Electrophilic aromatic substitutions are an important class of synthetic organic chemistry reactions, as they allow for the introduction of different functional groups onto an aromatic ring. They are reactions in which an atom, typically a proton (H+), on an aromatic ring such as benzene is replaced by a strong electrophile (E+). The electrophile usually has a positive charge and is substituted onto the aromatic ring. The nucleophile is the aromatic ring which contains conjugated double bonds with electrons available to be donated to the electrophile. Some examples of important electrophilic aromatic substitutions include nitration, halogenation, F-C alkylation/acylation, and sulfonation. The overall mechanism for these reactions consist of a series of steps; some of the major steps include: the formation of a suitable electrophile, the formation of a sigma complex, and removal of a proton to regain aromaticity. Aromatic nitration involves the reaction of benzene with a mixture of nitric acid (HNO3) and sulfuric acid (H2SO4). Sulfuric acid is a catalyst which allows for the nitration reaction to occur at a faster rate and at relatively lower temperatures. The nitronium ion is formed upon protonation of nitric acid by sulfuric acid to form the strong electrophile, NO2+ which reacts with benzene in order to form a sigma complex. The positive charge of the sigma complex is stabilized by resonance from the ring’s double bonds. Following the attack on the electrophile and the formation of the sigma complex, a proton is abstracted to re-form the double bond, remove the positive charge, and regain aromaticity of the benzene ring. The final compound is the aromatic nitration reaction product, where an NO2 group ended up replacing a proton on the aromatic ring. The mechanism is shown further below in the introduction.Substituents on the aromatic ring have different effects on reaction rates and directing abilities. Activating groups donate electron density to the ring through inductive or resonance (pi) stabilization. They increase reaction rate because the aromatic ring is better able to react with the electrophile since it has greater electron density available for the substitution reaction. For example alkyl groups are not electronegative, so they are electron donating activators through inductive effect while alkoxy groups can donate a pair of electrons from the oxygen atom to form a pi bond and donate electrons through resonance effect. Activating groups are also ortho, para-directors because the positive charge in the sigma complex resonance structures becomes distributed so that the electron donating group is located adjacent to the positive charge, decreasing the overall magnitude of the positive charge. However, if EAS occurred meta to an activating group, the resulting positive charge would not end up adjacent to the electron donating activating group at all, decreasing stabilization effect. Deactivating groups are electron-withdrawing and remove electron density from the aromatic ring which reduces its nucleophilicity, making the aromatic ring more deactivated toward substitution reactions with electrophiles. This causes an increase in the activation energy required to form a sigma complex and therefore a decrease in reaction rate for EAS. Deactivating groups are meta directors because the positive charge in the sigma complex does not end up being adjacent to the electron withdrawing group. Because it is unstable to have positive charges adjacent to one another, which is the case for the deactivating nitro group at ortho and para positions, the meta position is less deactivating and thus favoured. An exception to this pattern are halogen groups, which are deactivating because they withdraw electron density due to high electronegativity but are ortho and para directing because of their ability to donate an electron pair to form a pi bond. Resonance stabilization is very strong, so the ortho and para positions would provide greater stabilization when halogen groups are present in EAS.
Mechanism of aromatic nitration:
First, personal protective equipment-gloves, goggles and a lab coat- were put on before starting to handle any of the materials and chemicals. A small magnetic stir bar was initially added to a 50 mL Erlenmeyer flask. Then, under a fumehood, 3.5 mL of prediluted nitric acid was measured and added to the same flask. After obtaining a container of ice bath, the 50 mL flask was placed on the ice bath with a rubber stopper for later use.
3.0 mL of 3.4 M veratrole solution in glacial acetic acid was measured carefully into a small graduated cylinder (under the fumehood), then poured into a separate 25 mL flask, which was also placed in the ice bath, until ready for use. The larger flask was removed from the ice-water bath and placed on the magnetic stir plate. Vigorous stirring without heat was initiated and the dial on the stir plate was set to around the middle. Then, the veratrole solution was added dropwise using a disposable glass pipette.
For the first few drops, no colour change was observed. However, after adding several more drops, light yellow oily droplets started to form and accumulated in the solution, forming a separate layer on top of the clear solution. After checking the temperature with a thermometer, it was found that some heat was evolved. Over approximately 10 minutes of adding the veratrole, the larger flask was periodically removed from the stir plate and the temperature of the reaction mixture was checked with a thermometer. If necessary, the flask was placed back into the ice bath for a couple of minutes to decrease the temperature to below 20 C. The temperature was not checked while the flask was on the stir plate to prevent cracking of the thermometer.
