Facile alcoholysis of l-lactide catalysed by Group 1 and 2 metal complexes

Article abstract of DOI:10.1039/b800308d

The application of simple metal amides MN(SiMe₃)₂ as effective catalysts for the alcoholysis of cyclic esters are demonstrated. Excess dry methanol and L-lactide were added to a Schlenk flask at room temperature (RT) 1 mol% of MN(SiMe₃)₂, where M = Li, Na or K was added. A blank test was also performed where no catalyst was added giving no reaction. The conversion of M = Li, 45% to methyl (S,S)-lactyllactatewas obtained in 10 minutes at room temperature. Similar behaviors were observed for m = Na and K, where the reactions decelerated after 20 and 30 minutes. The application also extended to other cyclic esters such as capralactone where the ring-opening product was obtained rapidly in quantitative yield.

Full text of DOI:10.1039/b800308d

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Number 23 | 21 June 2008 | Pages 3017–3124
ISSN 1477-9226
COVER ARTICLE
Phomphrai et al.
ARTICLE
Guo et al.
Facile alcoholysis of L-lactide
catalysed by Group 1 and 2 metal
complexes
Eꢀect of adenine moiety on DNA
binding property of copper(II)–
terpyridine complexes

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COMMUNICATION
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Facile alcoholysis of L-lactide catalysed by Group 1 and 2 metal complexes†
Khamphee Phomphrai,* Supathana Pracha, Phenphak Phonjanthuek and Manat Pohmakotr
Received 9th January 2008, Accepted 18th April 2008
First published as an Advance Article on the web 1st May 2008
DOI: 10.1039/b800308d
Alkyl (S)-lactate and alkyl (S,S)-lactyllactate were rapidly
and conveniently synthesized from L-lactide using Group 1
and 2 metal complexes as catalyst in alcohol.
Lactic acid is one of the safe and environmentally friendly
compounds used in the food, pharmaceutical, cosmetic, and textile
1
industries. The applications extend beyond its simple monomeric
structure where esters, oligomers, and polymers of lactic acid have
Scheme 2
also found numerous uses. Lactate and lactyllactate esters of low
molecular weight alcohols are colorless and odorless liquids. The
low vapor pressure has made them suitable as green solvents and
where Novozym 435 was used in the alcoholysis of rac-lactide
selectively giving alkyl (R)-lactate and alkyl (S,S)-O-lactyllactate
in 8 h at room temperature. Most systems reported to date either
required a protecting strategy, a stoichiometric amount of catalyst,
or long reaction times at high temperatures. Thus, a more effective
synthesis of alkyl lactate and alkyl lactyllactate is needed.
6
2
plasticizers.
Alkyl lactates can simply be synthesized from the reaction
3
of lactic acid with excess alcohol (Scheme 1). However, the
reaction usually required reflux at high temperature and long
reaction times. Product distribution was also a major problem
with this method where by-products such as short-chain oligomers
of lactic acid were usually formed. Thus, product separation and
purification were needed afterwards.
In order to maximize atom efficiency, we turned to the system
shown in Scheme 2 where every atom in the starting materials
was used in the reaction. Furthermore, the synthesis of alkyl
lactate and alkyl lactyllactate needed to be catalytic rather than
stoichiometric. Several research groups have shown that single-
site metal alkoxide complexes containing suitable metals and
ligand sets were fast and effective catalysts for the ring-opening
7
polymerisation of lactides. With this in mind, we focused on metal
alkoxide complexes. In order to prevent polymerisation, excess
dry alcohol was required to promote chain transfer (Scheme 3).
However, excess alcohol such as methanol was normally added to
quench the polymerisation in standard lactide polymerisation.
Scheme 1
Because lactic acid has both hydroxyl and carboxylic groups
in the same molecule, intermolecular esterification can easily
occur giving oligolactates. One way to solve this problem was
to use a protecting group strategy. Early synthesis of alkyl
lactyllactates was from the reaction of potassium lactate and ethyl
2
-chloropropionate. However, this method was complicated and
inconvenient. A better synthesis was later developed by Claborn
using alcoholysis of lactide in benzene with a trace of benzene
4
sulfonic acid as catalyst (Scheme 2). Nonetheless, this process
required long reaction times at reflux temperature. Feijen et al.
showed that calcium bisalkoxides generated in situ could ring-
i
open lactides when [lactide] : [ PrOH] : [Ca] = 2 : 8 : 1 was used in
5
THF at room temperature giving isopropyl lactyllactate. This
method used a stoichiometric amount of calcium bisalkoxide to
prevent further ring-opening polymerisation to polylactide. An
interesting enzymatic system was recently developed by Lee et al.
Scheme 3
Thus, if excess alcohol was used in our system, it would simply
destroy the ligated metal alkoxide complexes. To allow the presence
of excess alcohol in the reaction, we turn to a simple metal alkoxide
MOR where M = Li, Na, or K. The excess alcohol would simply
exchange rather than destroy the metal alkoxide.
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6
Road, Bangkok, 10400, Thailand. E-mail: sckpp@mahidol.ac.th; Fax: +66
2
-354-7151; Tel: +66 2-201-5146
†
Electronic supplementary information (ESI) available: Experimen-
In order to make the system simple to use and applicable to most
alcohols, commercially-available and easy-to-handle metal amides
tal procedures, characterization of all alkyl (S)-lactate, methyl (S,S)-
lactyllactate, and methyl 6-hydroxyhexanoate. See DOI: 10.1039/
b800308d
MN(SiMe
3
)
2
where M = Li, Na, K were used. Metal alkoxides will
3
048 | Dalton Trans., 2008, 3048–3050
This journal is © The Royal Society of Chemistry 2008

