What’s the Diels? Part II

The Diels Alder reaction between furan and maleic anhydride typically it done in THF. The nice thing about this solvent is that the product crystallizes in the reaction media over the course of a week and can be filtered to recover an essentially pure product. My hypothesis was that changing the solvent may influence the reaction’s preference for the exo isomer. I tried a variety of solvents but found that maleic anhydride is sparingly soluble in most solvents at room temperature. Methyl tert-butyl ether and ethyl ether were satisfactory as far as their ability to dissolve maleic anhydride, but they did not provide the variety in solvent polarity and character that I had hoped for. As an undergraduate experiment, the reaction is always done at room temperature with at least a day or two reaction time. I do not know if the reaction can be done quicker with reflux as most Diels Alder reactions are performed. Heating the reaction mixture would also increase the solubility of maleic anhydride. In the chemical literature the reaction has been run in various solvents such as dichloromethane, acetonitrile, acetone, and water. See “stereochemistry of the furan-maleic anhydride cycloaddition,”   “an NMR study of the reaction of furan with maleic anhydride and maleic acid,” and “An experimental and theoretical study of stereoselectivity of furan-maleic anhydride and furan-maleimide Diels-Alder reactions.” Evidently, the experiment needs some more method development to accommodate different solvents that can dissolve maleic anhydride but not the Diels-Alder adduct. Evaporation of the filtrate yielded a gooey mixture of the exo isomer, maleic anhydride, and furan. The reaction is reportedly highly reversible. NMR analysis of the filtrate did yield signals that could be attributed to the endo isomer but they were quite small.

What’s the Diels? Part I

This year we preformed the Diels Alder reaction between maleic anhydride and furan. There are many Diels Alder reactions to choose from when planning an organic chemistry lab. I chose this one because it has an interesting history. Diels and Alder concluded that the endo product had been formed when they reported the reaction in 1931 in Justus Liebigs Annalen der Chemie. About twenty years later, the reknown synthetic chemist R. B. Woodward and his collaborator H. Baer looked more closely at this same reaction. They analyzed the product with a complicated bromination and hydrolytic process and reported that Diels and Alder had been wrong. The product of the addition, they claimed was the exo adduct: exo-cis-3,6-endoxo-Δ4-tetrahydrophthalic anhydride. Since then there have been many publications on this fascinating reaction. It is one of few known exceptions to the “endo rule” which states that Diels-Alder products prefer the endo stereochemistry. We investigated the reaction in three different solvents. We also attempted to detect the presence of the elusive “exo” isomer in the filtrate.


An Azo Dye Zoo

This year we performed the “Combinatorial Synthesis of an Azo Dye” experiment with new aniline derivatives. The aromatic nucleophiles were the “traditional” phenolic 1-naphthol, 2-naphthol , and salicylic acid. The aniline derivatives were the three nitroaniline positional isomers. The dye colors were the usual assortment of earthy reds, oranges, and yellows that we have been producing with sulfanilic acids. Understandably, the solubility of nitroaniline and its derivative in water was different than the sulfonic acids we had done previously. A few of the nine different combinations represent commercial dye structures. For example, Para Red, 1-[(E)-(4-nitrophenyl)diazenyl]-2-naphthol, is the likely product of 4-nitroaniline and 2-naphthol. Apparently this was one of the first commercial azo dyes produced. The dyes were analyzed by dying a multifiber swatch and observing the dying pattern with six different kinds of cloth. Also, the visible spectrum of the dyes in water was recorded. The figure shows the aromatic hydrogens of 2-hydroxy-5-[(3-nitrophenyl)diazenyl]benzoic acid. The impurity is likely unreacted 3-nitroaniline.


King Fischer

This year we performed the Fischer esterification synthesis of a series of ethyl cycloalkane carboxylates. The starting carboxylic acids were cyclopropane, cyclobutane, cyclopentane, and cyclohexane carboxylic acid. A couple of the carboxylic acids had a distinctive butyric acid type odor: ugh! We used sulfuric acid an excess of ethanol to complete the reaction. The products were recovered with liquid-liquid separation with methyl tert-butyl ether or hexane as the organic phase to add some volume to the water immiscible esters. The recovery of ethyl cyclopropane carboxylate was rather low. Most likely this was due to partial solubility of ethyl cyclopropane carboxylate in water. The products were all liquid so a refractive index was taken. All the esters had a vaguely fruity odor which is common for simple esters. An IR was performed on all samples. It was possible to distinguish between the four esters in IR by the shape and pattern of their C-H stretching bands.  In the NMR it is interesting to compare the chemical shifts and dddd multiplicities of the methine (methanetriyl?) hydrogen: cyclopropane (1.45 ppm), cyclobutane (2.85 ppm), cyclopentane (2.55 ppm), cyclohexane (2.09 ppm).


