Investigation of DNA as a catalyst for Henry reaction in water

Article abstract of DOI:10.1039/b805767b

Double-stranded DNA of natural origin can be used to facilitate nitro-aldol (or Henry) reaction in aqueous solution. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805767b

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Investigation of DNA as a catalyst for Henry reaction in waterw
Jinmin Fan,a Gaojun Sun,a Changfeng Wan,a Zhiyong Wang*a and Yingfu Li*b
Received (in Cambridge, UK) 4th April 2008, Accepted 12th May 2008
First published as an Advance Article on the web 23rd June 2008
DOI: 10.1039/b805767b
Double-stranded DNA of natural origin can be used to facilitate
nitro-aldol (or Henry) reaction in aqueous solution.
(entries 7 and 8). That the presence of DNA was essential
was confirmed: when the DNA was omitted from the reaction
mixture, the yield dropped to merely 6% (entry 9). Moreover,
an excellent yield (90%) was registered when the DNA from a
different source (herring sperm) was used (entry 10). We also
observed that reaction yields were enhanced with an increase
in the amount of the DNA (see supporting information).w As
expected, a small synthetic dsDNA (the self-complementary
16-mer duplex d(TCAG)2(CTGA)2) also produced a similar
yield (87%; entry 11), which helps to rule out the possibility
that the catalysis might be caused by some unknown impurity
in the DNA from natural sources. Finally, an excellent yield
(96%) was obtained when the reaction was performed at 37 1C
(comparing entry 12 to entry 8).
DNA, with its characteristic right-handed helix structure and
well-defined geometry, is a robust biopolymer that can with-
stand a range of pH, temperature and solvent conditions.1
Recent years have witnessed the growth of interest in exploring
DNA for the construction of catalytic systems.2,3 For exam-
ple, many studies have used DNA as a catalyst in the ‘‘DNA-
templated organic synthesis’’ (DTS) where two small-molecule
substrates are linked to two separate DNA strands that are
held together on a complementary DNA template in one of
several geometries.3 The advantages of DTS include: (1) the
templated reaction proceeds much faster than the uncatalyzed
reaction, and (2) DTS could lead to the discovery of novel
chemical transformations.4 Recently, the Silverman group has
successfully performed in vitro selection experiments and
derived many DNA based enzymes that catalyze Diels–Alder
reaction.5 It has also been reported that DNA can mediate
chemical reactions in a highly enantioselective fashion.6 To the
best of our knowledge, however, exploiting unmodified dou-
ble-stranded DNA as a catalyst for organic reactions has not
been reported yet.
A series of experiments were then carried out from which we
established the following optimal reaction conditions to be
used in the remaining reactions of this work: 0.5 mmol scale,
0.5 mL of CH3NO2, 10 mg of salmon testes DNA, 3 mL of
20 mM MES buffer (pH = 5.5), 37 1C.z
We next studied the influence of DNA on the reaction time
and yield in reactions involving different carbonyl substrates.
Referring to Table 2, all the aromatic aldehydes generated the
Table 1 Screen for different solvents and reaction temperaturea
Nitro-aldol (or Henry) reaction is an important carbon–
carbon bond formation reaction widely used in organic synth-
esis.7 Henry reactions are usually performed in organic sol-
vents and only a few studies have involved water as the
reaction medium.8 Herein, we describe a straightforward use
of DNA as the catalyst to facilitate the Henry reaction in
water without tethering the substrates to any DNA strands.
