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.

Watered Down Dehydration

We are continuing our investigation of the acid catalyzed dehydration of 2-methyl-1-cyclohexanol. This year we compared diluted phosphoric acid to the concentrated phosphoric acid (48% w/w aqueous solution) that we have been routinely using. The procedure calls for 11.5 grams of alcohol and 2.5 mL of concentration H₃PO₄ which may be a large excess of this purported “catalyst.” We tried 1.5 mL of H₃PO₄ with 1 mL of water and 0.5 mL of acid with 2.0 mL of water. GC FID analysis of the alkene products showed that there was little difference between the concentrated acid and the dilutions in the product distribution. In particular the first dilution seemed to behave very much like the concentrated acid in the way the reaction occurred and in terms of yield. The second dilution did look different than the other in two in that the reaction mixture had thick vapors at the beginning of boiling and the boiling action tended to foam and bump a lot. The yields of alkene certainly seemed lower for the second dilution. What seems to happen is that unreacted alcohol is distilled over along with water and alkenes. Overall, the amount of alcohol in the distillate seems to depend somewhat on how fast the distillation occurs and is not directly proportional to the amount of acid used. This reaction is amazing stable in terms of product distribution.

E2 Brutus? Part IV

We did not remove the solvent because the amount of liquid product would have been too small to do analyses like RI and IR. Instead, the students performed a Br₂ qualitative test with the upper (organic) phase. This was a little problematic as well. The students were instructed to count how many drops it took to make the bromine solution colorless. It turns out that the end point of this titration is somewhat subjective. Some students added a considerable amount of their upper layer to the test tube. The students should have had been instructed to observe the color change after adding a fixed amount of drops.

We ran the product on a Restek Rtx- 5 Column (5% diphenyl 95% dimethyl polysiloxane
30 M 0.53 mmID  5.0 micromdf).  The retention times for hept-1-ene, E-hept-2-ene, and Z-hept-2-ene were 10.6, 11.2, and 11.6 minutes respectively for this particular program. Generally, this was baseline separation for the three peaks. There was a pesky peak between 10.6 and 11.2 which might have been hept-3-ene or heptane. The starting material, 2-bromoheptane came out at 22.4 minutes. I was surprised that many student samples had a significant amount of starting material left. We refluxed the reaction mixture for nearly 45 minutes in a thermwell. The only thing that I can think of is that this may be due to solubility issues that may arise because of poor mixing. We did not follow this quantitatively.

The methoxide experiment gave a peak at 18.0 minutes which may be the substitution product. The ethoxide experiment gave a similar peak at 20.2 minutes which may be the substitution product. The substitution product was not seen for the tert-butoxide base. We did not follow this quantitatively either.

In the lab report the students were asked to describe the trends as the bases changed from methoxide to ethoxide and tert-butoxide.  Then the students were asked to explain these trends based on what we had learned about E2 reactions. This is a good example where a reaction does not give a single predicted product but gives a mixture of 3 different products. The ratio of those three products is sensitive to the structure of the base as shown in this experiment. It is quite likely that the ratio of these three products is also sensitive to other factors related to the reaction conditions.

E2 Brutus? Part III

The manner of heating and stirring the reaction was also an issue I considered. I decided to use boiling stones rather than stirbars. Stirbars are expensive and students tend to dump them down the drain or wash them into the waste bucket. I went with using the thermwells rather than the boiling water bath. We will be using the thermwells next week as well. This is the first time for the students to use thermwells and set up a reflux apparatus. We did not use drying tubes on the top of the condenser.

We did a liquid-liquid extraction of the reaction mixture after adding water and pentane. We added the water first to dissolve the solids that form during the reaction. I went with pentane though petroleum ether or hexanes are cheaper solvents. The cheaper solvents show several peaks on the GC that makes things pretty confusing. I made the mistake of using heptane as the hydrocarbon solvent the first couple times I tried the experiment. It turns out that the heptane has about the same GC retention time as the heptene products. So I ordered some pentane. Tert-butanol is fairly soluble in pentane so I gave it a slightly different extraction procedure than for the other two.

I was challenging for the students to do an extraction in a 25 mL round bottom flask with about 4 or 5 mL of total liquid. The first extraction was fairly easy because the aqueous is darker than the organic layer. However, for the next two extractions both layers are clear and colorless so it is difficult to see the interface. I had to check every GC vial the students prepared to make sure there were not two phases in the vial. This is something to troubleshoot for next time. We could have used more pentane and more water for the extractions. A different flask , or even their 125 mL separatory funnels, may be beneficial as well.

