4.2 Nitration of Vanillin
4.2.4 Continuous experiments in 5 mL reactor
reactor The rea through system decided reaction
MS experim n, 3,4-dihyd trated prod with HNO3
analysis of t dihydroxy-5 us the corres
omer was n onding carb
280 O
H
e 74. Nitrati
ontinuous ex st continuo
in order to actions wer h the pump are cerami d to use HNO n stream wa
ments revea droxybenza ducts of 280
3, and corre the reaction 5-nitrobenza sponding 2 not determ boxylic acid
1 equiv HN AcOH,
ion of 3,4-d
experiments ous experim be able to re carried o s into the ic and high O3 as a dilu as analyzed
aled that th aldehyde 2 0. To confir sponding p n mixture (S aldehyde 28 - or 6-nitra ined. HPLC ds of 281 an
NO3(60-w%) rt, 5 min
22 2
dihydroxybe
in 5 mL rea ments were
visually mo out by feed
heated reac hly resistant ute solution d by HPLC
he impurity 280. Impur rm the resu eaks of mo Scheme 74) 81 was analy ated isomer C/MS expe nd 282, but i
) HO HO
282: 25 (A)%
281: 13% at 2,6-dinitratio
enzaldehyde
actor carried out onitor both ding stock
ctor coil. A t to a wide in AcOH to . Temperatu
at 4.14 is rities at 7 ults, an auth ononitrated p
. In a simila yzed and co 282 is the eriments al in minor am
NO2 281
O H
% on HPLC a rt 7.7; isome on product (p
e 280
t with a tra reaction in solutions o Although th e range of o minimize ure, concen
the demeth 7.7 and 8 hentic samp products we ar manner, a onfirmed as impurity at lso indicate mounts.
HO HO
2 +
analysis of rx eric282(puta
utative): 17%
ansparent 5 nitiation and of vanillin a he pump he
conditions possible co ntration of s
hylation pro 8.5 were i ple of 280 w
ere observe an authentic
the impurit at 8.5, but t
ed the pres
282 O
H NO2(2- o
xn mixture at ative): 12% a
% at rt 12.0
5 mL HT-P d possible b and HNO3
eads in the and chemi orrosive effe
stock soluti
oduct of isomeric was also ed via an c sample ty at 7.7, he exact sence of
or 6-)
rt 8.5 at rt 9.4
PFA coil blocking.
directly Uniqsis cals, we ects. The ions and
107 residence time were varied during the experiments. The temperature was varied from 65 °C to 105 °C and residence time from 1 to 5 minutes. The concentration of stock solutions was varied from 0.30 M to 0.55 M. Some variation in HNO3 stoichiometry was explored, but mostly a small excess was enough to ensure full conversion. Thus, in a general experiment, flow rates of both lines were kept equal, and the stoichiometry was determined by the concentration of the stock solutions.
Chart 2 presents the results according to constant residence time and variable temperature.
The concentration of stock solutions was 0.30 M (271) and 0.32 M (HNO3), and the residence time 3.33 minutes, equating to a combined flow rate of 1.50 mL/min. From the chart it may be seen that the conversion of vanillin is enhanced at higher temperature from 98.3% to above 99%, and the amount of 272 is raised correspondingly. The main impurities are the demethylation product 280, isomeric nitration-demethylation product 282, and 275. Curiously, the amount of 280 is higher at higher temperatures, and correspondingly the amount of nitration product 282 decreases.
Chart 2. Nitration of 271 in 5 mL coil at constant residence time of 3.33 min and varying temperature at stock solution concentrations of 0.30 M (271) and 0.32 M (HNO3).
Chart 3 shows the variation of the crude reaction mixture according to residence time at a constant temperature of 70°C. The stock solution concentrations were 0.35 M 271 and 0.38 M HNO3. The conversion of vanillin stays nearly constant at over 99.5% under these conditions,
0 1 2 3 4 5 6 7 8
87 88 89 90 91 92 93
70 80 90 100 110
Impurities A-%
272 A-%
T(°C)
272 271 280 282 275 276
108
and the longer residence time also seems to be beneficial for the selectivity of 272.
Correspondingly, the main impurity 282 is found in smaller amounts at longer residence times.
The reason for this remains unclear, but it may be due to the change of encounter velocity of the reactant streams at the T-piece and subsequent diffusion-controlled mixing during the flow through the reactor. Due to the integrated pressure sensor of the Uniqsis FlowSyn system, we were not able to test differently shaped mixing pieces, as the pressure data was crucial for monitoring the condition of the system.
Chart 3. Nitration of 271 at 70 °C and varying residence time at stock solution concentrations of 0.35 M (271) and 0.38 M (HNO3).
Further selected results from continuous experiments in 5 mL coil are presented in Table 13.
The best selectivity from a single experiment is shown in Entry 1, with stock solution concentrations of 0.40 and 0.43 M. The conversion of 271 was 99.2% and selectivity of 272 94.2%, with 282 being the most significant impurity. From entries 1-4 it can be seen that increasing the temperature too high may be detrimental to the selectivity. Entries 5-8 highlight the stoichiometry of HNO3, with the surprising result that going from 1.3 equivalents to 1.7 equivalents at 70 °C has no significant effect on product distribution. The presence of 5% of H2O in the stock solution of 271 has a slight detrimental effect on conversion at lower temperatures, but at 90–100 °C the conversions and selectivities are once again at around 99.9%
and 92.2% (entries 9-12). When the reaction is run at 105 °C, shortening the residence time once again has the effect of lowering selectivity (entries 13-16). Entries 17 and 18 are performed at the same temperature and with the same residence time, but the reactor coil was
0 1 2 3 4 5 6 7 8
88 89 90 91 92 93 94
0 2 4 6
Impurities A-%
272 A-%
Residence time (min)
272 271 280 281 282 275
109 changed from a 5 mL HT-PFA coil to 10 mL stainless steel coil in the latter experiment. The conversion and selectivity were improved upon changing to the longer coil. The flow rates are doubled, which might be beneficial for mixing. Likewise, the thermal properties of the reactor change significantly based on the material, steel being a much better heat conductor than perfluoroalkoxy polymers. Indeed, the coil and back-pressure regulator were blocked almost immediately after obtaining the HPLC sample due to rapid cooling of the reaction mixture and subsequent precipitation of 272. The working concentrations were judged to be nearing their practical limits within our reactor setup.
Table 13. Selected results from continuous reactions in 5 mL reactor coil
Entry c(271/M) tR (min) T(°C) 271 272 280 281 282 275 276 1 0.40 2 80 0.753 94.22 0.902 0.871 1.517 0.678 0.189 2 0.40 2 90 0.273 92.994 1.297 1.217 1.887 0.845 0.18 3 0.40 1.7 90 0.083 91.901 1.327 1.355 2.207 0.988 0.176 4 0.40 1.7 100 0.085 91.449 1.703 1.503 1.556 1.335 0.137 5 0.35a 2.9 70 20.409 73.853 0.948 n.d. 3.449 0.035 0.043 6 0.35b 2.5 70 3.3 89.438 0.927 n.d. 5.102 0.059 0.065 7 0.35c 2.2 70 0.765 91.792 1.036 n.d. 5.195 0.091 0.084 8 0.35d 2.5 70 0.117 91.953 1.099 n.d. 5.237 0.108 0.119 9 0.35 3.3 70 42.284 53.87 0.79 n.d. 2.198 0.064 0.04 10 0.35 3.3 80 11.955 81.766 0.964 n.d. 3.934 0.072 0.092 11 0.35 3.3 90 0.085 92.189 1.81 1.419 2.331 0.344 0.179 12 0.35 3.3 100 0.114 92.112 2.155 1.515 1.702 0.521 0.147 13 0.30 3.3 105 0.878 91.293 2.303 n.d. 1.946 0.893 0.081 14 0.30 2.5 105 1.119 90.594 2.249 n.d. 1.358 0.847 0.089 15 0.30 1.7 105 0.852 90.179 2.029 n.d. 2.805 0.862 0.119 16 0.30 1 105 0.931 89.818 1.928 n.d. 3.488 0.84 0.092 17 0.55 5 90 9.182 88.949 0.99 1.547 1.656 0.903 0.211 18 0.55 5 90 2.412 91.546 0.802 1.151 1.284 0.677 0.365 a) 0.80 equivalents of HNO3. b) 1.05 equivalents of HNO3. c) 1.30 equivalents of HNO3. d) 1.75
equivalents of HNO3.
110
Experiments performed with stock solutions of 0.45 M 271 and 0.50 M HNO3 are shown in Table 14. Within this parameter range (temperature 75-95 °C, residence time 1.5-3.5 minutes) the reaction was functioning quite well in a robust fashion (entries 1-7). The conversion was excellent in all cases, and selectivity of 272 was nearly constant, with parameter variation leading mostly to changes in the composition of impurities – even with 2 equivalents of HNO3 (entry 8). This was the optimal and most consistent series of experiments in the 5 mL coil. At higher concentrations the conversion of 271 started to suffer, and in many cases full conversion was not reached.
Table 14. Continuous experiments in 5 mL coil with 0.45 M and 0.50 M stock solutions
Entry tR (min) T(°C) 271 272 280 281 282 275 276 1 3.3 75 0.17 91.87 1.01 0.223 5.475 0.248 0.094 2 2 75 0.284 91.296 1.065 0.149 5.724 0.204 0.085 3 3.3 85 0.126 91.992 1.663 1.071 2.954 0.577 0.151 4 2 85 0.146 91.375 1.477 0.901 3.774 0.587 0.136 5 3.3 95 0.125 92.567 1.839 1.374 1.342 0.764 0.143 6 2 95 0.095 92.142 1.853 1.339 1.878 0.795 0.132 7 1.4 95 0.129 92.124 1.771 1.308 2.247 0.757 0.130 8a 2.2 95 0.156 92.132 0 0.629 0.317 1.89 0.765 a)2 equivalents of HNO3 were used, and 2.189% of a previously disregarded impurity at Rrt 1.22 observed.