[puffincatz23]

In substitution/elimination chemistry, we're faced with the inevitable task of ranking nucleophilicit/basicity to determine the type of reaction taking place. I know that certain species such as hydroxides and alkoxides are strong nucleophiles AND bases, and that other species such as water and alcohols are weak nucleophiles AND bases.

When it comes to weak nucleophiles and strong bases, I know that the reduced nucleophilicity is based off of steric bulk in the bases (eg t-butoxide and LDA), so it'll have a harder time accessing the electrophile. But what about strong nucleophiles and weak bases? For certain species such as the halogen anions, I know that since they are the conjugate bases of strong mineral acids (except HF), they are extremely weak bases. So what makes them still nucleophilic? Also, what about other species like potassium cyanide and sodium azide? Why are they nucleophilic but weakly basic? Any input would be greatly appreciated!

[zsinger]

Size and Negative charge density.
      -Zack

[zsinger]

Weakly basic b/c of the electron density being tied up in the sigma and 2 pi bonds.

[spirochete]

Nucleophilicity is a kinetic descriptor. It describes how quickly the species can form a new bond to an electrophile. There are two main things that make molecule nucleophilic: polarizability and basicity. For the purposes of predicting reactivity, a base strong enough to do an E2 reaction generally has a conjugate acid with a pKa of roughly 16 or larger. In other words, hydroxide/alkoxides or a stronger base.

I break nucleophiles up into 4 electronic classes. I'm ignoring steric effects here because I'm already typing a lot...

Polarizable nucleophiles: Larger elements are more polarizable. By larger, people generally mean below the second row in the periodic table. Polarizable elements are "soft" and their electrons are easily pulled toward partial positive charges in electrophiles. This makes them better nucleophiles. Examples of polarizable nucleophiles are: Iodide, bromide and Sulfides (RS minus). These polarizable nucleophiles are also by definition weaker bases than similar non-polarizable nucleophiles because the larger elements form weaker bonds to hydrogen than the smaller elements. So there's no risk of E2 reaction.

Moderately basic non polarizable nucleophiles: There are also some of examples of what I call "medium" base nucleophiles containing non polarizable nucleophilic atoms. Examples of these are carboxylates, cyanide and phenoxide. These guys have conugate acids with pKa ranges of around 4-10. They are not particularly great bases, but they are sufficiently basic that they can do fairly fast Sn2 reactions despite their lack of polarizability. They work well for primary and secondary substrates, because elimination does still does not compete well.

Strongly basic non polarizable nucleophiles: Alkoxides, hydroxides, R₂N^-, R₃C^-, etc. These have conjugate acids with pKa's of 16 or greater. These ones work mainly for primary halides due to competition from elimination with secondary halides. And things much stronger than acetylide (conjugate acid pKa=25) don't even work very well for primary substrates, possibly due to competition from E2 elimination although I'm not 100% sure why.

Very weakly basic, non polarizable nucleophiles: The include water, alcohols, and the conjugate bases of oxoacids such as HSO4^-. These guys don't work very well for any kind of Sn2 or E2 reaction because they lack both properties that make up a good nulcleophile, one of which is basicity.

[zsinger]

But watch out…..NaH is a TERRIBLE nucleophile, but a great base.  H- is just too tiny, and not polarizable.  Therefore, no attack.

[spirochete]

I did say that bases with conjugate acids with pKa's significantly higher than 25 are bad for most Sn2 reactions, and hydride falls into that category with H₂ having a pKa of about 35. I did know about that reasoning for hydride, but I am 100% sure of a generalizable reason why very strong bases don't work well for most Sn2 reactions. I was just speculating that the issue is competing elimination, although there are other quirks like with grignards the issue is cross coupling also. Grignards do open epoxide, though.

[puffincatz23]

Thank you for the replies! Few follow up questions:

zsinger, does the hydride from NaH act any differently than the hydride from NaBH4 or LiAlH4? I know that the latter two can act as nucleophiles (I think?) eg reducing ketones to secondary alcohols by attacking the carbonyl carbon. I've never really heard of NaH acting that way though...but I could be mistaken?

spirochete, when evaluating nucleophiles, you mention that it depends on polarizability and basicity. Just to make sure I understand this correctly, polarizability is purely based off of atomic size? And polarizable molecules can't be basic? Using the polarizability and basicity argument, what creates the "strongest" nucleophiles? Sorry for all the questions, I'm just really curious!

