Subject Chemistry Paper No and Title Module No and Title Module Tag 9: Organic Chemistry-III (Reaction Mechanism-2) 13: Addition of Grignard reagent CHE_P9_M13
TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. Grignard reagent 3.1Reaction with Aldehydes and Ketones 4. Reaction with other Carbonyl compounds 4.1 Reaction with Esters 4.2 Reaction with Acid Chlorides 4.3 Reaction with CO2 4.4 Reaction with Nitriles 4.5 Reaction with Oxiranes 5. Industrial applications of Grignard reagent 5.1 Organotin compounds 5.2 Organosilicon compounds 5.3 Organophosphorous compounds 6. Summary
1. Learning Outcomes After studying this module, you shall be able to Know about Grignard reagent and its synthesis. Learn about its reaction with carbonyl compounds. Identify transition states involved when Grignard reagent reacts with carbonyl compounds as well as alkenes. Evaluate the effects of solvent on Grignard reagent and oraganolithium compounds. Analyze the industrial importance of Grignard reagent. Learn about the reaction of Grignard reagent with nitriles and oxiranes and various other functional group moieties. 2. Introduction Organomagnesium compounds frequently called Grignard reagents after their discoverer. They are an important class of extremely reactive chemical compounds used in the synthesis of hydrocarbons, alcohols, carboxylic acids, and other compounds. They are prepared by adding an alkyl halide to magnesium shavings being stirred in anhydrous diethyl ether or THF. The magnesium is inserted between the carbon and the halogen.
The C-Mg bond in Grignard reagents is covalent and not ionic. The actual structure of Grignard reagents in solution has been a matter of much controversy over the years. In 1929, it was discovered that the addition of dioxane to an ethereal Grignard solution precipitates all the magnesium halide and leaves a solution of R2Mg in ether; (i.e., there can be no RMgX in the solution since there is no halide). The following equilibrium, now called the Schlenk equilibrium, was proposed as the composition of the Grignard solution: Here the last species on the RHS is a complex. 3. Preparation of Grignard Reagent The carbon atom of organic halide which is directly attached to the halogen is, of course, electrophilic. This electrophilic reactivity can be switched to nucleophilic reactivity by conversion to an organomagnesium halide, i.e., a Grignard reagent. The carbon-magnesium bond in a Grignard reagent is polar and covalent with carbon being the negative end of the dipole. Thus the nucleophilicity of carbon in a Grignard reagent. Note also that the magnesium-halogen bond is largely ionic, as shown in the structure above. The mechanism of formation of a Grignard reagent is shown below. It involves radical intermediates. There is one major difference that should be noted. Grignard formation does not involve a radical chain mechanism. It is a non-chain radical reaction.
The first step is rate-determining and involves the transfer of one electron from Mg (which has two electrons in its valence shell) to the carbon-halogen bond. This forms Mg +1, which is a radical. This then couples with the alkyl radical formed. 3.1 Role of Solvent Organomagnesium and organolithium compounds are such strong bases that they will react immediately with any acid that is present in the reaction mixture-even with very weak acids such as water and alcohols. When this happens, the organometallic compound is converted into an alkane. If D2O is used instead of H2O a deuterated compound will be obtained. This means that Grignard reagents and organolithium compounds cannot be prepared from compounds that contain acidic groups (OH, NH2, NHR, SH, COOH groups). Because even trace amounts of moisture can destroy an organometallic compound, it is important that all reagents be dry when organometallic compounds are being synthesized and when they react with other reagents.
Diethyl ether is an especially good solvent for the formation of Grignard reagents because ethers are non-acidic (aprotic). Grignard reagents are stable in ethers Another reason for ethers being good solvents for Grignard reagents is that the MgX bond is ionic and thus benefits greatly from being effectively solvated. The formation of ions in very nonpolar solvents, where they would not be effectively solvated is very difficult. Ethers are surprisingly good at solvating cations, because the C-O bond is relatively polar, thus allowing the oxygen end of the ether dipole to solvate and stabilize (electrostatically) the magnesium ion. 4. Reactions of Grignard Reagent with Carbonyl Compounds Addition of a Grignard reagent to a carbonyl compound is a versatile reaction that leads to the formation of a new bond. The reaction can produce compounds with a variety of structures because both the structure of the carbonyl compound and the structure of the Grignard reagent can be varied. A Grignard reagent reacts as if it were a carbanion. Attack of a Grignard reagent on a carbonyl carbon forms an alkoxide ion that is complexed with magnesium ion. Addition of water or dilute acid breaks up the complex. 4.1 Reaction with Formaldehyde Grignard reagent reacts with formaldehyde to form primary alcohols.
4.2 Reaction with Other Aldehydes Grignard reagent with aldehydes other than formaldehyde to form secondary alcohol. 4.3 Reaction with Ketones When a Grignard reagent reacts with a ketone, the addition product is a tertiary alcohol. 4.4 Why do Grignard reagent react with Carbonyl compounds? The bond between the carbon atom and the magnesium is polar. Carbon is more electronegative than magnesium, and so the bonding pair of electrons is pulled towards the carbon. That leaves the carbon atom with a slight negative charge.
