Synthesis of 5-aminolevulinic acid with nontoxic regents and renewable methyl levulinate

Article abstract of DOI:10.1039/c9ra01517e

Synthesis of 5-aminolevulinic acid (5-ALA) was presented with novel bromination of biobased methyl levulinate (ML), followed by ammoniation and hydrolysis. Copper bromide (CuBr₂) was employed as the bromination reagent with higher selectivity and activity instead of the conventional liquid bromine (Br₂). 5-ALA was obtained in a high yield (64%) and purity (>95%) by optimum design, which is of great potential in industrialization.

Full text of DOI:10.1039/c9ra01517e

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Synthesis of 5-aminolevulinic acid with nontoxic
regents and renewable methyl levulinate†
Cite this: RSC Adv., 2019, 9, 10091
Yuxia Zai, Yunchao Feng, Xianhai Zeng, *abc Xing Tang,
a
a
abc
abc
Yong Sun
abc
and Lu Lin
Synthesis of 5-aminolevulinic acid (5-ALA) was presented with novel bromination of biobased methyl levulinate
ML), followed by ammoniation and hydrolysis. Copper bromide (CuBr ) was employed as the bromination
reagent with higher selectivity and activity instead of the conventional liquid bromine (Br ). 5-ALA was
obtained in a high yield (64%) and purity (>95%) by optimum design, which is of great potential in industrialization.
Received 28th February 2019
Accepted 20th March 2019
(
2
2
DOI: 10.1039/c9ra01517e
rsc.li/rsc-advances
14–16
5-Aminolevulinic acid (5-ALA) is generally known as an essential processing of biomass at a competitively low price.
Thus, to
precursor molecule for tetrapyrrole synthesis such as porphyrin, synthesize 5-ALA from LA or its esters is exceptionally prom-
1
heme, chlorophyll and vitamin B12. It has been widely applied ising. Typically, 5-ALA can be effectively prepared from levuli-
2–4
in localizing and photodynamic therapy for various cancers. It nates via
has also been used as a selective biodegradable insecticide, ammoniation and acidolysis. However, the bromination of
herbicide, salt tolerance agent or plant growth regulator in levulinates with Br in this course has low selectivity to 5-bromo
derivatives. Besides, Br is hazardous and environmentally
a three-stage process including bromination,
17
2
5
agricultural elds.
2
To date, 5-ALA was mainly synthesized by microbial produc- unfriendly. Hence, a crucial step of the production of 5-ALA
6
tion methods, but the long-time and high-cost course restrict its from levulinates is to explore a safe bromide agent with higher
scaled applications. On the other side, chemical routes using 2- selectivity and activity.
hydroxypyridine, tetrahydrofurfurylamine and furfurylamine as
2
CuBr , a green and low toxic brominated reagent, was usually
starting materials involved in numerous bottleneck including used for the synthesis of a-bromination of cyclopentenone
7,8
toxic intermediates and rigorous reaction conditions. Thus, to derivatives and its closest analogues-indanone of carbonyl
develop a new pathway for 5-ALA production is of great signi- compounds for its advantages of short reaction times, high
cance, especially one that is a green and sustainable.
selectivity of the products, high yields and easily handle
18,19
Biomass is an appealing starting material in value-added procedures.
In this content, various unsymmetrical aliphatic
chemicals synthesis because of its advantages of renewability, ketones including levulinic acid, methyl levulinate, ethyl levu-
9
sustainability and availability. Several biomass-derived plat- linate, 5-hydroxy-2-pentanone and 2-butanone was attempted
2
form compounds such as 5-hydroxymethylfurfural (HMF), 5- for bromizing with CuBr (Table 1). Interestingly, the yields of
chloromethylfurfural (CMF), levulinic acid (LA) or its esters bromination products were different, depending on the source
have been reported as efficient raw materials in the production of aliphatic ketones.
10,11
of 5-ALA.
However, the industrial manufacture of furan-type
In this work, we present the synthesis of 5-ALA from biomass
HMF and CMF cannot currently be achieved easily due to the derived methyl levulinate (ML) under mild conditions using
12,13
high production and environment costs.
Furthermore, CuBr as a greener bromine donor, and a high yield of 5-bro-
2
conversion of furan-type chemicals to 5-ALA also suffers the molevulinate (M5B) up to 85% was achieved. Furthermore,
economic problems concerning the use of expensive oxidants in a detailed discussion of ammoniation and acidolysis was also
the ring-opening stage. Unlike CMF and HMF, LA and its esters presented, corresponding a high total 5-ALA yield over 64%
can be easily produced both from hemicellulose and cellulose, (Scheme 1).
and its yearly tonnage is therefore available via the acidic
The rst attempt to screen the reaction conditions for the
