Question

Each of the following equations represents a "possible" but not actually feasible Grignard synthesis. Consider each equation and determine why it will not proceed satisfactorily as written. Give your reasoning and show what the actual product will be. a. \(\left(\mathrm{CH}_{3}\right)_{3} \mathrm{CMgBr}+\left[\left(\mathrm{CH}_{3}\right)_{2} \mathrm{CH}\right]_{2} \mathrm{C}=\mathrm{O} \rightarrow \rightarrow\left(\mathrm{CH}_{3}\right)_{3} \mathrm{C}\left[\left(\mathrm{CH}_{3}\right)_{2} \mathrm{CH}\right]_{2} \mathrm{COH}\) b. \(\left(\mathrm{CH}_{3}\right)_{3} \mathrm{CCH}_{2} \mathrm{MgBr}+\left[\left(\mathrm{CH}_{3}\right)_{3} \mathrm{C}\right]_{2} \mathrm{C}=\mathrm{O} \rightarrow \rightarrow\left(\mathrm{CH}_{3}\right)_{3} \mathrm{CCH}_{2}\left[\left(\mathrm{CH}_{3}\right)_{3} \mathrm{C}\right]_{2} \mathrm{COH}\) ?. \(\mathrm{CH}_{3} \mathrm{MgI}+\mathrm{CH}_{3}\left(\mathrm{CH}_{3}\right)_{2} \mathrm{COCl} \rightarrow \rightarrow \mathrm{CH}_{3}\left(\mathrm{CH}_{3}\right)_{2} \mathrm{COCH}_{3}\) d. \(\mathrm{CH}_{3} \mathrm{MgI}+\mathrm{CH}_{3} \mathrm{CCH}=\mathrm{N}-\mathrm{CH}_{3} \rightarrow \rightarrow \mathrm{CH}_{3} \mathrm{CH}_{2} \mathrm{~N}\left(\mathrm{CH}_{3}\right)_{2}\) e. \(\mathrm{BrCH}_{2} \mathrm{CH}_{2} \mathrm{O}_{2} \mathrm{CCH}_{3} \underset{\left(\mathrm{CH}_{2} \mathrm{H}_{5}\right)_{2} \mathrm{O}}{\stackrel{\mathrm{Mg}}{\longrightarrow}}\) Grignard reagent \(\stackrel{\mathrm{CH}_{2} \mathrm{O}}{\longrightarrow} \rightarrow \mathrm{HOCH}_{2} \mathrm{CH}_{2} \mathrm{CH}_{2} \mathrm{O}_{2} \mathrm{CCH}_{3}\) f. \(\mathrm{CH}_{2}=\mathrm{CHCH}_{2} \mathrm{MgCl}+\mathrm{C}_{2} \mathrm{H}_{5} \mathrm{Br} \rightarrow \mathrm{CH}_{2}=\mathrm{CH}\left(\mathrm{CH}_{2}\right)_{2} \mathrm{CH}_{3}\)

Short answer

All reactions are incorrect due to issues like steric hindrance or reactivity mismatch (e.g., attack on imine instead of carbonyl), leading to no reaction or unintended products.

Step-by-step solution

Identify the Problem in Reaction (a)

The Grignard reagent \( (\mathrm{CH}_3)_3 \mathrm{CMgBr} \) is a strong base and will react with any acidic hydrogen it encounters. In the equation, \((\mathrm{CH}_3)_2 \mathrm{CH}_2 C=O\), the hydrogen adjacent to the carbonyl is mildly acidic, leading to deprotonation by the Grignard reagent. This will result in the formation of an alkoxide, not the alcohol as intended.

Correct Reaction for (a)

The Grignard reagent will deprotonate \((\mathrm{CH}_3)_2 \mathrm{CH}_2 C=O\) instead of adding to the carbonyl group. No reaction will occur as intended to form an alcohol.

Identify the Problem in Reaction (b)

The Grignard reagent \((\mathrm{CH}_3)_3 \mathrm{CCH}_2 \mathrm{MgBr}\) and the ketone \([(\mathrm{CH}_3)_3 \mathrm{C}]_2C=O\) are both bulky compounds. Steric hindrance prevents the Grignard from effectively attacking the carbonyl carbon, thus hindering the reaction.

Correct Reaction for (b)

Due to steric hindrance, the Grignard reagent will likely result in no reaction occurring, as the addition to the carbonyl group is hindered.

Identify the Problem in Reaction (c)

This reaction involves a Grignard reagent (\(\mathrm{CH}_3 \mathrm{MgI}\)) reacting with an acid chloride (\(\mathrm{CH}_3(\mathrm{CH}_3)_2 \mathrm{COCl}\)). Acid chlorides typically react with Grignard reagents to form tertiary alcohols, not ketones, after two equivalents of the Grignard reagent are added.