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Table 1 Summary of methanolysis of L-lactide using metal amides as
catalyst precursors
lactide was attempted using 1 mol% Ca[N(SiMe ) ] ·2THF at
3
2 2
room temperature. As anticipated, the reaction proceeded very
quickly giving 87% methyl (S,S)-lactyllactate in only 5 min under
the same conditions. However, a close inspection of the H NMR
◦
a
b
Catalyst
T/ C
t/min
%LA
%MLL
1
LiN(SiMe
3
)
2
RT
RT
RT
55
10
55
53
53
52
42
40
39
40
38
25
17
16
46
28
19
3
45
47
47
48
58
60
61
60
62
75
83
84
54
72
81
97
spectrarevealednew resonances atd
.24 (q, 1H) ppm in addition to the chemical shifts of methyl (S,S)-
lactyllactate. The new species was identified as methyl (S)-lactate
see ESI†) and found at about 4% compared to the original lactide
concentration. That means the highly active calcium alkoxides
are capable of attacking not only the cyclic lactide but also
the less active linear methyl (S,S)-lactyllactate. At longer times,
the concentration of methyl (S)-lactate continued to increase
while the concentration of methyl (S,S)-lactyllactate decreased.
Nonetheless, the formation of methyl (S)-lactate increased rather
slowly from 4% in 5 min to 11% in 1 h. The considerably slow
rate implied a catalyst deactivation possibly as metal alkoxide
aggregation.
H
1.34 (d, 3H), 3.70 (s, 3H), and
2
3
6
0
0
0
4
(
NaN(SiMe
3
)
2
10
2
3
6
0
0
0
KN(SiMe
3
3
)
2
10
2
3
6
0
0
0
KN(SiMe
)
2
10
2
3
6
0
0
0
Subsequent experiments were then performed by increasing the
Reaction conditions: Lactide (0.500 g, 3.47 mmol), methanol (8.0 mL),
a
b
catalyst (1 mol%, 34.7 lmol). LA = L-lactide. MLL = methyl (S,S)-
amount of Ca[N(SiMe
3
)
2
]
2
·2THF to 5 mol% in order to enhance
lactyllactate.
the methyl (S)-lactate formation before the catalyst deactivation
set in. At 5 min and room temperature, methyl (S)-lactate was
obtained exclusively in quantitative yield. The mechanism for
the formation of methyl (S,S)-lactyllactate and methyl (S)-lactate
using metal amide as catalyst is proposed in Scheme 4. Metal
amide did not directly attack lactide but was transformed into
metal methoxide in the pressence of excess dry methanol before
further methanolysis of L-lactide took place. This mechanism
be generated in situ upon mixing with alcohol eliminating the need
to synthesize MOR in advance. To test our hypothesis, excess dry
methanol and L-lactide were added to a Schlenk flask at room
temperature (RT). 1 mol% (compared to lactide) of MN(SiMe
3 2
)
where M = Li, Na, or K was added. At different times, small
aliquots were taken and quenched with 2 drops of acetic acid. After