We first examined the Henry reaction between p-nitrobenz-
aldehyde and nitromethane at 12 1C under various solvent
conditions (Table 1) in the presence of salmon testes DNA
(entries 1–6). Product formation was observed in all these
conditions. However, the yield in water (90%, entry 6) was
much better than those in organic solvents, such as methanol,
ethanol, ether, toluene and DMSO (entries 1–5). Similar
results were obtained in different aqueous buffer solutions
Entry
Solvent
T/1C
Yield (%)b
1
2
3
4
5
6
7
8
MeOH
EtOH
Et2O
Toluene
DMSO
H2O
MOPS, pH = 6.5
MES, pH = 5.5
MES, pH = 5.5c
MES, pH = 5.5d
MOPS, pH = 6.5e
MES, pH = 5.5
12
12
12
12
12
12
12
12
12
12
12
37
40
45
15
12
48
90
96
92
6
9
10
11
12
a
90
87
96
a Hefei National Laboratory for Physical Science at Microscale,
Joint-Lab of Green Synthetic Chemistry and Department of
Chemistry, University of Science and Technology of China, Hefei,
230026, P. R. China. E-mail: zwang3@ustc.edu.cn; Fax: (+86)
551-360-3185; Tel: (+86) 551-360-3185
All reactions were performed on 0.5 mmol scale, using 0.5 mL of
CH3NO2, 10 mg of salmon testes DNA, 3 mL of solvent (for organic
solvent, suspension was employed and the reaction was carried out in a
heterogeneous system; for aqueous buffer, concentration = 20 mM).
b Department of Biochemistry and Biomedical Sciences and
Department of Chemistry, McMaster University, Hamilton, Ontario,
Canada L8N3Z5. E-mail: liying@mcmaster.ca
w Electronic supplementary information (ESI) available: Procedure
for catalyst recycling, determination of the pH value of the DNA
aqueous solution (in super-pure water) and characterization data for
the products. See DOI: 10.1039/b805767b
b
Isolated yields are the average values of duplicate experiments
c
d
(standard deviation: ꢀ4%). Without DNA. With herring sperm
e
DNA. DNA = synthetic duplex d(TCAG)2(CTGA)2 (2.8 mM),
p-nitrobenzaldehyde (46.4 mM), nitromethane (186.0 mM). Buffer:
20 mM of MOPS, pH = 6.5, 150 mM of NaCl, 50 mM of MgCl2.
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3792 | Chem. Commun., 2008, 3792–3794

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Table 2 DNA as catalyst for Henry reaction in watera
Entry
R
t/h
Yield (%)b
1
2
3
4
5
6
7
8
4-NO2
2-NO2
4-Br
4-Cl
3-Cl
2-Cl
4-F
H
4-OMe
2-OMe
4-Me
4-OH
2-OH
1-Naphthaldehyde
R = H, X = N
1-(Pyridin-2-yl)ethanone
2-Phenylacetaldehyde
i-But
8
8
96
92
80
77
76
78
74
82
70
75
88
76
82
25
93
88
67
64
Trace
82
24
24
36
36
36
72
72
72
72
72
72
72
8
Fig. 1 Recycling experiments for the Henry reaction. The reaction is
performed for 12 h using 0.5 mmol of the aldehyde, 0.5 mL of
CH3NO2, 10 mg of salmon testes DNA, 3 mL of solvent in 20 mM
MES (pH = 5.5). Isolated yields are the average values of duplicate
experiments (standard deviation: ꢀ3%).
9
10
11
12
13
14
15
16
17
18
19
20c
that without DNA, all the substrates produced no (or trace
amounts of) Henry reaction product. We also found that the
DNA-mediated Henry reaction can be performed on a large
scale with a very good yield (entry 20).
36
72
72
48
48
We also investigated the recycling of the catalytic DNA.
Fig. 1 shows the efficiency of the same catalyst used five times
to catalyze the reaction of p-nitrobenzaldehyde and nitro-
methane under the optimized reaction conditions. Even after
the fifth round, no reduction in reaction yield was observed.
Considering that DNA possesses a right-handed helix struc-
ture, the chiral information within DNA may transfer to the
organic reaction products. Thus, we also performed experi-
ments to test the chiral selectivity of the DNA-mediated Henry
reaction. However, no ee value was observed, indicating that
the DNA catalyst does not provide a chiral selectivity under
our conditions.
