Knoevenagel condensation reactions catalysed by metal-organic frameworks
Andrew R. Burgoyne, Reinout Meijboom*
Research Centre for Synthesis and Catalysis, Department of Chemistry, University of Johannesburg, PO Box
524, Auckland Park 2006, Johannesburg, South Africa. Tel.: +27 (0)11 559 2367, fax.:+27 (0)11 559 2819;Email: rmeijboom@uj.ac.za
Supplementary information
Synthesis of Metal Organic Frameworks:
Preparation of IRMOF-3: Zn4O(BDC-NH2)3
O OH
NH2
DMF
+ Zn(NO3)2 . 6H2 O
NH2
110o C, 18h
IRMOF-3:
Zn4O(NH2BDC)3
O OH
Zn(NO3)2.6H2O (1.5 g, 5.04 mmol) and 2-aminobenzenedicarboxylic acid (0.3 g, 1.68 mmol) were dissolved in
100 cm3 of dimethylformamide (DMF). The solution was heated at 100 oC for 24 hours. Then the mixture was
cooled to room temperature and the solvent was decanted and the product was washed three times with fresh
DMF. Afterwards the product was left for 24 hours a further two times, after which the crystals which crushed
out were left in fresh chloroform. This yielded 50% product [20]. 1H NMR (d6-DMSO, 35% DCl in D2O, 400
MHz, p.p.m.): 7.40 (d, 1H, aromatic), 6.97 (s, 1H, aromatic), 6.90 (d, 1H, aromatic), 2.50 (d6-DMSO). 13C NMR
(d6-DMSO, 35% DCl in D2O, 400 MHz, p.p.m.): 170 (carboxylic), 136 (ipso-aromatic), 130 (aromatic). IR (cm1
): 3296 (νNH2), 3041 (νNH2), 1550, 1503, 1431, 1400 (ν C-O-Zn), 1314, 1054 (νC-N), 654, 896, 852, 808, 772, 726,
670, 621, 617, 614, 606. PXRD (2θ): 7.00, 9.83, 11.31, 13.86, 15.50, 17.94, 19.36, 20.74, 22.71, 24.65, 26.61,
28.34, 30.02, 31.76, 32.91, 34.78, 35.46, 36.23, 37.33.
Preparation of MIXMOF: Zn4O(BDC-NH2)0.15(BDC)2.85
O
O OH
OH
NH2
DMF
+
+ Zn(NO3 )2. 6H2O
O
O OH
NH2
110oC, 18h
OH
Zn(NO3)2.6H2O (11.90g, 40.000 mmol) and 2-aminoterephtalic acid (0.272 g, 1.500 mmol) and benzene
dicarboxylic acid (4.734 g, 28.500 mmol) were dissolved in 50 cm3 of DMF. The solution was heated at 40oC
(without stirring) for 7 days. After cooling to room temperature, the mother liquor was decanted and crystals
washed three times with 10 cm3 of dry DMF (dried over molecular sieves) followed by one rinse with 10 cm3 of
CHCl3. The crystals were then soaked in 10 cm3 of CHCl3 for three days with fresh CHCl3 added every day.
After three days of soaking, the crystals were stored in the last CHCl 3 until needed. This yielded 10.99 g [7]. 1H
NMR (d6-DMSO, 35% DCl in D2O, 400 MHz, p.p.m.): 8.15 (d6-DMSO), 7.12-7.00 (m, 4H, aromatic).
13
C
6
NMR (d -DMSO, 35% DCl in D2O, 400 MHz, p.p.m.): 168 (carboxylic), 135 (ipso-aromatic), 130 (aromatic).
IR (cm-1): 3262 (νNH2), 3048 (νNH2), 2936, 2360, 2164, 2034, 1960, 1667, 1570, 1550, 1504, 1375 (ν C-O-Zn),
1316, 1295, 1154, 1133, 1117, 1091, 1062 (ν C-N), 1018, 888, 823, 773, 747, 700, 634, 600, 578. PXRD (2θ):
6.99, 8.94, 9.71, 10.46, 12.77, 13.80, 16.13, 16.47, 16.90, 17.24, 17.80, 19.41, 20.79, 21.88, 23.05, 24.55, 25.38,
26.71, 27.37, 29.00, 29.55.
