[Il Divo]

Hey all, just had two quick questions about very different organic chemistry reactions.

1) With regard to the Grignard reagents, OrganoLithium Reagents, and Lithium Aluminum Hydride reagents which all aid in reduction of carbonyl compounds, one topic which often comes up is the fact that these are all great bases and will readily abstract a proton from an oxygen or nitrogen if given the chance.

Where this becomes confusing is that I've often seen these reagents used to engage in nucleophilic addition to the carbonyl carbon. Technically, since the alpha carbon has an acidic proton, in all those cases shouldn't we be worried about a quick acid-base reaction occurring over addition? If so, how do I balance these two factors?

2) With regard to equilibrium expressions, it was drilled into my head that solids and liquids are not considered part of the equilibrium expression due to having constant densities/molarities. I thought this was a bit weird with liquids since alot of the equilibrium reactions I've run into (Ex: hydrolysis of esters or esterification of carboxylic acids) tend to recommend either using an excess of water or pulling water off as a product in order to drive equilibrium in one direction. If water isn't part of the expression, shouldn't this have no effect on the reaction?

Thanks, in advance.

[curiouscat]

2) With regard to equilibrium expressions, it was drilled into my head that solids and liquids are not considered part of the equilibrium expression due to having constant densities/molarities.

Wrong reason. A mixture of miscible liquids would definitely show up in an  equilib. expression.

I'm not a 100% sure, but I'd rephrase this as: "Pure phases are not relevant in equilibrium expressions, their activity is always invariant"

[Il Divo]

2) With regard to equilibrium expressions, it was drilled into my head that solids and liquids are not considered part of the equilibrium expression due to having constant densities/molarities.

Wrong reason. A mixture of miscible liquids would definitely show up in an  equilib. expression.

I'm not a 100% sure, but I'd rephrase this as: "Pure phases are not relevant in equilibrium expressions, their activity is always invariant"

So if I had a mixture of Dioxane and water where both were involved in the reaction, addition/removal of either would impact equilibrium?

[orgopete]

1) Basically correct, therefore acidic protocol solvents cannot be used. As less acidic protons may also be present, you may find some kinetic factors more important than equilibrium

2) Sort of, there are equilibria involved in the reactions, however the purpose of adding or removing water is to shift the equilibrium of the reaction. For example, in a Fischer esterification, the kinetic of attack by water or methanol are probably nearly equal. Since the equilibrium is dependent on the concentrations, adding water or removing water can shift the equilibrium. If this is taken a step further, then you may discover reactions that may occur despite unfavorable equilibria, e.g., Claisen condensation with ethoxide on an ester. Even though proton abstraction does not occur readily, once it does (and further reaction), the equilibrium of the reaction shifts by formation of a more acidic product.

[curiouscat]

2) With regard to equilibrium expressions, it was drilled into my head that solids and liquids are not considered part of the equilibrium expression due to having constant densities/molarities.

Wrong reason. A mixture of miscible liquids would definitely show up in an  equilib. expression.

I'm not a 100% sure, but I'd rephrase this as: "Pure phases are not relevant in equilibrium expressions, their activity is always invariant"

So if I had a mixture of Dioxane and water where both were involved in the reaction, addition/removal of either would impact equilibrium?

Yes.

[PhDoc]

This is the typical confusion resulting from incomplete understanding kinetics vs. thermodynamics when it comes to base/nucleophiles.

First, all bases are nucleophiles and all nucleophiles are bases. Employ the Lewis definition here. Second, basicity is a thermodynamic property whereas nucleophilicity is a kinetic property. Also, keep in mind reagent control is a variable. Something as innocent as changing the counterion on a base/nucleophile can lead to different results under different conditions.

The question to ask is, "Under these conditions [insert here], will the reagent be more basic or more nucleophilic?"

A Grignard reagent is an excellent nucleophile when used with a "good" electrophile under conditions that support it's application. When there is no good electrophile present, then the Grignard reagent might, if conditions permit, do the only other trick it knows, i.e. act as a base.

Example, what happens when you add a ethylmagnesium bromide in THF to 5-bromopentane at -78C? At room temperature? What happens when you add ethylmagnesium bromide to 5-bromo-1-pentyne in THF at -78? At room temperature? Would you expect a difference? If so, what? Why?

What happens when you add ethylmagnesium bromide to acetophenone in THF at -78C? At room temperature? What happens when you add ethylmagnesium bromide to 2-(tert-butyl)-1-(2,6-di-tert-butylphenyl)-3,3-dimethyl-1-butanone in THF at -78C? At room temperature? Would you expect a difference? If so, what? Why?

As Einstein, and others, learned upon their deathbeds, there is no Theory of Everything (TOE), students taking organic chemistry must realize many rules of thumb are useless, with the exception of one:

Nucleophile/bases make bonds with electrophiles when conditions permit. When conditions don't support the bond making process, if deprotonation can occur, it will. It's also important to keep in mind that even a proton is an electrophile, and that a deprotonation may be technically classified as a Lewis acid-base reaction.

Hope this helps.