E2 Brutus? Part II

Scale: The original lab is written for microscale using 0.22 mL of 2-bromoheptane with an overall reaction volume of 2.22 mL. The 2-bromoheptane is a pretty expensive reagent and ended up being the limiting factor in how much the reaction could be scaled up. The smaller the reaction volume, the greater skill is required of the students for certain manipulations. There are, of course, advantages and disadvantages to this. It is good it help students learn to work with small quantities but the risk of “losing it all” are greater with microscale labs. I have almost always gone for quantity. There is something satisfying about seeing what you have made and subjecting it to a variety of analyses. This time I kept the scale about the same as the original lab because of the cost of the reagents. The result was that the only analyses we did were a bromine qualitative test for alkenes and GC-FID. If we would have had more quantity we could have done IR and RI as well like we do with the dehydration of 2-methyl-1-cyclohexanol lab.

The Addition of Base: The original procedure has the students mixing commercial (25% w/w) methoxide in methanol, methanol, and 2-bromoheptane. It seemed more efficient to eliminate the extra methanol –by either using the straight commercial mix or making the diluted solution for the students. We  ended up using the commercial mix right from the bottle. In the original procedure, the tert-butoxide salt is added as a solid and mixed with tert-butyl alcohol. This was problematic, I thought. The solid is rather unstable and t-butyl alcohol is a pain to work with because it freezes at room temperature. I thought I could make up the solution ahead of time. It turned out that sodium tert-butoxide has very limited solubility in tert-butyl alcohol. I was surprised. The potassium salt is not much better but I could make a 12.5% w/w solution that seems to be stable.

E2 Brutus? Part II

Scale: The original lab is written for microscale using 0.22 mL of 2-bromoheptane with an overall reaction volume of 2.22 mL. The 2-bromoheptane is a pretty expensive reagent and ended up being the limiting factor in how much the reaction could be scaled up. The smaller the reaction volume, the greater skill is required of the students for certain manipulations. There are, of course, advantages and disadvantages to this. It is good it help students learn to work with small quantities but the risk of “losing it all” are greater with microscale labs. I have almost always gone for quantity. There is something satisfying about seeing what you have made and subjecting it to a variety of analyses. This time I kept the scale about the same as the original lab because of the cost of the reagents. The result was that the only analyses we did were a bromine qualitative test for alkenes and GC-FID. If we would have had more quantity we could have done IR and RI as well like we do with the dehydration of 2-methyl-1-cyclohexanol lab.

The Addition of Base: The original procedure has the students mixing commercial (25% w/w) methoxide in methanol, methanol, and 2-bromoheptane. It seemed more efficient to eliminate the extra methanol –by either using the straight commercial mix or by making the diluted solution for the students. We ended up using the commercial mix right from the bottle. In the original procedure, the tert-butoxide salt is added as a solid and mixed with tert-butyl alcohol. This was problematic, I thought. The solid is rather unstable and tert-butyl alcohol is a pain to work with because it freezes at room temperature. I thought I could make up the solution ahead of time. It turned out that sodium tert-butoxide has very limited solubility in tert-butyl alcohol. I was surprised. The potassium salt is not much better but I could make a 12.5% w/w solution that seems to be  stable.

 

E2 Brutus? Part I

This is an experiment that I performed as part of a Chemistry Collaborations Workshops & Community of Scholars (cCWCS) workshop during the summer of 2011. I had planned on incorporating the experiment the next time I taught Organic Chemistry I. Since substitution and elimination is a topic in first semester organic chemistry (Chapter 6 in the Wade textbook), this lab is likely to be part of the students’ adventure in learning new laboratory techniques. For this reason, it is important to keep it simple because it is likely that they are doing some of these techniques for the first time. I wanted to use three different bases with a common substrate.

Reagents – bases:

I did a search of alkoxide bases in Sigma-Aldrich. Methoxide and ethoxide are available a concentrated solutions at a pretty reasonable price. Interestingly, both sodium and potassium salts are available for many of the bases. Generally, sodium is less expensive. The hindered alcohol, t-butoxide, is available as a solid with both sodium and potassium cations for about the same price. I ended up ordering both.  Other alkoxy bases are available but the price goes up considerably. Sigma-Aldrich has isopropoxide and tert-pentoxide salts. Sodium and/or potassium hydroxide may also be an option. There seem to be several cation variations besides sodium and potassium for many of these alkoxy bases.

Reagents – substrate:

I’m not sure what is all available for substrates. The most straightforward was to stick with 2-bromoheptane from the orginal article in Modern Projects and Experiments in Organic Chemistry: Miniscale and Standard Taper Microscale. 2^nd ed. Mohrig, Hammond, Schatz, & Morrill. I found other references that used 3-chloro-3-methylpentane (Microscale & Miniscale Organic Chemistry Laboratory Experiments. Schoffstall, Allen; Gaddis, Barbara; Druelinger, Melvin) and 2-bromo-2-methylbutane (Experimental Organic Chemistry: A Miniscale and Microscale Approach. By John C. Gilbert, Stephen F. Martin).