The carbon-oxygen double bond is also highly polar with a significant amount of positive charge on the carbon atom. The Grignard reagent can therefore serve as a nucleophile because of the attraction between the slight negative charge of the carbon atom in the Grignard reagent and the positive charge of the carbon in the carbonyl compound. A nucleophile is a species that attacks positive (or slightly positive) centers in other molecules or ions. 4.5 Mechanism and Transition State Involved in the Grignard Reagent Reactions with Carbonyl Compounds 4.5.1 Mechanism: Formation of alcohols via addition of Grignard reagents to aldehydes and ketones is carried out in two separate steps Step 1: Addition of the nucleophilic alkyl group to the carbonyl carbon, aided by Lewis acid interaction between MgX + and the carbonyl oxygen. The product of this step is a halomagnesium alkoxide. Step 2. Protonation of the alkoxide oxygen. The product of this step is an alcohol. 4.5.2 Transition state model for the Grignard addition reaction to a carbonyl compound:
The alkoxide character derives from the product (P) character of the TS. This alkoxide character is further stabilized by covalent and ionic bonding to the magnesium ion. The Mg-O bond is a very stable one. A final factor which makes this TS an especially favorable (low energy) one is the electrostatic attraction between the positively charge carbonyl carbon and the partially negatively charged carbon of the Grignard reagent. This derives from reactant (R) character in the TS (properly positioned reactants, of course). 4.5.3 Transition state model for the hypothetical addition of a Grignard reagent to an alkene for comparative analysis By simply substituting carbon for oxygen in the transition state model for addition to a carbonyl group (along with generalized valencies to that carbon),
we can obtain a TS model for the analogous but hypothetical addition of a Grignard reagent to an alkene. We use the Method of Competing Transition States to compare the relative merits of these two reaction (relative rates). Carbanion character is much less favorable than oxyanion character. Mg-C bond character is less favorable than Mg-O bond character in the TS. Electrostatic attraction is present in the carbonyl addition TS but is simply missing in the alkene addition TS, because the alkene pi bond is not polar. Consequently, since all of these effects favour the TS for the addition of Grignard reagents to carbonyl compounds, it is much more favorable than the TS for addition to an alkene. 5. Additional Reactions of Grignard Reagent 5.1 Reaction with esters When an ester reacts with a Grignard reagent, the first reaction is a nucleophilic acyl substitution reaction because an ester, unlike an aldehyde or a ketone, has a group that can be replaced by the Grignard reagent. The product of the reaction is a ketone. The reaction does not stop at the ketone stage, however, because ketones are more reactive than esters toward nucleophilic attack. Reaction of the ketone with a second molecule of the Grignard reagent forms a tertiary alcohol. Because the tertiary alcohol is formed as a
result of two successive reactions with a Grignard reagent, the alcohol has two identical groups bonded to the tertiary carbon. 5.2 Reaction with Acid Chlorides Tertiary alcohols are also formed from the reaction of two equivalents of a Grignard reagent with an acyl halide. In theory, we should be able to stop this reaction at the ketone stage because a ketone is less reactive than an acyl halide. However, the Grignard reagent is so reactive that it can be prevented from reacting with the ketone only under very carefully controlled conditions. There are better ways to synthesize ketones 5.3 Reaction with CO2 Carboxylic acids are formed as a result of addition of Grignard reagent to CO2.
5.4 Reaction with Nitriles Grignard reagent react with nitriles to give ketone as a product. 5.5 Reaction with Oxiranes Grignard reagent add to epoxides to form carbon-carbon bonds. One thing to keep in mind here is that the tendency is for them to add to the less substituted end of the epoxide that is, the less sterically hindered end. We can think of this reaction as being essentially similar to an SN2 reaction. After addition of acid, an alcohol is obtained.
6. Industrial Applications of Grignard Reagent Production of Grignard reagents requires various industrial techniques for raw material and solvent dehydration/drying, reaction heat reduction etc. Grignard reagents produced by employing these techniques are used to produce organometallic compounds (organotin compounds, organosilicon compounds, organoboron compounds etc.), as well as primary materials and intermediates of pharmaceuticals and agrochemicals. Grignard reagents are widely used to produce organometallic compounds on an industrial scale. The following are typical examples of metals, semimetals and other metallic species that are produced industrially, and their applications. 6.1 Organotin compounds Various organotin compounds can be produced by reacting Grignard reagents with tin tetrachloride. Organotin compounds are used as stabilizer for vinyl chloride resins, catalyst for hardening urethane, catalyst for hardening silicon resin, and other industrial purposes. 6.2 Organosilicon compounds Combinations of Grignard reagents and suitable types of raw silicon compounds enable the production of various kinds of symmetric and asymmetric di-, tri- and tetraorganosilicon compounds. These compounds are used as protective groups in organic synthesis, metallocene catalyst materials for olefin polymerization and intermediates in pharmaceutical synthesis.
6.3 Organophosphorous compounds The phosphine compound is a typical example of industrially useful organophosphorous compounds produced using Grignard reagents. Phosphine compounds, which can be made from Grignard reagents and halide phosphates, are used as Wittig reagents for vitamin synthesis, the additives for various synthetic resins, and for other applications. Phosphonium salt, R3PR X, which can be produced by reacting the above R3P with an alkyl halide, is useful as a phase-transfer catalyst. 7. Summary In this module you have learnt that: Grignard reagents and organolithium compounds are the most common organometallic compounds-compounds that contain a carbon metal bond. They cannot be prepared from compounds that contain acidic groups. The carbon atom attached to the halogen in the alkyl halide is an electrophile, whereas the carbon atom attached to the metal ion in the organometallic compound is a nucleophile. The greater the polarity of the carbon metal bond, the more reactive the organometallic compound is as a nucleophile.
Grignard reagents react with aldehydes to form secondary alcohols, with ketones and acyl halides to form tertiary alcohols, and with carbon dioxide to form carboxylic acids. Aldehydes are reduced to primary alcohols, ketones to secondary alcohols, and amides to amines.