Preparation of UMCM-NH2: Zn4O(BDC-NH2)1.5(BTB)1.5
HO
HO
O
NH2
O
DMF
NH2
+
85 oC, 2 days
HO
O
HO
O
O
OH
Zn(NO3)2.6H2O (1.415 g, 4.755 mmol) and 2-amino-1,4-benzenedicarboxylic acid (0.144 g, 0.793 mmol) and
4,4’,4’’-benzene-1,3,5-triyl-tribenzoic acid (0.347 g, 0.793 mmol) were dissolved in 100 cm3 of DMF. The
solution was heated to 85 oC for 2 days and left to cool to room temperature. The mother liquor was decanted
and washed three times with 12 cm3 DMF. Following this the product was soaked in chloroform for 3 days,
washing with new chloroform every day. The product was dried under high-vacuum and yielded 2.34 g [8]. 1H
NMR (d6-DMSO, 35% DCl in D2O, 400 MHz, p.p.m.): 8.37 (d6-DMSO), 7.98-7.32 (m, 15H, aromatic). IR (cm1
): 3445 (νNH2), 3339 (νNH2), 2962, 2360, 1655, 1578, 1494, 1381 (ν C-O-Zn), 1258, 1091, 1061 (νC-N), 1016, 861,
798, 704, 660, 577, 562, 553, 542, 530. PXRD (2θ): 4.82, 7.02, 7.21, 8.97, 9.88, 10.91, 11.17, 12.25, 13.05,
13.70, 14.47, 15.46, 16.60, 18.17, 21.39, 23.51, 28.14.
70
60
Yield (%)
50
40
30
20
10
0
0
20
40
60
80
100
120
Time (minutes)
Figure 3: Knoevenagel condensation of benzaldehyde and ethyl acetoacetate in DMSO at 353 K catalysed by
IRMOF-3 (♦), aniline (■) and no catalyst (blank, ▲); n = 3 repeats.
140
60
50
Yield (%)
40
30
20
10
0
0
20
40
60
80
100
120
140
Time (minutes)
Figure 4: Knoevenagel condensation of benzaldehyde and ethyl acetoacetate in DMF at 353 (■); 333 (▲) or
313(♦) K) catalysed by IRMOF-3; n = 3.
60
50
Yield (%)
40
30
20
10
0
0
20
40
60
80
100
120
Time (minutes)
Figure 5: Knoevenagel condensation of benzaldehyde and ethyl acetoacetate in MeOH (▲) and EtOH (○) at
333 K catalysed by IRMOF-3; n = 3 repeats.
140
35
30
Yield (%)
25
20
15
10
5
0
0
20
40
60
80
100
120
140
Time (minutes)
Figure 6: Knoevenagel condensation of benzaldehyde and ethyl acetoacetate in DMF at 313 K catalysed by
IRMOF-3. Benzaldehyde (■) added first; ethyl acetoacetate (♦) added first; n = 3.
Statistical analysis
An ANalysis Of VAriance (ANOVA) was performed between groups of the final conversions of each catalytic
run at 130 minutes to statistically investigate the likelihood of such a result occurring for the heterogenous vs.
homogenous, solvent and temperature studies. This statistical analysis was selected over a Student’s t-test, for
these analyses, as only the variation between two groups can be compared at a time and with multiple sets of
data needing to be compared (heterogenous vs. homogenous – 3, solvent analysis – 5, temperature – 3) there are
a large number of resulting pairs to be compared against each other.
