Lab XI: Synthesis of a Bromohydrin

Pre-Lab Work

Complete the TPC below. Copy and paste it in your lab notebook.

Reading Assignment:

1. Addition Reacitons: Hornback; 2nd ed.; pp. 413-420
2. Microscale Extraction: Mohrig, Technique 8.5 - 8.6, pp. 85-92.

Table of Physical Constants (TPC)¹

¹All physical constants were obtained from the CRC Handbook of Chemistry and Physics, 52nd ed., unless otherwise noted.
Printable version of TPC!

Introduction
Regioselective electrophilic additions are an important class of reactions in organic chemistry, as transformations of this type provide synthetic routes to a number of different functional groups starting from alkenes. Addition reactions typically occur in two steps; in the first step of the reaction mechanism, as seen in Figure 1 below, the electrons of the pi bond are nucleophilic and form a bond to an electrophile. When the electrophile is Br⁺, electrophilic addition of a positively charged bromine atom to the alkene results in formation of the bromonium ion intermediate. N-Bromosuccinimide is a good source of electrophilic bromine, as the resulting succinimide anion is stabilized via resonance.

In the second step of the mechanism, water acts as a nucleophile and adds to the carbon which is best able to support positive charge in accordance with Markovnikov's rule, which can be predicted by looking at the Bromonium Ion below:

Of the two intermediates depicted above, the intermediate on the left is lower in energy relative to the intermediate on the right because the partial positive charge is more stable on a tertiary carbon. Therefore, the rate of nucleophilic attack of water at this carbon should be faster relative to addition of water to the secondary carbon of the intermediate on the right.

The expected product of Markovnikov addition is 2-Bromo-1-Hydroxy-1-Methylcyclohexane (also named 2-Bromo-1-Methylcyclohexanol), as seen in Figure 2.

Figure 2: Bromohydrin formation due to Markovnikov's rule

Experimental Work

Objectives:

1. To gain synthetic experience working at the microscale level.
2. To synthesize a bromohydrin and verify Markovnikov addition of Br and OH to the alkene by comparing your experimental MS to that reported in the literature.

Experimental Procedure²

To a small 13x100 mm test tube, add 350 mg of N-bromosuccinimide*, 1.0 mL distilled water, and 0.75 mL tetrahydrofuran. To this heterogeneous mixture, transfer 0.25 mL 1-methylcyclohexene via a disposable pipet. Note which layer is the organic material and which one is aqueous-based.

Facilitate gentle swirling of the reaction mixture by means of a vortex mixer; be sure the setting on the vortex mixer is low or set to "shake." Allow the reaction mixture to stir at room temperature until no solid NBS is observed in the colorless solution (about ten minutes). Record all observations in your notebook. If the mixture is still yellow after 10 minutes, add another 1-2 drops of 1-methylcyclohexene.

Dilute the resulting mixture with 2 mL water and stir for an additional 2 minutes. Allow the organic and aqueous layers to separate.

Add 1 mL CH₂Cl₂ to the test tube and stir, then allow the layers to separate. Transfer the organic layer containing the bromohydrin to a clean test tube via a disposable glass pipet. Extract the aqueous layer with an additional 1 mL of CH₂Cl₂ and combine organic layers.

Filter the organic solution through phase separation paper and anhydrous magnesium sulfate into a clean vial. Transfer this solution to a numbered GC-MS vial and dilute to 1.5 mL with CH₂Cl₂, if necessary. Give the vial to the Lab Assistant for analysis.

*N-bromosuccinimide (NBS) is corrosive; avoid contact with skin and wear gloves when handling the solid or solutions of NBS

²Modified slightly from the previously published report: Porter, D.J.; Stewart, Andrea T.; Wigal, Carl T. J. Chem. Ed. 1995, 72, 1039-40.

Special Waste Disposal
Dispose of any halogenated containing material in the appropriate waste container.

Post-lab Work

1. Print out your GC-MS information from this Lab and identify the major peak observed in the GC based on the MS data.
2. Compare the fragmentation pattern of your experimental MS to the literature reference for 2-Bromo-1-Hydroxy-1-Methylcyclohexane found in the Experimental Section of the following journal article from the Journal of Organic Chemistry: Bettadaiah, B.K.; Gurudutt, K.N.; Srinivas, P. J. Org. Chem. 2003, 68, 2460-2462. (This journal article can be accessed online through the Wellesley College Library website.)
3. Do you observe any evidence for the formation of the minor regioisomer in your GC-MS? Explain.
4. What is the expected stereochemistry of the major addition product? Would you expect your product to rotate plane-polarized light? Why or why not?
5. Would you expect to see the other organic product, Succinimide, in the GC-MS of your final product? Justify.

CLEAN OUT YOUR PERSONAL TOTE!
Place chemicals in appropriate containers and clean your glassware.