyl
acetate (55◦C, 3 × 200 mL). (Note: additional ex-
tractions with hot ethyl acetate could improve the
yield by a few per cent; extraction with other or-
ganic solvents such as ethyl ether, dichloromethane,
chloroform, 1,2-dichloroethane, etc. could also afford
moderate to good yields, but hot ethyl acetate was
chosen for its low toxicity and cost.) The combined
organic extracts were washed with brine (50 mL),
dried with MgSO4, followed by concentration under
diminished pressure to yield colourless flaky crystals
of I (3.57 g, yield of 80 %). M.p. 95–98◦C; IR (KBr),
νmax/cm−1: 3033, 2956, 1697, 1444, 982; HRESI-
MS, m/z (found/calc.): 155.0316/155.0314 ([M +
1
Na]+); H NMR (500 MHz, D2O), δ: 2.34–2.27 (4H,
m, HOOCCH2CH2CH2COOH), 1.80–1.73 (2H, m,
HOOCCH2CH2CH2COOH).
Results and discussion
Commercially available H3PO2 (50 mass % aque-
ous solution) was first chosen to perform the dediazo-
niation due to its strong reducing ability. The diazo-
nium salt was formed in the presence of sulphuric acid
and NaNO2, followed by a hydrogenation or dediazo-
niation process with the assistance of H3PO2 (Fig. 1).
Experimental
L-Glutamic acid (Shanghai, China) of chemical pu-
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W. Zhang et al./Chemical Papers 69 (5) 716–721 (2015)
Table 1. Optimisation of reaction conditions using H3PO2 as
ble 2), sodium hypophosphite (entry 3) and potas-
sium hypophosphite (entry 5) all afforded complex
products, while calcium hypophosphite (entry 7) and
H3PO2 (entry 9) both afforded moderate yields (64 %
and 68 %, respectively). When a double volume of sul-
phuric acid was employed in the cases of hypophospho-
rous acid salts, moderate to low yields of 51 %, 41 %,
22 % and 17 %, respectively, were obtained (entries
2, 4, 6 and 8). One possible reason is that the addi-
tion of a large amount (12 equivalents) of hypophos-
phorous acid salt might have neutralised the H2SO4
required for effective diazoniation and also for pre-
venting the side-reactions of diazonium salt by poten-
tial nucleophiles. Beyond the phosphorus-containing
reagents, no target product could be found in the pres-
ence of ethanol (entry 10), ethyl acetate (entry 11) or
sodium bisulphite (entry 12). However, it afforded a
70 % yield in the combined action of formaldehyde
(HCHO) and NaOH (entry 13). None of these reduc-
ing agents emerged as a reductant superior to H3PO2
for this transformation in terms of the chemical yield
of I.
From previous reports on the dediazoniation mech-
anism (Kornblum, 1944; Kornblum et al., 1950; DeTar
& Kosuge, 1958; Skrunts et al., 1983; Wassmundt &
Kiesman, 1997; Pazo-Llorente et al., 2006), a possible
mechanism for the free radical chain for the deamina-
tion of II via the diazoniation/hydrogenation sequence
using H3PO2 as the reductant is shown in Fig. 2. The
diazonium salt (III ) was first formed in the presence of
NaNO2 and mineral acid, followed by the formation of
the 1,2,3-oxadiazolium salt (IV ) by the neighbouring
nucleophilic attack from the 1-carboxylic group. Next,
the free radical chain initiation resulted from the inter-
action between IV and H3PO2, leading to the glutaric
acid radical (V ) and the free radical [H2PO2] (VI ).
The radical V could subsequently be converted to I
by extracting a hydrogen radical from H3PO2 along
reductanta
Entry
II/mg
H3PO2/equiv
Acid
Yield/%
1
2
3
4
5
6
7
50
50
50
50
50
8
10
12
14
12
12
12
H2SO4
H2SO4
H2SO4
H2SO4
HCl
37
64
88
87
cp
28
80
50
5000
H3PO4
H2SO4
a) General reaction conditions: II (50 mg, 0.34 mmol), mineral
acid (H2SO4, 98 mass %, 6.5 mL; or HCl, 37 mass %, 10 mL;
or H3PO4, 85 mass %, 8.2 mL), NaNO2 (235 mg, 3.4 mmol),
H3PO2 (8–14 equivs); cp = complex products.
In order to preclude the formation of the byproducts
resulting from the attacks from nucleophiles such as
water and carboxylic groups of the substrate within
the reaction system, the use of a great excess of re-
ductants was necessary to guarantee the yield of the
target product. The H3PO2/II ratio (in equivalents
(equivs)) was optimised (entries 1–4, Table 1). The
highest yield (88 %, entry 3) was obtained when 12
equivalents of H3PO2 were used. A further increase
in equivalents of H3PO2 (14 equivalents, entry 4) did
not enhance the yield. On the other hand, the replace-
ment of H2SO4 with HCl (entry 5) afforded complex
products which could only be separated with diffi-
culty, while with H3PO4 it afforded a much lower yield
(28 %, entry 6).
Under the optimised reaction conditions, the sub-
strate mass increase up to 5 grammes (see Experimen-
tal for details) was possible with a satisfactory yield
(80 %, entry 7).
Some other reducing reagents were tested in this
reaction. Ammonium hypophosphite (entry 1, Ta-
Table 2. Screening of reductantsa
Entry
II/mg
Reductant/equiv
Acid
Yield/%
Reference
1
2
3
4
5
6
7
8
9
10
11
12
13
50
50
50
50
50
50
50
50
50
50
50
50
50
NH4H2PO2/12
NH4H2PO2/12
NaH2PO2/12
NaH2PO2/12
KH2PO2/12
H2SO4
H2SOb4
H2SO4
H2SOb4
H2SO4
H2SOb4
H2SO4
H2SOb4
H2SO4
H2SO4
H2SO4
HCl
cp
51
cp
41
cp
22
64
17
68
nr
nr
nr
70
–
–
–
–
Mitsuhashi et al. (2000)
Mitsuhashi et al. (2000)
Mitsuhashi et al. (2000)
Mitsuhashi et al. (2000)
Kornblum et al. (1952)
Coleman and Talbot (1933)
Bacherikov et al. (2004)
Geoffroy et al. (2001)
Brewster and Poje (1939)
KH2PO2/12
Ca(H2PO2)2/12
Ca(H2PO2)2/12
H3PO3/12
EtOH/50
EtOAc/25
NaHSO3/12
HCHO/2 + NaOH/5
HCl
a) General reaction conditions: II (50 mg, 0.34 mmol), mineral acid (entries 1, 3, 5, 7: H2SO4, 98 mass %, 6.5 mL; entries 9–13: as
reported in the corresponding reference), NaNO2 (235 mg, 3.4 mmol), reductant (entries 1–8: 12 equivs; entries 9–13: as reported
in the corresponding reference); b) the amount of H2SO4 was increased to 13 mL; cp = complex products; nr = no reaction.
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719
Fig. 2. Possible mechanism for diazoniation/hydrogenation sequence.
with the formation of the free radical VI. On the other
hand, this radical can react with IV to yield phos-
phorous acid (H3PO3) and V. As the reaction mecha-
nism of the diazoniation/hydrogenation process using
H3PO2 was not thoroughly understood (Romanova &
Demidenko, 1975; Golubev et al., 2006), more inves-
tigation was needed to elucidate this transformation
mechanism.
Haoyuan Zhang in Changsha Nutritopper Biotechnology Co.
and a reviewer for valuable comments.
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