The 5 solvent triplicate results would generate 9 pairs of data to be compared. In so many pairings we should not
be surprised to observe things that happen only 5 % of the time and thus P = 0.05 cannot be considered
significant. ANOVA compiles all that data into a single number, the F ratio, which is the found variation of the
group averages to the expected variation of the group averages and a single probability, P, for Ho, the null
hypothesis. Thus the F ratio is the ratio between the variation of the experimental treatment and the variation
due to experimental error.
𝐹=
̅𝑖 − 𝑌̅)2 ⁄(𝐾 − 1)
∑𝑖 𝑛𝑖 (𝑌
found variation
=
̅𝑖 )2 ⁄ (𝑁 − 𝐾)
expected variation
∑𝑖𝑗 (𝑌𝑖𝑗 − 𝑌
̅𝑖 is the sample mean within the ith group which has ni observations and 𝑌̅ is the overall mean for the data
where 𝑌
and Yij is the jth observation within the ith out of K groups in a sample size of N
If the F ratio is equal to 1 then the treatment effect is the same as the experimental error and the experimental
treatment actually does not affect the outcome of the conversion in the catalytic cycle and the null hypothesis is
accepted. The null hypothesis states that there is no real effect in the conversion, of benzaldehyde and ethyl
acetoacetate or ethyl cyanoacetate in the Knoevenagel condensation, when the statistically analysed variable
such as temperature or solvent is changed. The null hypothesis can be rejected when the F ratio is significantly
larger than 1, such that the probability of it equalling 1 is less than 5 % as P < 0.05.
Besides the much larger conversion ability and larger kobs that IRMOF-3 has as compared to aniline or when no
catalyst is present the ANOVA F ratio, Table 1, was 237.4 which is significantly larger than 1, indicating a
large effect due to the presence of the IRMOF-3 catalyst, with P < 0.0001 thus Ho is rejected allowing the
alternative hypothesis to be accepted, which is that IRMOF-3 catalyses the Knoevenagel condensation of
benzaldehyde and acetoacetate.
The effect of choice of solvent was studied and the reliability of the differences in conversion of the substrate
over the range of solvents was studied using ANOVA. The choice of solvent, in promoting high reaction
conversion, was shown to be significant and have a large effect as F = 91.53, with P < 0.0001 thus Ho is rejected
allowing the alternative hypothesis to be accepted, which is that solvent choice is significant to determine the
reaction conversion in the Knoevenagel condensation of benzaldehyde and acetoacetate.
The conversions obtained when varying the temperature were also statistically analysed revealing that F = 79.00
and that temperature is also significant in determining the conversion of substrate, with P < 0.0001 thus Ho is
rejected allowing the alternative hypothesis to be accepted, which is that temperature is significant to determine
the reaction conversion in the Knoevenagel condensation of benzaldehyde and acetoacetate.
Table 1: ANOVA results for heterogenous vs. Homogenous, solvent and temperature studies
Mean
Median
reaction
reaction
95 % Confidence
Standard
conversion
conversion
Interval
deviation
(%)
(%)
IRMOF-3
64.533
64.60
60.30; 68.77
4.40
Aniline
27.633
29.40
22.78; 32.49
3.59
Blank
3.9000
4.20
-0.9530; 8.753
1.77
DMSO
64.533
64.60
60.30; 68.77
4.40
DMF
54.000
54.00
49.76; 58.24
0.500
MeOH
43.000
46.00
38.76; 47.24
5.20
EtOH
42.267
42.00
38.03; 46.50
1.42
Toluene
15.767
16.00
11.53; 20.00
2.36
353 K
54.000
54.00
50.32; 57.68
0.00
333 K
36.472
36.23
32.79; 40.15
1.42
313 K
27.733
26.50
24.05; 31.42
4.29
Factors compared
Heterogenous vs
Homogenous
Solvent
Temperature
F ratio
P
237.4
<0.0001
91.53
<0.0001
79.00
<0.0001
The Student’s t-test was selected as a statistical tool to investigate into the reliability of the differences within
the catalysed conversion of benzaldehyde and ethyl acetoacetate or ethyl cyanoacetate. In this test, developed by
Student (W. S. Gossett) for small data sets where few samples are taken, the calculated mean and standard
deviation might per chance deviate from the true mean and standard deviation. If the differences between the
two measured samples are large enough the null hypothesis, that the differences are in fact due to chance, should
be rejected. This occurs if P < 0.05.
As mentioned before the catalytic Knoevenagel condensation of benzaldehyde and ethyl acetoacetate at 353 K
in MeOH and EtOH gave what appeared to be similar results and the reaction was rerun at 333 K, which was
below their respective boiling points. A Student’s t-test on the conversion results of MeOH and EtOH at 353 K
proved that null hypothesis cannot be rejected as P = 0.825 and therefore must be accepted, thus the small
differences between the conversion and thus kobs and TOFs can be ignored, and that there is no significant
difference in the reaction conversion at 353 K between these two solvents. However, at 333 K significance was
seen between MeOH and EtOH in the catalytic conversion of benzaldehyde and acetoacetate as P = 0.003 and
the Ho must be rejected as the difference between the conversions of MeOH and EtOH are not by chance and the
conversion obtained is governed by the solvent chosen.
The order of addition of substrate into the reaction mixture was shown to be negligible by the statistical analysis
of the conversion when adding either benzaldehyde or ethyl acetoacetate first as P = 0.966. This high
probability is explained by the near exact replication of the conversion of substrate when adding either substrate
first into the reaction mixture.
Table 2: Student t-test results for solvent, order of addition and substrate studies
Mean
Factors compared
yield
(%)
Median
yield (%)
95 %
Confidence
Interval
Standard
deviation
Solvents
MeOH
43.0
46.0
36.90; 49.10
5.20
(353 K)
EtOH
42.3
42.0
36.16; 48.37
1.42
Solvents
MeOH
53.5
52.8
47.84; 59.23
2.19
(333 K)
EtOH
34.7
36.6
28.97; 40.36
4.52
Order of
Benzaldehyde
27.6
26.4
21.80; 33.40
2.80
substrate
Ethyl
addition
acetoacetate
27.7
26.5
21.93; 33.53
4.29
IRMOF-3
27.7
26.5
22.32; 33.15
4.29
MIXMOF
30.0
30.6
24.62; 35.45
2.11
IRMOF-3
27.7
26.5
21.52; 33.95
4.29
44.0
45.2
37.75; 50.18
3.42
IRMOF-3
62.3
62.5
58.19; 66.34
1.66
MIXMOF
62.9
63.5
58.86; 67.01
3.19
IRMOF-3
62.3
62.5
59.62; 64.92
1.66
73.1
72.5
70.48; 75.78
1.64
Ethyl
aceto
acetate
substrate
UMCM-1-NH2
Ethyl
cyano
acetate
substrate
UMCM-1-NH2
t value
Standard
P
deviation
0.236
3.81
0.825
-6.50
3.55
0.003
0.0451
3.62
0.966
-0.834
3.38
0.451
-5.13
3.88
0.007
-0.321
2.54
0.764
-8.05
1.65
0.001
In both cases of comparing IRMOF-3 and MIXMOF when catalysing the Knoevenagel condensation between
benzaldehyde and ethyl acetoacetate or ethyl cyanoacetate P = 0.451 and P = 0.764 respectively. These
significant probabilities indicate that the conversions obtained are significantly the same and their slight
disparities are random.
Lastly, the catalytic conversions of benzaldehyde and ethyl acetoacetate or ethyl cyanoacetate when using
UMCM-1-NH2 and IRMOF-3 were analysed using the Student’s t-test to compare their performance and
abilities relative to one another. In both compared cases, P < 0.05 outlining that UMCM-1-NH2 has a higher
ability than IRMOF-3 to catalyse the reaction and specifically of that between benzaldehyde and ethyl
cyanoacetate as P = 0.0001, which is less than P = 0.007 for that of the benzaldehyde and ethyl acetoacetate.