Cram Rules in the Kingdom of Grignard Reactions

This Spring we revisited an experiment we had done a couple of years ago that involved adding a phenylmagnesiumbromide Grignard reagent to a series methylcyclohexanone positional isomers. This time I performed an NMR analysis that I had not done before. A 1971 Journal of Organic Chemistry article entitled “Sterochemical Considerations of the Reactions of Phenylmagnesium Bromide and Phenyllithium with Isomeric Methylcyclohexanones” reports limited data on the melting point, refractive index (of liquid products), IR, proton NMR, and MS for all 6 diastereomers obtained from 2, 3, and 4-methylcyclohexanone. The two diastereomers of 3-methyl-1-phenyl-1-cyclohexanol and 4-methyl-1-phenyl-1-cyclohexanol are difficult to cleanly separate with GC. Therefore, I performed an NMR of two student samples to determine whether the same diastereomers could be clearly distinguished with NMR. The methyl groups were easily detected on both pairs of diastereomers. The 3-methyl-1-phenyl-1-cyclohexanol spectrum seems to have an impurity: possibly 3-methyl-1-phenyl-1-cyclohexene. The J coupling values, in Hz, for the 3-methyl-1-phenyl-1-cyclohexanol pair were 6.0 (0.983 ppm) and 6.4 (0.961 ppm), while the values for the 4-methyl-1-phenyl-1-cyclohexanol pair were 5.6 (1.054 ppm) and 6.8 (0.986 ppm).


In Praise of Poor Teachers

When I am looking through online textbook recommendations and professor evaluations, I occasionally come across the remark by a student something to the effect of, “ I had to learn the material by myself for this course!” This, I think, is meant to be an indictment against the professor. “I spent a ton of money to learn from this professor, but this person was so inept that I ended up having to learn it myself.” Certainly, there may be merit to this. However, it seems that throughout the whole of our lives we need to learn things “by ourselves” quite alot. The ability to take responsibility for our own learning and understanding of the world is an important life skill. Typically, we are required to learn about a topic of importance from the various resources that we have available to us: advice from other non-experts, internet research, focused inquiries to an expert, informational media, and personal experience. From this we make the best informed decision that we can. This may be learning about a particular medical condition, a new recreational activity, or a new skill that we need for our work. Therefore, the “poor teacher” who forces students to take responsibility for their own learning may be giving them the best learning experience of all.

A Dibromination Dibromance Part IV

We divided the procedure into three different studies. One study involved the “traditional” use of 1 mL of concentrated HBr and H2O2. The second study mixed 0.5 mL of HBr and 0.5 mL of HCl, and the third study used 1 mL of HCl. The products were recovered by neutralizing the reaction mixture and collecting the precipitate. The reaction mixtures containing HBr turn bright orange and cloudy and then eventually fade to white.  The HCl-only reaction stayed clear and colorless throughout the reflux but did form a white precipitate after neutralization and cooling. Both the HBr-only and HBr-HCl mix yielded abundant white solid. The HCl-only reaction gave a very cloudy solution but the product oiled out and/or passed through the filter paper. We performed IR spectroscopy on the recovered solids.  It was difficult to distinguish between the different products by IR. Interestingly, the dihalogenated products gave very small unsaturated C-C bond peaks. Some differences in the fingerprint region were tentatively identified but the presence of small amounts of ethanol in the products was a complication as well. Gas Chromatography was more helpful in identifying products. Commercial meso-1,2-dibromo-1,2-diphenylethane and trans-stilbene were used as known standards. The HBr-only experiments showed a major peak corresponding to meso-1,2-dibromo-1,2-diphenylethane (~36 min). The HBr-HCl mix gave two major peaks. One of the peaks was associated with meso-1,2-dibromo-1,2-diphenylethane. The area under the peak likely corresponding to 1-bromo-2-chloro-1,2-diphenylethane (~33 min) was typically greater than the dibromo peak. The HCl-only study gave two peaks at ~30 min. The area under the higher retention time peak was typically about 4x the other. This may correspond to two diastereomers of 1,2-dichloro-1,2-diphenylethane. The HCl-only reaction often had a significant peak close to the retention time of trans-stilbene (~28 minutes). All three experiments tended to give a cluster of small peaks between 25 and 30 minutes.

A Dibromination Dibromance Part III

The protocols for the in situ formation of bromine from hydrobromic acid and hydrogen peroxide and subsequent reaction with an alkene vary somewhat in the literature. If the alkene can be dissolved in a water-miscible solvent such as ethanol, then the reaction can be done without a phase transfer compound. For example, trans-stilbene is dissolved in hot ethanol. Concentrated hydrobromic acid is added to the reaction mixture followed by 30% w/w aqueous hydrogen peroxide solution. I had never worked with concentrated aqueous HBr before. I noticed that concentrated (48% w/w) aqueous HBr produces much less noxious hydrohalide fumes than concentrated (38% w/w) aqueous HCl!