was confirmed by the absence of a –C(O)N(SiMe
3
2
) chemical
1
solvent removal, the samples were analysed by H NMR. With
shift in the ring-opening product. The metal methoxide reacted
with lactide giving the ring-opened product. Chain transfer with
excess methanol subsequently took place giving methyl (S,S)-
lactyllactate and metal methoxide. This catalytic cycle continued
giving methyl (S,S)-lactyllactate for Group 1 metal amides. For the
more active Group 2 metal complex, methyl (S,S)-lactyllactate re-
acted further with metal methoxide giving methyl (S)-lactate. The
other equivalent of methyl (S)-lactate was obtained subsequently
after proton exchange with excess methanol. At the end of the
1
time, H NMR showed the disappearance of L-lactide resonances
at d
1.46 (d, 3H), 1.49 (d, 3H), 3.72 (s, 3H), 4.33 (q, 1H), and 5.15
q, 1H) ppm. The new compound was identified as methyl (S,S)-
H
5.02 and 1.60 ppm and an appearance of new resonances at
d
H
(
lactyllactate (see ESI†). The results are summarized in Table 1.
Table 1 shows that methyl (S,S)-lactyllactate was formed
catalytically for all metal complexes. The final conversions to
methyl (S,S)-lactyllactate at 60 min were 48, 60, and 84% for
MN(SiMe
3
)
2
where M = Li, Na, and K, respectively. A blank
test was also performed where no catalyst was added giving no
reaction. From %conversion of methyl (S,S)-lactyllactate, the
general reactivity of MOR (generated in situ) was in the order
K > Na > Li attributed to the difference in polarity of the M–
OR bond. For M = K, the metal is more electropositive. Thus, the
−
alkoxide oxygen has more d charge making it a better nucleophile
to attack lactide.
For M = Li, 45% conversion to methyl (S,S)-lactyllactate was
obtained in 10 min at room temperature. However, the reaction
stopped shortly after that at about 48% conversion. Similar
behaviors were observed for M = Na and K where the reactions
decelerated after 20 and 30 min, respectively, possibly due to the
n
formation of metal alkoxide aggregates of the type [MOR] . The
aggregation decreased the amount of active MOR in the reaction.
◦
To increase the reactivity, the reaction was performed at 55 C
for KN(SiMe
S,S)-lactyllactate in almost quantitative yield in 1 h.
In addition to Group 1 metal complexes, Group 2 metal
3
)
2
. The methanolysis proceeded faster giving methyl
(
complexes were also surveyed. Chisholm and Feijen and co-
workers reported that calcium alkoxide complexes were highly
5,8–10
active for lactide polymerisation.
Thus, methanolysis of L-
Scheme 4
This journal is © The Royal Society of Chemistry 2008
Dalton Trans., 2008, 3048–3050 | 3049

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Table 2 Summary of alcoholysis of L-lactide using Ca[N(SiMe
3
)
2
]
2
·2THF
in excess dry methanol at room temperature. The reaction
proceeded very rapidly and the ring-opened product methyl 6-
hydroxyhexanoate (see ESI†) was obtained in quantitative yield in
only 5 min.
as a catalyst precursor
In conclusion, we have demonstrated the application of simple
metal amides as effective catalysts for the alcoholysis of cyclic
esters. Group 1 metal complexes catalyzed the methanolysis of
L-lactide giving methyl (S,S)-lactyllactate rapidly in high yield.
For the more active calcium amides, the reaction proceeded
further giving methyl (S)-lactate very rapidly and exclusively.
Alcoholysis of L-lactide using a slight excess of ethanol, n-butanol,
and benzyl alcohol gave alkyl (S)-lactate very rapidly in high
yield. The application also extended to other cyclic esters such
as e-caprolactone where the ring-opened product was obtained
rapidly in quantitative yield. This method was proven to be much
more effective and more selective than the conventional acid-
catalyzed esterification method where short-chain oligomers of
lactic acid were usually formed. Well-defined single-site catalysts
for alcoholysis and transesterification are being developed in our
laboratory to solve the problems of metal alkoxide aggregation.
We acknowledge financial support from Commission on Higher
Education and The Thailand Research Fund. Financial support
from the Center for Innovation in Chemistry: Postgraduate
Education and Research Program in Chemistry (PERCH-CIC),
Commission on Higher Education, Ministry of Education is
gratefully acknowledged. This work is supported in part by
funding from Faculty of Science and Center of Alternative Energy,
Mahidol University. We thank Phongnarin Chumsaeng for the
artwork of the cover.
◦
a
Entry
R
T/ C
t/min
%AL
1
2
3
4
5
Me
Et
30
30
30
30
30
10
10
10
5
94
92
92
95
48
n
Bu
CH
2
Ph
i
Pr
60
Reaction condition: Lactide (0.500 g, 3.47 mmol), HOR (2.2 equiv.,
.94 mmol), Ca[N(SiMe
6
3
)
2
]
2
·2THF (5 mol%, 174 lmol), toluene (4 mL),
a
room temperature. AL = alkyl (S,S)-lactate.
reaction, excess methanol can be removed under reduced pressure
for recycling. The result from chiral HPLC of methyl (S)-lactate
revealed no sign of methyl (R)-lactate indicating that epimerisation
was negligible in this system.
In addition to methyl (S)-lactate, we have attempted to synthe-
size other alkyl (S)-lactates using ethanol, isopropanol, n-butanol,
and benzyl alcohol with a similar approach. We also attempted
to minimize the amount of alcohol for future applications where
alcohol could be expensive or difficult to remove from the product.
The results are summarized in Table 2. By using only a slight
excess of alcohol (2.2 equiv.) in toluene as a solvent, we were
able to synthesize alkyl (S)-lactate rapidly in high yield for
Notes and references
1
R. Datta and M. Henry, J. Chem. Technol. Biotechnol., 2006, 81, 1119–
129.
D. Wyffels, US Pat., 5 688 850, 1997.
primary alcohols (entries 1–4). For a secondary alcohol (entry
, PrOH), the reaction proceeded much more slowly giving 48%
1
i
5
2
isopropyl (S)-lactate in 1 h. Data at shorter sampling times
revealed interesting information. NMR data of entry 5 at 5 min
revealed a complete consumption of lactide giving 59% isopropyl
3 G. Martino-Gauchi and R. Teissier, US Application Publication,
0060014976, 2006.
2
4
5
H. V. Claborn, US Pat., 2 371 281, 1945.
Z. Zhong, S. Schneiderbauer, P. J. Dijkstra, M. Westerhausen and J.
Feijen, J. Polym. Environ., 2001, 9, 31–38.
(
S,S)-lactyllactate, 13% isopropyl (S)-lactate and 27% oligomers.
At longer times, isopropyl (S,S)-lactyllactate and oligomers were
slowly consumed giving isopropyl (S)-lactate. This observation
suggested that the transesterification of alkyl (S,S)-lactyllactate
was slower for secondary alkoxides compared to the primary
alkoxides.
6 N. Y. Jeon, S.-J. Ko, K. Won, H.-Y. Kang, B. T. Kim, Y. S. Lee and H.
Lee, Tetrahedron Lett., 2006, 47, 6517–6520.
7
O. Dechy-Cabaret, B. Martin-Vaca and D. Bourissou, Chem. Rev., 2004,
1
04, 6147–6176.
8 M. H. Chisholm, J. Gallucci and K. Phomphrai, Chem. Commun., 2003,
8–49.
M. H. Chisholm, J. C. Gallucci and K. Phomphrai, Inorg. Chem., 2004,
4
9
To further demonstrate the effectiveness of alcoholysis of
cyclic esters using metal amides as catalyst, methanolysis of e-
4
3, 6717–6725.
1
0 Z. Zhong, P. J. Dijkstra, C. Birg, M. Westerhausen and J. Feijen,
caprolactone was performed using 1 mol% Ca[N(SiMe
3
)
2
]
2
·2THF
Macromolecules, 2001, 34, 3863–3868.
3
050 | Dalton Trans., 2008, 3048–3050
This journal is © The Royal Society of Chemistry 2008