Organic Chemistry II  | Lecture | Laboratory

Organic Chemistry Laboratory II
Williamson Ether Synthesis: Preparation of Racemic Guaifenesin
Experiment Description and Background

In this two-week experiment, students will work in pairs to prepare guaifenesin, an expectorant found in cough syrups and tablets. The compound is prepared through the Williamson ether synthesis which involves an SN2 mechanism between the sodium phenoxide salt dervied from guaiacol (2-methoxyphenol) and 3-chloro-1,2-propanediol.   The percent yield of the reaction will be determined as well as the experimental melting point of the product.  TLC analysis of the product will be done and compared with authentic guaifenesin and guaiacol.  Proton NMR and mass spectral data is provided and students are required to match the provided spectra with the proper starting material and the product based on analysis of this spectral data.  Students are exposed to a variety of laboratory techniques in the experiment, including synthesis using a reflux apparatus, use of a rotary evaporator, extraction using a separatory funnel, and filtration methods.   A reaction scheme of the Williamson ether synthesis for the preparation of guaifenesin is shown below.

Williamson Ether Synthesis
The Williamson ether synthesis is an organic reaction that occurs between an alkoxide or phenoxide, dervived from the alcohol or phenol respectively, and an uinhindered alkyl halide.  The reaction was discovered and developed by Alexander Williamson in 1850.  In this reaction, the alkoxide or phenoxide is generally generated in situ and the alkyl halide is subsequently added to the reaction mixture.  The reaction occurs through an SN2 mechanism and the alkoxide/phenoxide serves as the nucleophile and the alkyl halide the electrophilic substrate.  In this experiment, the Williamson ether synthesis is  used to prepare guaifenesin. 2-Methoxyphenol (as referred to as guaiacol) is reacted with sodium hydroxide (NaOH) to generate the phenoxide anion.  This nucleophilic anion reacts with the primary alkyl chloride carbon of 3-chloro-1,2-propanediol to give the target product.  The mechanism of the reaction is provided below.

Analysis and Characterization of Reaction Products
Analysis of the reaction products includes a combination of chromatographic techniques that involve comparison of the reaction products to known standards (starting material and product, if available).  Thin layer chromatography is most commonly used for this purpose.  The melting point of the product (if it is a solid) is also used to verify the product identity.  Recording and interpreting spectroscopic data for the synthesized product  (IR, NMR and Mass) is essential  to unequivocally identify a product structure. 

IR Spectroscopy
IR spectroscopy provides information about the functional groups present in the compound undergoing analysis.  Characteristic peaks in the IR spectrum reveal the presence (or absence) of certain types of bonding or functional groups.  The most characteristic peaks in an IR spectrum are those associated with O-H bonds (strong, broad peaks, 3200-3600cm-1) and the carbonyl group (C=O, strong peaks 1650-1850cm-1).  In the synthesis of guaifenesin from guaiacol and 3-chloro-1,2-propanediol, IR spectroscopy is not particularly useful.  The reason for this is that the starting materials both contain OH groups (guaiacol has a phenol OH and 3-chloro-1,2-propanediol has a primary and secondary alcohol).  The product also contains an OH group.  Since there are not other distinguishing functional groups in the starting materials and the product,  IR spectroscopy does not allow for unequivocally distinguishing the product from the reactants in this synthesis. 

Proton NMR Spectroscopy
Proton NMR spectroscopy provides information about the carbon skeleton of a compound undergoing analysis.  The guaiacol contains a characteristic ortho-substituted aromatic ring with one of its substituents being a methoxy group.  This starting material's carbon skeleton is easily distinguished from the carbon skeleton of 3-chloro-1,2-propanediol.  The product in this reaction contains the carbon skeleton elements of both reactants and is also distinguishable from either guaiacol and 3-chloro-1,2-propanediol.

Mass Spetrometry
Mass spectroscopy is an analytical technique used for determining the molecular weight of organic compounds.  Mass spectroscopy also detects the presence of significant isotopes of atoms in molecules, most notably, bromine and chlorine. The two reactants and the product  all have unique molecular weights and are readily distinguished by mass spectrometry.  Furthermore, the 3-chloro-1,2-propanediol contains a chlorine atom which has a characterisitic distribution of the 35Cl (75%) and 37Cl (25%) isotopes in the mass spectrum.