Correct Reaction for (c)

After adding two equivalents of the methyl Grignard reagent to the acid chloride, a tertiary alcohol is formed rather than the intended ketone product.

Identify the Problem in Reaction (d)

The Grignard reagent \(\mathrm{CH}_3 \mathrm{MgI}\) is highly reactive and will likely attack the imine bond \(\mathrm{CH}_3 \mathrm{CCH}=\mathrm{N}-\mathrm{CH}_3\). However, imines are similar to carbonyl groups and can react with Grignard reagents but are limited in producing the intended product.

Correct Reaction for (d)

The Grignard reagent reacts with the imine, forming a secondary amine instead of the primary amine group envisaged in the problem.

Identify the Problem in Reaction (e)

In this scenario, there seems to be confusion about the role of Grignard reagents. The main reaction listed lacks clarity, but typically, Grignard reagents would not form directly from an ester like in the problematic statement.

Correct Reaction for (e)

When an ester is subjected to a Grignard reagent, typically, you obtain a tertiary alcohol after reaction with formaldehyde (\(\mathrm{CH}_2 \mathrm{O}\)). Thus, the intended reaction product is unlikely as per the planned statement.

Identify the Problem in Reaction (f)

A Grignard reagent like \(\mathrm{CH}_2=\mathrm{CHCH}_2 \mathrm{MgCl}\) is expected to add to an electrophile, not simply partake in an elimination reaction with \(\mathrm{C}_2 \mathrm{H}_5 \mathrm{Br}\) as proposed in the problem.

Correct Reaction for (f)

The initial reaction suggests a substitution, but a more probable scenario is for the Grignard reagent to add via nucleophilic attack, which is not favorable in reaction with an alkyl bromide directly.

Key concepts

Grignard Reagent

A Grignard reagent is a powerful and versatile tool in organic chemistry. Formed by the reaction of magnesium metal with an alkyl or aryl halide, it results in the compound \( ext{R-Mg-X}\), where \( R \) represents an alkyl or aryl group, and \( X \) stands for a halogen. This reagent is incredibly reactive because of the strong bond polarization between magnesium and the carbon it is attached to.
The carbon atom in a Grignard reagent carries a partial negative charge, making it an excellent nucleophile. This nucleophilic property allows it to attack various electrophilic species, making the Grignard an essential player in forming carbon-carbon bonds.

• Grignard reagents must be handled under anhydrous conditions because they react vigorously with water, converting back into the original hydrocarbon and Mg(OH)X.
• Their reactivity makes them critical in carbonyl chemistry, enabling the formation of alcohols and other complex organic structures through additions.

Steric Hindrance

Steric hindrance refers to the prevention of chemical reactions due to the physical size of the molecules involved. When dealing with bulky groups, these hinder the approach of reactants to each other, often slowing or completely stopping reactions.
For example, in the case of reaction (b) from the exercise, both the Grignard reagent and the carbonyl compound are large, bulging molecules. This steric bulk occupies space, preventing the Grignard reagent from effectively reaching the carbon atom it needs to attack.

• This is why sometimes a reaction doesn’t proceed as expected – it's simply because there isn’t enough physical space for the molecule to perform the required chemical attack.
• This hindrance can be mitigated by using smaller groups or changing the reaction conditions, but it’s a crucial factor in predicting reaction feasibility.

Acid-Base Reaction

Grignard reagents, due to their strong base character, can engage in rapid acid-base reactions. When these reagents encounter even mildly acidic protons, they react preferentially rather than proceeding with their intended reaction path in forming new bonds.
In the case of reaction (a), the hydrogen adjacent to the carbonyl group is acidic enough to be deprotonated by the Grignard reagent. This acid-base interaction leads to the formation of an alkoxide, which halts further reaction transformation that would typically produce an alcohol.

• This inadvertent acid-base reaction is a common pitfall when using Grignard reagents, as it prevents the reagent from achieving its primary synthetic purpose.
• Sometimes, the reactivity towards acidic protons needs to be controlled by altering solvents or protecting groups to ensure the Grignard reagent performs as needed.

Carbonyl Chemistry

Carbonyl chemistry is fascinating due to the carbon-oxygen double bond present in functional groups like aldehydes and ketones. This bond is highly polar, with a partial positive charge on the carbonyl carbon making it susceptible to nucleophilic attack.
In the context of Grignard reactions, the nucleophilic carbon from the Grignard reagent attacks the electrophilic carbonyl carbon, resulting in the addition of the Grignard moiety and formation of an alcohol upon subsequent work-up with water or acid.

• This nucleophilic addition is a foundation for synthesizing alcohols and other functional groups in organic chemistry.
• However, in complex scenarios, competition with other reactions or steric hindrance can prevent the reaction from occurring as intended.