Generally, an excess of hydrogen peroxide is used to convert concentrated hydrobromic acid into bromine. The theoretical yield (in moles) of the bromine is greater than the number of moles of trans-stilbene starting material.

I decided to go with trans-stilbene as the alkene starting material instead of trans-cinnamic or a trans-cinnamate ester. The symmetrical nature of trans-stilbene tends to simplify the results a little. Also it is nice to have a commercial source of the major product available for comparison.

I noticed that in the original Tetrahedron article the authors used both hydrochloric and hydrobromic acids as halogen sources. In order to create bromochloro compounds the alkene in dioxane was mixed with 10 equivalents of HCl before the addition of 1.5 equivalents of hydrogen peroxide and 1.0 equivalents of HBr. The authors state that the chloride ion attacks the intermediate bromonium ion to give the bromochloro products. They also reported that hydrogen peroxide would convert HCl to diatomic chlorine which would perform the dichlorination of the alkene. Therefore, I thought that a good way to study this reaction would be to vary the hydrohalide substrates and look at the formation of products (dibromo, dichloro, and bromochloro) by gas chromatography.

A Dibromination Dibromance Part II

Another interesting aspect to the dibromination reaction is that three different methods have been developed to perform the same reaction in the undergraduate laboratory. Of course, many more methods of dibromination exist in the chemical literature.

Some laboratory manuals, such a Nimitz, still propose the dibromination reaction using diatomic bromine in a halogenated solvent such as dichloromethane. As far as I can tell, this dates back to a 1942 Journal of the American Chemical society (JACS) article by Marie Reimer: Preparation of Phenylpropiolic Acid. Ernst Berliner also did a series of articles on bromination reactions using diatomic bromine in acetic acid. Using diatomic bromine, except in very small quantities, in the undergraduate laboratory does not seem advisable for safety  and environmental reasons.

Using pyridinium bromide (pyridine hydrobromide perbromide) as a reagent to deliver diatomic bromine has also been around from quite some time. I found a 1948 article by Djerassi and Scholz in JACS: Brominations with Pyridine Hydrobromide Perbromide. Glacial acetic acid is often used as a solvent for this reagent. Though it may be superior to diatomic bromine, there are significant safety and environmental concerns associated with this reagent as well.

More recently, the in situ formation of bromine from hydrobromic acid and hydrogen peroxide has been proposed as a bromination method: Simple and practical halogenation of arenes, alkenes and alkynes with hydrohalic acid/H2O2 (or TBHP). This safer and more environmentally friendly method was picked up by the “green chemistry” folks at University of Oregon. I’m sure that this is a cool story – how an obscure reaction in a low-impact-factor journal came to be vaulted into undergraduate chemistry laboratory stardom. The Oregon group has focused on trans-stilbene as a starting material. However, any number of alkene starting materials can employed. From personal experience, I can say that the trans-stilbene product produces a pile of pure white crystals straight from the reaction mixture. The content of this post is explained in detail in the Journal of Chemical Education article entitled: The Evolution of a Green Chemistry Laboratory Experiment: Greener Brominations of Stilbene.


A Dibromination Dibromance Part I

This year we performed a dihalogenation reaction that is featured in the reactions of alkenes: a topic  typically covered during first semester Organic Chemistry. This reaction has been a popular undergraduate experiment for decades. I did quite a bit of background research in setting this one up. The two most popular substrates are trans-cinnamic acid and trans-stilbene. Both give solid products when dibrominated. The dibromination reaction can be studied from the point of view of stereochemistry of addition. For example, the dibromination of cinnamic acid has to possibility of creating two pairs of enantiomers while the same reaction with stilbene has the possibility of creating a meso compound and a pair of enantiomers. As far as I am aware only the meso-1,2-dibromo-1,2-diphenylethane is available commercially for a reasonable price to use as a standard. Chemspider gives the systematic name of “meso-dibromostilbene “ as [(1R,2S)-1,2-Dibromo-2-phenylethyl]benzene. I would prefer to call it meso-1,2-dibromo-1,2-diphenylethane. Cis-stilbene is commercially available but is more than a 100x more expensive than trans-stilbene. Cis-cinnamic acid is not readily available. An interesting study published in the Journal of Chemical Education, The Addition of Bromine to 1,2-Diphenylethene, was done comparing the dibromo products of trans and cis-stilbene. Generally, cis-stilbene was more likely to give significant amounts of both isomers compared with the trans-stilbene which produces an excess of a single diastereomer. Bromination of cis-stilbene with elemental bromine in dichloromethane gave almost equal amounts of the two diastereomers! The authors remark that since crystallization is the routine method of recovering the dibrominated product, the R,R/S,S diastereomer is simply not recovered.