After the addition of about one-third of the veratrole solution, the colour and transparency of the solution changed to a translucent light brown with a few small specks of brown precipitate starting to form. Some heat was evolved, with the temperature occasionally increasing to several degrees above 20 C. After adding approximately another 1.0 mL of veratrole, a significant amount of brown precipitate accumulated in the flask, turning the solution into a more opaque, thicker mixture of liquid and solid precipitate. More heat was evolved with progression of the reaction and caused quicker elevation of the temperature. Precipitate formed at an increased rate, requiring placement of the flask on the ice bath. After the addition of the remaining veratrole solution, a thick orangish-brown slurry consisting of a significant amount of orangish-brown precipitate remained in the bottom of the flask.
The crude product was filtered using vacuum filtration and a Buchner funnel with filter paper. The crude product was rinsed with cold distilled water during the filtration. The filtered dry product was a yellow opaque powdery precipitate. The dry crude product was weighed to be 0.82 g and the melting point was measured to be 86 C. Afterwards, recrystallization was performed by placing the crude product in a separate clean flask and adding around 10 mL of methanol. The steam bath in the fume hood was used to heat the flask until all of the crude product dissolved. The flask and solution were slowly cooled to room temperature; crystallization occurred as the solution cooled down. The pure product was filtered using vacuum filtration using a new piece of filter paper. The appearance of the dry pure product was bright, golden-coloured crystals; it was also shown to the TA. The pure product was weighed to be 0.54 g and the melting point was measured to be 87 C. After conducting the experiment, any remaining products/used waste were appropriately disposed, the glass pipette was disposed in the blue glass waste bin and the other glassware/stir bar were washed thoroughly with ethanol. The lab bench was also wiped down at the end.
The experimental yield of the final product, was 0.54 g. The theoretical yield of final product is required to calculate the percent yield (experimental yield/theroretical yield) x 100%. The calculations for the theoretical yield and percent yield are shown below.
Veratrole: 3.0 mL of 3.4 mol/L; molar mass=138.16 g/mol
C=n/V; n = CxV = 3.4 mol/L x (0.0030 L)
= 0.0102 mol of veratrole used in reaction
(m = 0.0102 mol x 138.16 g/mol = 1.41 g)
Final Product (4-nitroveratrole): molar mass=183.16 g/mol;
[0.0102 mol of final product theoretically expected because in the pre-lab it was mentioned that the stoichiometric ratio of reactants is assumed to be 1:1]
Theoretical yield of final product = 0.0102 mol x 183.16 g/mol
= 1.87 g
Percent yield = experimental yield/theoretical yield x 100%
= (0.54 g / 1.87 g) x 100% = 28.9%
The percent yield was only 28.9%; it is inferred that the percent yield is so small because of experimental errors, a lot of which were preventable and some which were not. A major human error that could have been prevented was the spilling of product while transferring to the funnel for filtration and transferring the dry product to the weighing boat. Some of both the crude and pure product was lost during the transferring steps. During the recrystallization process, a fair amount of product was accidentally lost while pouring the crude product into the flask and while pouring the recrystallized pure product from the flask to the funnel (not all of the precipitate could be removed from the flask). In addition, some product always remained on the filter paper and could not be completely removed. An error that may have been less preventable could be associated with the weighing equipment as there may have been incorrect calibration of the machine.
The melting point for the crude product (86 C) and pure product (87) C were only one degree apart. This suggests the pure product may not have been purified enough since the melting point is similar to the crude product which likely has impurities that affect the melting point. The lab manual did not have the melting point for 4-dinitroveratrole but the experimental melting point from the Alpha Aesar website is around 96 C, which is relatively close to the observed melting point. This suggests that the observed product likely contains the actual product, but possibly with some impurities as well.
The structure of the final product is:
The 1H NMR spectrum contains 5 different signals, with a total of 9 protons being represented in the spectrum. The two peaks at 4.005 ppm and 3.989 ppm appear to be a doublet, however, each peak represents different proton environments. This is evident because there are separate integral values under each peak. Thus, the signal can be interpreted as two separate singlets that have very similar chemical shifts, but still have slightly different environments in the nitroveratrole molecule. The peak at 4.005 ppm with an integral of 3H corresponds to the 3 hydrogen atoms on the CH3 of the methoxy group (-O-CH3) which is located closer to the nitro (-NO2) group or meta to the nitro group. Therefore, the peak at 3.989 ppm, also with an integral of 3H corresponds to the 3 hydrogen atoms on the CH3 of the methoxy group (-O-CH3) which is located para to the nitro group, located farther away from the nitro (-NO2) group on the benzene ring. In both cases however, the atom next to the CH3 group is the de-shielding electronegative oxygen atom, which explains the 1H NMR chemical shift around 3-4 ppm.
