Electrophilic Aromatic Iodination of Vanillin

Electrophilic Aromatic Iodination of Vanillin Introduction: The ability to synthesize novel aromatic compounds from the simplest aromatic ring, benzene, has proven to be fundamentally useful in the industrial setting. This technique permits the synthesis of a myriad of benzene derivatives whose corresponding functional groups can be arranged around the ring in a particularly selective manner by means of orthopara directing activating groups as well as meta directing deactivating groups. Ortho/para directors include activating groups that can donate electron density (such as ethers, alcohols, and amines) and promote attraction of electrophiles at the ortho and para positions relative to the activating group. An exception to this is halides, which are actually deactivating groups that still promote ortho-para substitution through resonance. On the other hand, meta directors are typically deactivating groups (such as nitro and sulfonic groups) that consume electron density from the aromatic ring and ultimately decrease the electrophilic attraction to the ortho and para positions, resulting in new substituents being added to the relative meta position. For this experiment, vanillin is to be converted to iodovanillin by converting the iodide ion in potassium iodide (KI) to a cationic electrophile that can attack vanillin’s aromatic ring at an unoccupied carbon atom. The following reaction scheme illustrates the basic synthetic pathway utilized to accomplish this electrophilic aromatic substitution: Figure 1: the reaction scheme followed for this experiment and the three possible regioisomers produced. As indicated by figure 1, there are three distinct products that could theoretically be formed during this reaction. To determine which regioisomer is the most likely product, the functional groups already attached to the vanillin ring must be taken into account. The methyl ether and the hydroxyl group on the left side of the ring in the diagram are both ortho-para directing activating groups, which means that the carbons at the top and bottom vertex in the diagram will attract electrophiles. However, the aldehyde functional group is a meta-directing deactivating group that will promote electrophilic attraction at the only meta position—the bottom vertex—and restrict substitution at the carbon atoms adjacent to it. Additionally, the aldehyde group adds steric hindrance to its surrounding environment. Due to these chemical and electrical effects observed in these types of substitution reactions, it is hypothesized that the first isoform in the diagram, with iodine attaching to the bottom vertex of the ring (next to the hydroxyl group), will be the dominant iodovanillin isomer formed. The following mechanism illustrates the selectivity of this reaction: Figure 2: the mechanism for this reaction that utilizes the iodonium cation to substitute. Iodination is generally more difficult to accomplish than chlorination or bromination, which simply use aluminum or iron-based catalysts to produce cationic halogens. For this particular reaction, sodium hypochlorite (bleach) oxidizes the iodide anion formed from the dissolution of potassium iodide to ultimately produce an iodonium cation. This cation will then react with the aromatic ring to perform an electrophilic attack, followed by proton removal by ethanol, to produce 4-hydroxy-3-iodo-5-methoxybenzaldehyde. For the oxidation step, it is crucial to add sodium hypochlorite very slowly, in a dropwise manner, to prevent the occurrence of double or triple additions of iodonium to the aromatic ring. Although iodination is favored at the carbon atom adjacent to the hydroxyl group, additions at the other two positions are possible, though much less likely. Rapid addition of sodium hypochlorite will reduce product purity at the end of the experiment. Despite the relative difficulty of aromatic iodination, many mechanisms have been devised to more efficiently produce an iodinated aromatic ring system. Single electron transfers in the aromatic ring result in an aromatic radical that can then interact with a neutral halogen to result in halogenation. However, this method is typically complicated by charge- transfer complexes that often reduce selectivity. Another effective method of iodination involves iodine monochloride (ICl) in a polar solvent (such as acetic acid). This reaction results in heterolytic cleavage of the iodine-chlorine bond where chlorine becomes an anion and iodine becomes a cation. As suspected, the reverse of this cleavage can occur and produce undesirable chlorinated products, but chlorination is much less likely in a polar solvent as opposed to a solvent with a lower dielectric constant 1. Analysis of the compound is to be facilitated by determining its melting point, then analyzing IR, proton NMR, and carbon NMR spectra to confirm the identity of the synthesized compound. The IR spectra is expected to reveal the presence of an aromatic ring around 1500 cm-1, an alcohol around 3000 cm -1, a carbonyl around 1600-1700 cm-1, the aldehyde proton around 2700 cm-1, and a carbon-iodine bond in the fingerprint region. The proton NMR spectra should contain a cluster of aromatic protons, each one being affected by the adjacent functional groups. Additionally, the aldehyde proton should be easily distinguishable on the left-hand side of the spectra around 10 ppm. It may also reveal a phenol proton anywhere from 4-7 ppm as well as deshielded methyl protons on the other end of the ether. The main distinguishing factor between vanillin and the newly synthesized compound will most likely concern the new halogen that will deshield the adjacent aromatic proton. The carbon NMR between vanillin and iodovanillin should reveal very similar peaks aside from the discrepancies caused by the halogen that further deshields its carbon atom. Experimental: 1 The experiment was initiated by adding 1.00 gram of vanillin into 20.0 mL of ethanol and subsequently dissolving 1.30 grams of potassium iodide (KI) into the solution. The solution was stirred to dissolve all solid salts into the solvent and then cooled in an ice bath. With constant stirring, 7.1 mL of 8.25% sodium hypochlorite was added dropwise over a period of 12.5 minutes. The solution was then allowed to warm to room temperature for about 15 minutes with constant stirring. 