Acetone
4-NO2
a
All reactions were performed on 0.5 mmol scale, using 0.5 mL of
CH3NO2, 10 mg of salmon testes DNA and 3 mL of solvent; for
b
aqueous buffer, concentration = 20 mM. Isolated yields are the
average values of duplicate experiments (standard deviation: ꢀ4%).
c
Reaction is performed on 10 mmol scale using 30 mg of salmon
testes DNA in the optimized conditions.
corresponding Henry reaction products with good to excellent
yields (entries 1–13). Generally, electron-withdrawing substi-
tuents on the phenyl ring of 1 favored the reaction (entries
1–7). More specifically, benzaldehyde produced a yield of 82%
(entry 8) in a 72-h reaction. The aromatic aldehydes bearing
strong electron-withdrawing substituents (entries 1 and 2) had
better reactivities and gave better yields than those bearing
weak electron-withdrawing substituents (entries 3–7). In con-
trast, the aromatic aldehydes with electron-donating substitu-
ents produced slightly lower yields than benzaldehyde (entries
9–13). In these cases, an ortho-substitution had a greater
influence on the reaction than a para-substitution (entries 9,
10, 12 and 13). On the other hand, the steric hindrance of the
reaction substrates also affected the reaction. For instance, 1-
naphthaldehyde, with a bigger steric hindrance than benzal-
dehyde, gave rise to a low yield of the Henry reaction product
(25%), accompanied by a dehydrated product, 2-((E)-2-nitro-
vinyl)naphthalene in 42% yield (entry 14). When an aliphatic
ketone, which has more steric hindrance than aldehydes, was
employed in the reaction almost no product was observed
(entry 19). Notably, excellent yields were obtained for nicotin-
aldehyde and 1-(pyridin-2-yl)ethanone after 8 h and 36 h,
respectively (entries 15 and 16). Aliphatic aldehydes, such as
pivalaldehyde and 2-phenylacetaldehyde, also generated the
desired Henry reaction product with good yields (64% and
67%, entries 18 and 17, respectively). It is important to note
In summary, we have shown that double-stranded DNA
from natural sources can be used as a catalyst to facilitate the
Henry reaction in aqueous solution under mild reaction con-
ditions. Most of the substrates we tested resulted in good
(B60%) to excellent (490%) yields of the expected reaction
products. More interestingly, the DNA catalyst could be
recycled several times without any loss of activity. The me-
chanism of the DNA-catalyzed Henry reaction as well as the
scope of other reactions that may be catalyzed by natural
DNA will be the subjects of future investigations by us.
Double-stranded DNA is conveniently available from a
variety of natural sources (including bacteria and plants).
Therefore, the direct use of DNA to facilitate organic synthesis
in aqueous solution may offer an excellent way to prepare
useful organic compounds.
This work was supported by the National Natural Science
Foundation of China (20628202).
Notes and references
z Representative procedure for DNA-catalyzed nitro-aldol or Henry
reaction: to an aqueous MES buffer solution (20 mM, pH = 5.5) was
added DNA (herring sperm or salmon testes DNA 10 mg, purchased
from Sigma). After 10 min, 0.5 mmol of p-nitrobenzaldehyde in 0.5 mL
of CH3NO2 was added. After the mixture was heated at 37 1C for 8 h,
the mixture was extracted three times with chloroform. The combined
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organic extracts were dried with anhydrous Na2SO4 and evaporated
under reduced pressure; the residue was then purified by column
chromatography over silica gel to afford the corresponding Henry
product with high purity. 1H NMR (CDCl3, 300 MHz, ppm): d 8.25
(d, J = 8.4 Hz, 2 H), 7.61 (d, J = 8.4 Hz, 2 H), 5.57–5.62 (m, 1 H),
4.57 (m, 2 H), 3.18 (br, 1 H).
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This journal is The Royal Society of Chemistry 2008
3794 | Chem. Commun., 2008, 3792–3794