The doublet signal with peaks at 6.951 ppm and 6.922 ppm has an integral of 1H, and corresponds to the hydrogen directly bonded to the benzene ring. It is also magnetically coupled/split with one neighbouring proton which is also on the aromatic ring, as evident by the doublet splitting pattern. This doublet at around 6.930 ppm is more upfield and corresponds to the proton on the carbon atom which is closer to the methoxy group on the benzene because it is slightly more shielded by the O-CH3 which is less electron withdrawing than the NO2 substituent, with two electronegative oxygens and one positively charged nitrogen. The neighbouring proton’s 1H NMR signal is represented by the doublet signal at 7.934 ppm and 7.958 ppm. Since hydrogens on benzene rings have a chemical shift of around 7-8 ppm, this second doublet signal also corresponds to the proton bonded to the benzene. However, the signal is more deshielded (downfield) which suggests that the chemical environment of nearby atoms is more electron-withdrawing. Thus, the doublet at around 7.940 ppm corresponds to the proton which is closer to the nitro group.
Finally, the signal at 7.775 is a singlet with an integral of 1H. The chemical shift between 7-8 ppm suggests that it is for the remaining proton on the benzene ring, located in between the nitro group and a methoxy group. The singlet also proves that there are no protons nearby that it can couple with, which is true for the proton in between the two substituent groups. The solvent signal at around 7.28 ppm likely represents the trace impurities from the solvent that the unknown was dissolved in. To avoid too much of the solvent signal, most 1H NMR spectra are recorded using a deuterated solvent such as deuterated chloroform. Deuteration is not always completely effective, however, so residual proton signals may occasionally be observed (Merlic).
Structure of 3-nitroveratrole (isomer of nitroveratrole; not experimentally observed):
Although more than one nitroveratrole isomer could be reasonably expected to be synthesized, only one isomer was experimentally observed. The observed product has less steric hindrance upon addition of the nitro group and it is lower in energy; thus the 4-nitroveratrole isomer has the greatest yield and is the major product of the reaction. The nitro group is para-substituted to one of the methoxy groups rather than ortho. The minor product 3-nitroveratrole had little yield and was not experimentally observed. Because the nitro group is ortho substituted to one of the methoxy groups there is a lot of steric hindrance, making it more difficult for the reaction to produce this isomer, and also requiring more energy. This decreases the reaction rate and overall yield. Since experiments in the laboratory are often not completely indicative of other minor products, side reactions or impurities, the experimentally observed isomer would logically be the major product, as it is the easiest to identify in the lab. In conclusion, based on the 1H NMR spectrum the major product represented by the 1H NMR and obtained in the experiment was 4-nitroveratrole.
1) The relative rate of reaction for the second nitration compared to the initial nitration is likely slower. It would require less time for veratrole to be initially nitrated once to form the nitroveratrole than for veratrole to be subsequently nitrated for the second time, to form the dinitroveratrole. This is largely due to the fact that the nitro group is a strong deactivating group as it is an electron-withdrawing substituent. Thus, it removes electron density from the aromatic ring and reduces its nucleophilicity, making the aromatic ring deactivated toward reactions with electrophiles. This leads to an increase in the activation energy required to form a sigma complex with the electrophile in the presence of a deactivator such as the nitro group. Veratrole is originally quite a reactive aromatic compound, as it has two activating methoxy groups (-O-CH3), so the initial mononitration occurs rapidly and under milder conditions than some other aromatics such as benzene. However, once the initial nitro group is added in the first EAS to the ortho/para position, the compound becomes deactivated by the nitro group and the resulting reaction rate of the secondary nitration would be much slower. Below are the structures of the two most likely dinitroveratrole isomers:
ISOMER A ISOMER B
Dinitroveratrole Isomer A is 4,5-dinitroveratrole and could have been obtained by initially nitrating veratrole at the para position to a methoxy group (ortho, para-director). Then, a second nitro group was added para to the second methoxy group. Although the nitro group is added ortho to the previous nitro group (deactivator and meta director), its location is still reinforced by being para to a methoxy group. When there is a conflicting activating and deactivating group, the activating group usually has a stronger directing effect than a deactivating group. Since the methoxy group is a powerful activating group that stabilizes sigma complexes through resonance, it directs the para position for the first and second nitration. Also, other than isomer B there is no more possible arrangements of nitro groups that are meta to each other in dinitroveratrole.
Dinitroveratrole Isomer B is 3,5-dinitroveratrole and could have been obtained by initially nitrating veratrole at the para position to a methoxy group (ortho, para-