10 mL of sodium bisulfite was then mixed into the reaction flask and acidified with 2.5 mL of 10% hydrochloric acid (HCl) until the pH paper used to test acidity turned pink. The flask was then heated over a steam bath for 15 minutes to remove excess ethanol and maximize product purity. Afterwards, the flask was cooled in an ice bath until ice-cold, at which point the method of suction filtration was utilized to collect the final desired product, iodovanillin. After being washed with several portions of ice-cold water, as well as a single portion of ice-cold ethanol, the product was stored for one week to dry. Upon returning to the lab, the final product from the previous week was weighed out and a melting point analysis was performed, followed by extraction of an infrared spectrum. After complete analysis, the final product was disposed of along with other halogenated wastes. Results: Compound Mass Melting Point 4-hydroxy-3-iodo-5- 0.78 grams 260° C+ methoxybenzaldehyde Decomposed prior to melting Table 1: dry mass and melting point of obtained compound; compound appeared to be melting at 212.5° C but quickly decomposed and still had not melted at 260° C (the highest temperature of the melting point device). Figure 3: IR spectrum obtained for the product. Shows severe discrepancies that may point to an impure product, including lack of a carbonyl/alcohol peak. Figure 4: this is the product obtained from the reaction; it is a white, flaky substance with an appearance similar to that of thin layers of styrofoam. It is hypothesized to be 4-hydroxy-3-iodo-5-methoxybenzaldehyde. Figure 5: interpreted proton NMR of the synthesized compound. Figure 6: interpreted carbon NMR of synthesized compound. More electronegative atoms adjacent to carbon atoms result in a further deshielding effect (higher ppm overall). Discussion: Following spectral analysis and melting point determination, it has been confirmed that the compound synthesized through this procedure is 4-hydroxy-3-iodo-5methoxybenzaldehyde, as hypothesized earlier. However, based on the IR spectrum obtained from this compound, it is clear that several impurities were present. The IR results are extremely unclear and nearly impossible to interpret accurately. Furthermore, the compound did not melt at temperatures suggested by primary literature (approximately 180° C – 184° C). It appeared to begin melting into a liquid state around 212.5° C but it never completely melted. By the time the 260° C mark came around, the compound had completely decomposed. It is possible that the addition of bleach (sodium hypochlorite) was performed too quickly, resulting in double or potentially even triple additions of iodine to the compound. Regardless, it is obvious that this experimental procedure is quite effective in producing iodovanillin if followed properly and with careful attention to detail. It is highly unlikely that a single iodination event occurred at either of the other two “open” positions on the aromatic ring due to the powerful, deactivating, meta-directing activity of the aldehyde group (namely the carbonyl group). Following a single iodination reaction at the position ortho to the alcohol group, the likelihood of another iodination reaction at either of the two remaining positions was unfavorable. However, assuming another iodination event did occur, the chances of it occurring at one position over the other was nearly equal. This is because iodine acts as an ortho-para director (although it is a deactivating group) and the ether group is also an ortho-para director. Therefore, these two “open” positions will have nearly the same partially negative charge, but will also be quite strongly deactivated. As stated earlier, iodination is typically more difficult to accomplish than other aromatic halogenations. Despite this, several methods still exist for aromatic iodination that differ in their reagents, as well as the “greenness” of their reactions. For example, one effective method of iodinating an aromatic compound is to combine molecular iodine with ceric ammonium nitrate, a large inorganic oxidizing agent 2. However, this reagent has a very large molar mass of 548.26 g/mol, resulting in a great amount of waste when compared to the amount of waste produced in this iodination mechanism. Another efficient way of accomplishing this reaction is to mix trichloroisocyanuric acid, molecular iodine, and wet SiO 2. This reaction was devised to 2 minimize the typical harsh conditions associated with iodination (i.e. reduces the occurrence of strong acidic conditions in heat) and to bring the reaction to completion very quickly, whereas most iodination reactions take a couple of hours to complete 3. However, this procedure is also observed to produce more waste than using potassium iodide in an ethanol solvent containing sodium hypochlorite. Regardless, these procedures may prove to be more efficient when it comes to synthesis of iodinated aromatic compounds. Notebook/Observations: