[Allendo]

Hi Team
I have learned that grignard reagent perform acid base reaction way faster than nucleophilic attack. This explains that when grignard reagent react with a substrate with acidic H (-OH, -NH2, COOH, -C三CH)

eg: CH3CH2-MgBr + R-OH----->CH3CH3 + R-O(-)
      CH3CH2-MgBr + R-COOH----->CH3CH3 + R-COO(-)

The grignard reagent will only deprotonate the acidic H and create CH3CH3 and RO- (The PKa of R-OH is 15, PKa of R-COOH is 5 and PKa of CH3CH3 is 50, meaning both rxns run to completion). Also, in these reactions the grignard reagent will not work as a nucleophile and attack the carbonyl carbon.

Now my question is why grignard reagent react with ketone and aldehyde as a nucleophile. The PKa of ketone and aldehyde is about 20. (compare to the deprotonation product alkane, pka=50).  Yes it is much less acidic than carboxylic acid, but it's not that far away from alcohol! In my opinion, grignard reagent should deprotonate the aldehyde or ketone as well before it behave as a good nucleophile and attack the carbonyl carbon!

Any help is appreciated!

Allen

[hollytara]

Another good question.  I suspect that the kinetics of the enolate formation are slower than those of alkoxide formation, so that the nucleophilic reaction is faster.

[Babcock_Hall]

Carbon acids, especially those which rely upon delocalization of charge in the conjugate base form tend not to be "normal" acids in terms of their rates of deprotonation, although there are some interesting exceptions.

[Allendo]

Hi!
Thanks for your reply!

"Carbon acids, especially those which rely upon delocalization of charge in the conjugate base form tend not to be "normal" acids in terms of their rates of deprotonation, although there are some interesting exceptions.
"

Can you please elaborate a little further? Or can you please recommend me some links，keywords concerning this topic specifically?

I am a newbie in OChem and Thanks in advance!

[Babcock_Hall]

https://books.google.com/books?id=ZSjL2NX_ofAC&pg=PA131&lpg=PA131&dq=eigen+curve+proton&source=bl&ots=d0UyVYzXHq&sig=ACfU3U35mPi4Oj0PnwPqU9Bneh_y4ok1Vg&hl=en&sa=X&ved=2ahUKEwjk-tfAnrLpAhVJcq0KHaihA2cQ6AEwAnoECAgQAQ#v=onepage&q=eigen%20curve%20proton&f=false

I know just enough about this subject to be dangerous.  However, there is something called an Eigen curve (p. 125 in Organic and Bioorganic Mechanisms by Michael Page and Andrew Williams), which is a plot of log(rate constant for proton transfer) versus ΔpK_a.  When the proton transfer is favorable thermodynamically, protons on nitrogen or oxygen often react at a rate that reflects the diffusion-controlled encounter of the acid and base.  On the other hand, carbon acids such as acetyl acetone often react more slowly than if they were simply limited by diffusion.  A simple explanation is that carbon acids require more reorganization of the electron density.  Claude Bernasconi studied this idea extensively.  See for example Bernasconi C Accts. Chem. Res. 25:9.

The exception I had in mind was the thiazolium C-H such as is found in thiamin pyrophosphate, which does follow a normal Eigen curve.  I think that the reference is Washabaugh M and Jencks WP JACS 111:674-683.

[hollytara]

I think terminal alkynes follow a normal Eigen curve also.  My impression is that it has to do with electronic rearrangement.  The hybridization model is flawed, but here it helps with understanding.  When an acid is deprotonated, does the resulting anion rehybridize to become the lowest energy structure.  For terminal alkynes, they are sp hybridized as is the acetylide.  Alcohols and alkoxides - the O is always sp3.  But when a carbonyl compound is deprotonated it changes from sp3 for the C-H bond to sp2 for the enolate.  You can also imagine that the lower pKa of the carbonyl compound only applies when the C-H bond is parallel to the carbonyl pi orbitals and can give the delocalized enolate.  If the C-H is perpendicular, it behaves like a regular C-H and has a much higher pKa.  So the base is only effective when it collides with the carbonyl in the right conformation.

[Allendo]

Hi
Thanks for your replies.

Your replies are beautiful.

hollytara:"When an acid is deprotonated, does the resulting anion rehybridize to become the lowest energy structure.  For terminal alkynes, they are sp hybridized as is the acetylide.  Alcohols and alkoxides - the O is always sp3.  But when a carbonyl compound is deprotonated it changes from sp3 for the C-H bond to sp2 for the enolate."

Please correct me if I were wrong. Your reply reminds me of the concept to differentiate nucleophilicity vs basicity. Or the concept of thermodynamic vs kinetic product. In other words, the deprotonation of aldehyde is thermodynamically favored (PKa difference is huge) but kinetically disfavored(nucleophilic attack much faster in this case compare to acid base reaction, due to a rough model of electron orbital re-hybridization). That's why grignard reagent behave bona fide as a nucleophile.