bromination of ML with CuBr are shown in Table 2. An
2
a
encouraging yield of the desired product (50%) is indeed ob-
College of Energy, Xiamen University, Xiamen 361102, China. E-mail: xianhai.zeng@
ꢀ
xmu.edu.cn; Fax: +86-592-2880701; Tel: +86-592-2880701
b
tained using CuBr as bromide agent in CH OH at 40 C for 3 h
2
3
Fujian Engineering and Research Centre of Clean and High-valued Technologies for (Table 2, entry 1). The investigation of the solvent indicated that
Biomass, Xiamen 361102, China
CH
CHCl
The results may due to the fact that CH
3
OH–CHCl
3
mixed solvent was superior to ethyl acetate (EA),
OH–EA and EA–CHCl (Table 2, entry 2–6).
OH can improve the
c
Xiamen Key Laboratory of Clean and High-valued Utilization for Biomass, Xiamen
3
, CH OH, CH
3
3
3
3
†
1
61102, China
3
Electronic supplementary information (ESI) available. See DOI:
0.1039/c9ra01517e
selectivity of M5B and haloalkanes are favourable to
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a
2
Table 1 The bromination of aliphatic ketones with CuBr
detected even aer 24 h (Table 2, entry 11–13). These metal
bromides were also found to be inactive in bromination as noted
22,23
in previous studies.
The conventional bromination agent such
as Br , 2C H NOHBr$Br and NBS can obviously improve the
2
4
9
2
reaction (Table 2, entry 14–17), although they were lower than
that achieved with CuBr (Table 2, entry 6). Experiments that
screened for the bromine donors suggested that CuBr was the
2
2
most effective for the bromination of ML (Table 2, entry 6). Note
that a detailed study of the reaction conditions were discussed
(
Tables S1, S2 and Fig. S1†), and a high M5B yield over 85% was
ꢀ
obtained at 40 C for 5 h (detected by GC-MS, Fig. S3†).
As shown in Fig. 1, XRD patterns indicated that CuBr was
2
transformed into CuBr (PDF#06-0292) aer the reaction. When
TEMPO and 2,6-di-tert-butyl-4-methylphenol (BHT) were intro-
duced to eliminate free radical, no M5B was detected. Based on
these results, a mechanism for the current bromination process
was proposed, as shown in Scheme 2. Initially, Lewis acidity of
CuBr2 promoted the transformation from carbonyl keto to
a
Reaction condition: compounds ¼ 2.5 mmol, CuBr
2
¼ 1.67 g, solvent
ꢀ
¼
30 mL, temperature ¼ 40 C, time ¼ 4 h.
24
copper-bound enolate at the a-position. Subsequently, the
hemolysis of enolate to get ethenyloxy radical, and the reactive
group reacts with CuBr
equivalent of CuBr.
2
to generate an M5B along with an
Intensive efforts have been devoted to introduce the key
17,25–27
amino group on M5B.
Among them, a typical Gabriel
reaction using potassium phthalimide (KPI) as ammonia
resource has a promising commercial availability, however, only
ꢀ
27
a moderate M5P yield of 59% was achieved at 110 C for 12 h.
In this work, optimizing the experimental conditions of Gabriel
reaction including reaction time, temperature, the amount of
solvent and the molar ratio of KPI to M5B (Tables S3 and S4†)
was subsequently conducted, and a maximum M5P yield of 88%
Scheme 1 Synthesis of 5-ALA from ML.
a
Table 2 The bromination of ML to M5B
ꢀ
was obtained at 40 C for only 4 h (detected by GC-MS, Fig. S4†).
This signicant improvement is no doubt accelerate the prac-
tical application of 5-ALA. Finally, an acid hydrolysis process
was applied with 6 M HCl (Fig. S2†). The obtained products were
Entry
Bromine source
Solvent
CH OH
M5B yield (%)
1
2
3
4
5
6
7
8
9
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
2
2
2
2
2
2
2
2
2
2
3
50
7
CHCl
EA
3
ꢀ
concentrated in vacuum at 40 C to avoid the polymerization of
13
32
14
80
56
75
74
66
0
0
0
55
40
28
18
13
5
8
-ALA at high temperatures, affording a satised 5-ALA yield of
5% (Fig. S11 and 12†) (determined by HPLC, Fig. S5†).
In summary, we have developed a new efficient bromination
CH
CHCl
3
OH/EA (1 : 1)
/EA (1 : 1)
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
3
3
OH/CHCl
OH/CHCl
OH/CHCl
OH/CHCl
OH/CHCl
OH/CHCl
OH/CHCl
OH/CHCl
OH/CHCl
OH/CHCl
OH/CHCl
OH/CHCl
3
3
3
3
3
3
3
3
3
3
3
3
(1 : 1)
(4 : 1)
(3 : 1)
(1 : 3)
(1 : 4)
(1 : 1)
(1 : 1)
(1 : 1)
(1 : 1)
(1 : 1)
(1 : 1)
(1 : 1)
method for the conversion of biomass derived ML to 5-ALA,
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
b
b
b
ZnBr
MgBr
2
2
AlBr
Br
2C
3
2
4
H
9 2
NOHBr$Br
NBS + BPO
NBS + AIBN
a
Reaction condition: ML ¼ 0.33 g, bromine source ¼ 3 mole of ML,
ꢀ
b
solvent ¼ 30 mL, temperature ¼ 40 C, time ¼ 3 h. Time ¼ 24 h.
1
3,20,21
halogenation.
ratio of CH OH to CHCl
of M5B to 80% (Table 2, entry 6). We then proceeded to evaluate
various metal bromides, including ZnBr , MgBr , and AlBr
under the identical conditions. However, no conversion was Fig. 1 XRD pattern of catalyst.
Based on the above, changing the volume
3
3
(Table 2, entry 6–10), improved the yield
2
2
3
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