Pre-lab

Two of the reagents in this experiment, NaBH₄ and MgSO₄, are hygroscopic, they absorb water from the air. Please keep their reagent bottles capped except when it is absolutely necessary to open them.

You may have trouble finding hazard information on the ketone (1) starting material, but you can assume that it is volatile and flammable (this is the case for most organic compounds), and you should protect yourself accordingly.

You may also have trouble finding the physical properties of your compounds. Some of these properties are listed below. As always, you need to complete this table and enter it in your lab notebook before coming to lab.

Reaction

Crush one pellet of NaBH₄ (~1 g) in a mortar and pestle. Transfer the powder to a capped round bottom flask, and add sufficient isopropanol so that the ketone will be roughly 0.5 M. To this solution, add 3,3,5-trimethylcyclohexanone (2 g), recap the flask, and stir.

Follow the progress of the reaction by TLC using a 4:1 mixture (v/v) of hexane:ethyl acetate as your eluting solvent [NOTE 1].

Workup

When the reaction is finished, pour the mixture into a separatory funnel containing 20 mL of saturated brine, 10 mL of deionized water, and 40 mL of ether [NOTE 2]. Separate the layers, and extract the aqueous layer with two additional 25 mL portions of ether. Dry the combined organic extracts with MgSO₄, gravity filter, and remove the ether from the filtrate by simple distillation [NOTE 3]. After the ether and isopropanol have been removed, replace the distillation apparatus with a short-path distillation head and a cow, and distill the residue under a water aspirator vacuum [NOTE 4 ]. Collect the main fraction as the temperature rises towards 100 ^oC (record the temperature range). Weigh your product and obtain its IR and ¹H NMR spectra [NOTE 5].

Chromatography

Separate the cis and trans isomers present in a 400 mg sample utilizing dry-column flash chromatography. This is the same technique that was used last semester to separate acetylferrocene from ferrocene, but recall that we were able to cut a few corners because the compounds were colored and behaved very differently. The compounds in this experiment are colorless, and they behave similarly, so much greater care is called for.

Please refer back to the ferrocene procedure for a complete set of instructions. However, as you read, remember that some of these instructions actually represent non-standard shortcuts. All of the shortcuts have been marked NonStd# and you need to click on each NonStd# link. This will direct you to a web page containing the standard procedure. Always substitute the standard instructions for the corresponding shortcut given in the ferrocene procedure.

A special note concerning solvents. As before, you will use hexane-ethyl acetate combinations as your solvent and begin eluting with the less polar solvent, hexane. However, you will need to use many more solvent mixtures in this experiment than you used in the ferrocene experiment (each fraction in this experiment is collected using a different solvent mixture). See NonStd6 and NonStd7.

You should also determine a mixture of hexane and ethyl acetate capable of resolving the two isomers on TLC so that you will be able to analyze the fractions obtained from the column. Combine fractions that are either pure or enriched in one of the two diastereomers. Then weigh the purified products and determine the column's efficiency. If either of your purified compounds crystallizes, measure its melting point.

Obtain a ¹H NMR spectrum of the purified cis and trans alcohols, expanding the 3.5-4.5 ppm region as you did previously.

Molecular modeling

A set of molecular modeling activities will be distributed in lab. These demonstrate the procedures and calculations required for a conformational analysis using molecules unrelated to this experiment. After you complete these activities, you should be able to perform the steps outlined below on your own.

Using Spartan Model (Chemistry computer lab), build a model of 2a [NOTES 6 & 7 ]. Click on the minimize button to calculate your model's equilibrium geometry and strain energy.

Record the strain energy in the energy units given by the program. Also inspect the model's structure carefully. There are many structural issues that might be considered, but, at the very least, you should describe the ring's shape (chair or otherwise), and say whether it is significantly distorted in any way.

Analyze 2e, 3a, and 3e in the same way.

Once you have collected your four strain energies, identify the preferred conformations of 2 and 3, and also calculate the difference in strain energies between alcohol conformers, i.e., between 2a and 2e, and between 3a and 3e. Use this energy difference to estimate the equilibrium constant for each conformational equilibrium at room temperature (assume ΔG = difference in strain energies; see the molecular modeling activities handout for helpful formulas connecting strain energy and equilibrium constant). Do your results support the qualitative conformational analysis (and subsequent coupling constant analysis) given in the Background?