Lab X: 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.

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

Molecular Models

You may view an interactive model of the methylcyclohexylbromonium ion by clicking here.

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 peaks 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.). What can you conclude about your major product?

3. Write the mechanism for the synthesis of 2-bromo-1-methylcyclohexanol from 1-methylcyclohexene, NBS, and water.

The next question requires the use of ChemDraw:

4. Using ChemDraw, build one of the four possible products of the reaction of 1-methylcyclohexene with NBS in water, as outlined below. Assume that 2-bromo-1-methylcyclohexanol is the preferred product.

a. Build this molecule by starting from cyclohexane.

1. Add a methyl group and hydroxyl group to one carbon.
2. Add a bromine atom to the adjacent carbon.
3. At the two chiral centers in this molecule, change the bonds to bromine and –CH3 to a specific stereochemistry by using or on the Main Drawing Toolbar.
4. Select the molecule with the marquee tool and, on the Object Menu, check “show stereochemistry”.
5. Name the molecule you have drawn, with R/S notation.

b. Build the remaining 3 diastereomers of  2-bromo-1-methylcyclohexananol. Which of these four molecules result from anti addition of bromine and water?

In order to answer the next two questions, you must examine the molecular models on the websites cited below.

5. Examine the geometry and atomic charges of the methylcyclohexylbromonium ion, the proposed intermediate in the electrophilic bromination of methylcyclohexene. An interactive model of this compound is provided for you. Is the bromine centered between the two carbons? To answer this question, compare the carbon-carbon bond lengths in the methylcyclohexylbromonium ion to those in propane and propene. (Models of propane and propene were introduced in Lab III.) Is the carbon-carbon bond in the methylcyclohexylbromonium ion more like a single bond or a double bond?

6. Look at the computed charges of the methylcyclohexylbromonium ion.

a. What is the charge on the bromine atom?

b. Based on the charges, at which carbon atom would you expect a nucleophile to attack?

c. How does this model support the mechanism of anti addition?

 

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