Reactions with Grignard Reagents.
A Grignard reagent has a formula RMgX where X is a halogen, and R is an alkyl or aryl (based on a benzene ring) group. For the purposes of this topic, we shall take R to be an alkyl group (e.g., BuMgBr). Grignard reagents are made by adding the halogenoalkane to small bits of magnesium in a flask containing diethyl ether. The flask is fitted with a reflux condenser, and the mixture is warmed over a water bath for 20 - 30 minutes.
Everything must be perfectly dry because Grignard reagents react with water (see below). Any reactions using the Grignard reagent are carried out with the mixture produced from this reaction. You can't separate it out in any way.
Grignard reagents and water.
Grignard reagents react with water to produce alkanes. This is the reason that everything has to be very dry during the preparation above. For example:The inorganic product, Mg(OH)Br, is referred to as a "basic bromide" and is a sort of half-way stage between magnesium bromide and magnesium hydroxide.
General Reaction between Grignards and carbonyls.
The reactions between the various sorts of carbonyl compounds and Grignard reagents can look quite complicated, but in fact they all react in the same way - all that changes are the groups attached to the carbon-oxygen double bond. It is much easier to understand what is going on by looking closely at the general case (using "R" groups rather than specific groups) - and then slotting in the various real groups as and when you need to.
The reactions are essentially identical to the reaction with carbon dioxide - all that differs is the nature of the organic product. In the first stage, the Grignard reagent adds across the carbon-oxygen double bond:
The reactions are essentially identical to the reaction with carbon dioxide - all that differs is the nature of the organic product. In the first stage, the Grignard reagent adds across the carbon-oxygen double bond:
Dilute acid is then added to this to hydrolyse it. (I am using the normally accepted equation, ignoring the fact that the Mg(OH)Br will react further with the acid).
An alcohol is formed. One of the key uses of Grignard reagents is the ability to make complicated alcohols easily. What sort of alcohol you get depends on the carbonyl compound you started with - in other words, what R and R' are.
Grignard reagents are widely used for the synthesis of various classes of organic compounds. Some examples are presented below.Why do Grignard reagents react with carbonyls?
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 negativeness of the carbon atom in the Grignard reagent and the positiveness of the carbon in the carbonyl compound. A nucleophile is a negative (or slightly negative) atom that attacks positive (or slightly positive) centers in other molecules or ions.
Preparation of the Grignard Reagent, Phenylmagnesium Bromide.
Grignard reagents play a commanding role in organic synthesis. These compounds can be adapted to the preparation of a large variety of functional groups, and the formation and reaction of organomagnesium derivatives are one of the major uses of alkyl halides in organic synthesis. The reaction of a halide and magnesium occurs on the surface of the metal and is formally an oxidation of the metal. The reaction is usually carried out in dry ether solvent, the ether functioning as a Lewis base by solvating the Grignard reagent and permitting it to diffuse away from the metal. The formation of the organometallic reagent requires an active surface on the metal, and some difficulty may be had in getting the reaction started because of metal oxides on the metal surface. Grinding the magnesium in a mortar for a few minutes before use is often effective in providing a clean surface. Another useful trick in starting a reaction is the addition of a small crystal of iodine to the mixture, which reacts with the magnesium to form the very reactive magnesium iodide (MgI2) salt.
Procedure.
The Grignard reagent is prepared by first fitting a dry 250 ml round-bottom flask with a CaCl2 drying tube. The magnesium to be used (2 g = 0.082 moles of magnesium turnings) is placed in the flask, the calcium chloride tube is attached directly, and the flask is heated thoroughly with a large heating mantel and rheostat. Adjust the controller for a large heating mantel to setting ‘6’ and heat the flask until it is too hot to touch with your finger. The flask on cooling pools dry air through the calcium chloride. Remove the heating mantel and cool to room temperature (the flask should feel just slightly warm to your hand, or cooler) before proceeding. Remove the calcium chloride drying tube and pour into the 250 round bottom flask 15 ml of absolute ether and 9 ml (13.5 g = 0.086 moles) of bromobenzene. Replace the CaCl2 drying tube. If there is no immediate sign of reaction, initiate the reaction by crushing some of the magnesium turnings. This is done by inserting a dry stirring rod with a flattened end and carefully crushing a piece of magnesium firmly against the bottom of the flask under the surface of the liquid, giving a twisting motion to the rod. When this is done properly, the liquid becomes slightly cloudy, and rapid bubbling commences at the surface of the compressed metal. At this point add 25 ml more of absolute ether and attach a reflux condenser to the flask and the CaCl2 tube to the top of the reflux condenser as shown in the picture.
