My two favorite orgo reactions!
The Fischer esterification is a reaction as essential to the beginner organic chemistry student as it is to the layman observing his fruit ripen. Esters are a weakly polar, organic compound of chemical characterized by the dehydration of an acid (generally carboxylic) and an alcohol; as such, they are named X-yl Y-oate for the alcohol X-ol and the acid Y-oic acid. As characterized by the carbonyl and the carbon-oxygen sigma bond, the compound is in between the polarity of a comparably sized ketone above (such as ethyl acetate and acetone) and ether below (such as ethyl acetate and diethyl ether), making them miscible with each but sparingly soluble in a highly polar compound such as water or glycerol [# pubchem etoac].
Esters are highly significant in the natural world and are even known among chemistry laymen, such as wine enthusiasts, for their generally pleasant odor reminiscent of fruit (aliphatic esters) or mint (aromatic esters). This stands in stark contrast to the acrid smell and taste of most carboxylic acids and alcohols. For example, butyric acid, a carboxylic acid, is named for being the primary component of rancid butter. This response is for a good reason, when bacteria grow in over-ripe fruit, they hydrolyze the esters into their constituents (enzymatically or with increasing acidity). Over many generations, animals evolved to detect the constituents with an unpleasant smell and/or taste and associate them with rotten fruit and therefore illness.
With a clever knowledge of chemistry, this natural process of hydrolysis can be directly reversed. An extreme pH is generally required to catalyze the hydrolysis of an ester, and the reaction equilibrium in nature is driven by an excess of water. Therefore, by le Chatelier’s principle an absence of water and an excess of alcohol or acid should drive the equilibrium in the opposite direction. Indeed this is the case: Fischer and Speier noted in 1895 that in dehydrating conditions (especially over 100 C) methanol or ethanol condensed with organic acids in the presence of mineral acids [#german source]. The ester can then be readily extracted from the reaction bath of alcohol and water with a weakly polar organic solvent like diethyl ether.
In this particular experiment, benzoic acid will be esterified with excess methanol under sulfuric acid catalysis to form methyl benzoate, a compound similar to the natural product wintergreen (methyl salicylate, or methyl (o-OH)benzoate. One should note that as well as aliphatic polar solvents (most commonly ethyl acetate is used as a non-toxic alternative to diethyl ether or acetone), esters are useful as protected precursors to other compounds. For example, the Grignard reagent RMgX is an extremely strong base and would deprotonate a carboxylic acid R'COOH rather than react with the carbonyl to form a carbon-carbon bond (as Grignard reagents are intended for); however, the ester R’COOR” reacts in the way one would otherwise expect of a carboxylic acid in forming carbon-carbon bonds with a Grignard reagent.
https://pubchem.ncbi.nlm.nih.gov/compound/ethyl-acetate#section=Solubility
https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cber.189502803176
While the basics of organic chemistry had been known since the 1800s, and inorganic chemistry for much longer, the bridge between the two (rather directly named “organometallics”) was not understood until much more recently. The Grignard reaction is one of the first such organometallic reactions; Victor Grignard was the first to publish on the chemistry of alkylmagnesium halides RMgX (named Grignard reagents) in 1900 and was awarded a Nobel prize for this groundbreaking discovery in 1912. This discovery was so revolutionary that the field of organometallic chemistry was not even approached again until the 1930s, when organolithium reagents RLi were developed as a less sterically hindered alternative to Grignard reagents. The phenomenon of bridging two seemingly unrelated fields is significant on its own, but the discovery of Grignard reagents opened the door to modern chemistry by providing a simple and reliable way of forming carbon-carbon sigma bonds.
Carbon is a relatively neutral element with regard to electronegativity, and as such it does not readily react with other carbon atoms in molecules and preferentially reacts with more electronegative compounds. In the case of Grignard reagents, the imbalance is in the opposite direction, disrupting an already polarized carbon-halogen bond with the highly electropositive and reducing magnesium metal (via a radical intermediate). This C-Mg bond is extremely unstable (so much so that the Grignard reagent is almost exclusively generated in situ), with a strong ionic character almost resembling a persistent carbanion coordinated to an oxidized Mg2+ ion. A carbanion is extremely nucleophilic and will readily attack any electrophile (such as a carbonyl) by donating its lone pair to form a sigma bond. In the case of a carbonyl a prized carbon-carbon bond is formed, transferring the spectator MgX+ ion from the carbanion to the newly formed alkoxide ion. However, carbanions are also extremely strong bases (arguably stronger than they are nucleophiles), and any protic solvent such as water or an alcohol will act as an acid and donate a proton to form the corresponding alkane and a magnesium-solvent salt. Therefore, it is prerequisite in any Grignard reaction to keep the reaction completely dry of moisture and any protic solvent.
The Grignard reagent was first explored with carbonyl chemistry, and when named without clarification the “Grignard reaction” implies reaction of an alkyl- or aryl-magnesium halide (generally chloride or bromide) with a carbonyl of some sort. The traditional introductory example is the reaction of a Grignard reagent with a ketone to form a tertiary alcohol, where the addition is relatively straightforward and the resulting alkoxide is neutralized with acidic aqueous workup (generally with a HCl, leaving a byproduct of MgCl2 or the mixed MgClBr). The reaction with aldehydes follows similarly, forming a secondary alcohol instead, and the Grignard reagent will react with electrophiles including nitriles, alkenes, and epoxides, and (more unusually) esters.
The reaction of Grignard reagents with esters behaves most regularly in at least a 2:1 excess to the ester, where the carboxylate group is turned into a tertiary alcohol. The first equivalent of carbanion attacks the ester carbonyl to form a hemiketal, which is unstable with respect to the alkoxide leaving group from the ester and forms a ketone between the (formerly) carboxyl and the carbanion. By preserving the carbonyl from the ester carboxyl group, the intermediate molecule is open to a second attack by the carbanion to form a tertiary alcohol as described previously. However, when only one equivalent of Grignard reagent is available, the reaction will not proceed uniformly and a mix of the ester, tertiary alcohol, and intermediate ketone will be present in the product. In this experiment, phenylmagnesium bromide (itself formed from phenyl bromide and magnesium metal in situ) is reacted with methyl benzoate to form triphenylmethanol, via the intermediate benzophenone.
