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WS 3 Assignment: Grignard Chemistry

A chemist attempts the reaction shown below using a 1 M commercially purchased solution of methyl magnesium bromide in tetrahydrofuran (THF).

A solution of methyl magnesium bromide (1 M THF; 7.40 mL, 7.40 mmol) was placed in an oven-dried flask. Under magnetic stirring, a solution of 4-(dimethylamino) benzaldehyde (1.00 g, 6.70 mmol) in anhydrous THF (5 mL) was added slowly, before heating the reaction mixture at 40 oC for 1 hour. Upon cooling, the reaction mixture was diluted with diethyl ether (30 mL).

An ammonium chloride solution (saturated aqueous; 30 mL) was added to the stirred reaction mixture. Next, sulfuric acid (aqueous; 2 M) was added slowly until pH = 2 (two clear layers were observed).

The biphasic mixture was transferred to a separatory funnel, and the aqueous phase was discarded. The organic phase was washed with deionised water (30 mL) and a sodium bicarbonate solution (saturated aqueous; 30 mL), before being dried over magnesium sulfate. After filtration, the organic phase was concentrated under reduced pressure but didNOTafford anyproduct.

1.    Based on the material safety data sheets (internet search) for 4-(dimethylamino)benzaldehyde, methyl magnesium bromide (1 M THF), and tetrahydrofuran, identify three principal hazards associated with each ofthese compounds. [4.5]

2.    Considering the polarity and density of the organic solvents used, THF and diethyl ether, explain the purpose of diluting the reaction mixture (THF) with diethyl ether before the aqueous work-up. [1.5]

3.    Assuming the “Grignard reaction” (C–C bond formation) proceeded smoothly, explain why the intended product was not obtained using the above “quenching”/isolation procedure.  Suggest a modified work- up to address this issue (to successfully isolate the product). [2]

4.    The same reaction was repeated with an amended work-up procedure.  The product isolated from the reaction mixture was found –without further purification– to have a melting point of 52–54 oC.

a.    Search the literature to find a previously reported value for the melting point of the product. Include the citation in your answer (see workshop 1; SciFinder & Reaxys). [2]

b.    By  comparing the  literature  and  experimentally  determined melting point values,  draw  a conclusion on the purity ofthe product. [1]

Unlike  aldehydes  and  ketones  (reaction via nucleophilic additionprotonation),  carboxylic  acid derivatives such as amides, esters, anhydrides, and acyl chlorides do react in a distinct mode (reaction via nucleophilic additionelimination), due to the presence of a leaving group at the carbon centre in the tetrahedral intermediate.   In turn, these substrates can react with two equivalents of a Grignard reagent.

Using your lecture & tutorial notes, please answer questions 5– 7 (p. t. o.).

5.    According to the scheme below, draw the structures of all organic reaction intermediates / final products after: (a) step 1, (b) step 2, and (c) step 3. [3]

O

Ph      Cl

(1) Bu–MgCl (1 equiv)

(3) H3O+

6.    According to the scheme below, draw the structures of all organic reaction intermediates / final products after: (a) step 1, (b) step 2, and (c) step 3. [4]

O

Ph      OPh

(1) Ph–Li (1 equiv)

(3) H3O+

7.    Assess the electrophilicity ofthe acyl–pyridinium species (left) compared with the acyl anhydride (right) by comparing the p* (LUMO) energy level of the corresponding C=O group [factors: (a) formal charge; (b) atomic size & electronegativity]. [2]

O

Ph      N

O      O

vs.