Don't start running water through the condenser until ether vapors have wet the joint at the top of the condenser. When necessary, cool the flask by touching the bottom of the flask with an ice-bath to slow the reaction, but don't use it unless it is necessary. It is necessary only if ether vapors are exiting the top of the drying tube. If you do have to cool the reaction, be careful not to slow the reaction down too much, or it may stop and not start again when the ice is removed. Swirl the flask vigorously every sixty seconds. Once the reaction begins, spontaneous boiling in the diluted mixture may be slow or become slow. If so, add a few additional mls of bromobenzene to the flask. The reaction is complete when the ether quits bubbling and only a few small remnants of metal remain. Mark the ether level in the flask. During the reaction, check to see that the volume of ether has not decreased. If it has, add more dry ether. Since the solution of the Grignard reagent deteriorates on standing, the next step should be started at once.
Condensation of the Grignard Reagent with Methyl Benzoate.
Condensation of the Grignard Reagent with Methyl Benzoate.
Mix 5 g (0.037 mole; 1.09 g/ml) of methyl benzoate and 15 ml of absolute ether in a separatory funnel, cool the flask containing the Grignard reagent solution briefly in an ice bath. Remove the drying tube, and insert a Claisen adapter and a separatory funnel into the top of the condenser, as shown at right. Run in the methyl benzoate solution dropwise, over a ten-minute period, with only such cooling as is required to control the exothermic reaction. The product salt separates as a white solid during this step. Swirl the flask at regular intervals until the reaction has subsided, and the flask is at room temperature. Go directly to the next step.
Hydrolysis of the Addition Product.
Hydrolysis of the Addition Product.
Pour the reaction mixture carefully into a 250 ml Erlenmeyer flask containing 50 ml of 10% sulfuric acid and about 25 g of ice. Use a few mls of ordinary (non-anhydrous) ether and a few mls of the 10% sulfuric acid to rinse the reaction flask. Add these washings to the Erlenmeyer flask. Swirl well to promote hydrolysis of the addition compound; basic magnesium salts are converted into water-soluble neutral salts, and triphenylcarbinol is distributed into the ether layer. An additional amount of ether (ordinary) may be required if your original ether layer has become too low through evaporation. You may stop at this point if there is not enough time to complete the next part. Store the labeled Erlenmeyer in the hood with a lightly fitted cork(not rubber) stopper. The stopper should be loose enough that any gas pressure from evolving hydrogen gas will be released.
When the unconsumed Mg metal comes in contact with the acid, there will be a vigorous evolution of hydrogen gas and the reaction mixture may froth over if addition is too rapid.
Isolation of the Product.
If your ether layer has solid white crystals, these product crystals which have formed because some ether layer has evaporated. These crystals may be isolated by pouring the mixture into a separatory funnel through a glass funnel with a small plug of glass wool in the stem. Rinse the crystals with a small amount of ether solvent. To isolate the remaining product, rinse the Erlenmeyer flask, from which you poured the original solution, with a few mLs of ordinary ether and add this to the separatory funnel. Shake the funnel, carefully being sure to vent the build up of gas in the funnel. Draw off the aqueous layer. Shake the ether layer with 10% sulfuric acid to further remove magnesium salts and remove the sulfuric acid layer. Wash the ether layer with saturated sodium chloride solution to remove water that has dissolved in the ether. Remove the sodium chloride solution. The amounts of liquid used in these washing operations is not critical. In general, an amount of wash liquid equal to one third of the ether volume is adequate. To effect final drying of the ether solution pour the ether layer out of the neck of the separatory funnel into an Erlenmeyer flask, add about 5g of granular anhydrous sodium sulfate swirl the flask from time to time, and after 5 minutes decant the ether from the solid drying agent into another clean, dry Erlenmeyer flask. Add 25 ml of ligroin to the ethereal solution and stopper the flask with a cork stopper. Allow the mixture to stand overnight or until the next lab period. After standing, crystals of triphenylcarbinol should have formed. The major impurity biphenyl should remain soluble in the recrystallization solvent. Filter the crystals by suction filtration until dry. Record the weight of product isolated and calculate the % yield. Take a melting point.
When the unconsumed Mg metal comes in contact with the acid, there will be a vigorous evolution of hydrogen gas and the reaction mixture may froth over if addition is too rapid.
Isolation of the Product.
If your ether layer has solid white crystals, these product crystals which have formed because some ether layer has evaporated. These crystals may be isolated by pouring the mixture into a separatory funnel through a glass funnel with a small plug of glass wool in the stem. Rinse the crystals with a small amount of ether solvent. To isolate the remaining product, rinse the Erlenmeyer flask, from which you poured the original solution, with a few mLs of ordinary ether and add this to the separatory funnel. Shake the funnel, carefully being sure to vent the build up of gas in the funnel. Draw off the aqueous layer. Shake the ether layer with 10% sulfuric acid to further remove magnesium salts and remove the sulfuric acid layer. Wash the ether layer with saturated sodium chloride solution to remove water that has dissolved in the ether. Remove the sodium chloride solution. The amounts of liquid used in these washing operations is not critical. In general, an amount of wash liquid equal to one third of the ether volume is adequate. To effect final drying of the ether solution pour the ether layer out of the neck of the separatory funnel into an Erlenmeyer flask, add about 5g of granular anhydrous sodium sulfate swirl the flask from time to time, and after 5 minutes decant the ether from the solid drying agent into another clean, dry Erlenmeyer flask. Add 25 ml of ligroin to the ethereal solution and stopper the flask with a cork stopper. Allow the mixture to stand overnight or until the next lab period. After standing, crystals of triphenylcarbinol should have formed. The major impurity biphenyl should remain soluble in the recrystallization solvent. Filter the crystals by suction filtration until dry. Record the weight of product isolated and calculate the % yield. Take a melting point.
Syntheses of psychoactive substances with Grignard reagent.
The Grignard reagent is used in the synthesis of several surfactants. For example, in the synthesis of synthetic cannabinoids for the attachment of an alkyl group to the indole nitrogen atom (see JWH-018 Synthesis example). The reaction proceeds rather quickly under mild conditions and does not require heating.
The nucleophilic addition of the Grignard reagent allows for some non-specific and stereospecific reaction to produce amphetamine and its precursor such as phenyl-2-propanone (P2P).
Another method of application of Grignard reagent is use in route to mephedrone (4-MMC) synthesis using 4-methylbenzaldehyde as the starting material.
The reaction of indolylmagnesium iodide with substituted alkyl halides, e.g., the nitriles Cl(CH2)nCN and chloroacetyl diethylamide, to give the corresponding 3-substituted indoles is well acknowledged although very reactive halides, such as methyl iodide and benzyl chloride, sometimes give 1,3-disubstituted indoles. This DMT route possible with helps of Grignard reagent.
In addition to previous variety of applications, this popular approach is utilized in Ketamine synthesis step of (o-chlorophenyl)-cyclopentyl ketone manufacturing.
Conclusion.
As you can see, Grignard reagent extensively used in organic syntheses and drug manufacturing in partially. Alkyl magnesium halides (also called Grignard reagents) act like nucleophiles, attacking an electrophilic carbon atom to form a carbon-carbon bond. The Grignard reaction is an important method for creating carbon-carbon bonds as well as carbon-heteroatom bonds. This list of the most popular reactions among clandestine chemists shows the enormous potential for Grignard reagent applications and constitutes a large field for research.
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