[orgopete]

I find this to be a very difficult topic to understand. Why should an acetylide anion change from a very good nucleophile to a very good base by changing the substrate? This tells me the difference isn't necessarily dependent on the base/nucleophile. How or why can weaker bases change the course of a reaction? For this reason, I prefer to use an example based approach. Which reactions do I know will react in a certain way? Then I try to compare other reactions to pathways I know. I prefer this approach than trying to classify or create a set of rules that are used to predict outcomes. I find there appear to be too many exceptions. The mechanism approach helps me to understand (guess at) the factors leading to given products for which a rank may not.

[zsinger]

Well….yes and no…..In LAH, it is nucleophilc AND basic……in NaH, just basic.
             -Zack

[zsinger]

The size and polarizability of the aluminum is the main reason for its nucleophilicity in LAH.

[phth]

spirochete, when evaluating nucleophiles, you mention that it depends on polarizability and basicity. Just to make sure I understand this correctly, polarizability is purely based off of atomic size? And polarizable molecules can't be basic? Using the polarizability and basicity argument, what creates the "strongest" nucleophiles? Sorry for all the questions, I'm just really curious!

Polarizability and basicity are referring to the Hard Soft Acid Base Principle http://en.wikipedia.org/wiki/HSAB_theory.  HSAB predicts observable trends in reactivity, but the principle has a few shortcomings.  The quantitative computation is done using gas phase assumptions (no solvent), and it does not take into kinetic and therodynamic control for molecules with two reactive centers.

For example, CN^- reacting with CH₃Br.  Whats the product?  CNCH₃ or NCCH₃.  At cold temperatures the product is isoacetonitrile, and acetonitrile at hot temperatures.  This means that isoacetonitrile forms faster (higher in energy) and is reversible; Nitrogen is more electronegative than carbon (harder to polarize), and it is an ionic interaction SN₁ (why it's higher in energy than carbon is beyond the scope of the discussion).  Carbon is less electronegative, and its transition states favor SN₂.  e.g. the sole product of Ph₃C⁺+CN^- is Ph₃CNC.

Acetonitrile forms a C-C bond, pulling the reaction to completion more so than C-N. Other parameters that matter are the shape and basicity (pKa); cyanide is a bad base pKa~9 (HCN<>CN^-), however.

[orgopete]

Re: polarizability and basicity

I agree with the comments on hard and soft theory, though I think some aspects may have some merit.

Another aspect of this topic that has not been delineated is the role of the cation/Lewis acid counterpart. In the instance of NaH vs NaBH4 or LiAlH4, sodium is not a good Lewis acid and does not have close contact with the electrons of the base/nucleophile. Trivalent boron and aluminum are putative intermediates and good Lewis acids. Their presence may play a significant role in the difference in the reactions of borohydride than hydride. The association of the hydride electrons with boron or aluminum facilitates their being soluble may also be significant.

The cyanide reaction differences are interesting. It contains the kind of question that I ponder myself. How are the electrons on carbon different than those on nitrogen? Indeed, it does not seem surprising that reaction might occur on nitrogen. How or why those on carbon fail to react is interesting. I don't think I agree with the proposed mechanisms though. I don't think methyl bromide is going to react by SN1 kinetics nor will triphenylmethyl bromide react via SN2.

[phth]

Re: polarizability and basicity

The cyanide reaction differences are interesting. It contains the kind of question that I ponder myself. How are the electrons on carbon different than those on nitrogen? Indeed, it does not seem surprising that reaction might occur on nitrogen. How or why those on carbon fail to react is interesting. I don't think I agree with the proposed mechanisms though. I don't think methyl bromide is going to react by SN1 kinetics nor will triphenylmethyl bromide react via SN2.

I made a mistake on the tritylisocyanate; it only forms when sillver blocks C attack, but the point is still valid. 
Thats not what I mean't by a SN1 pathway sorry if that was unclear. 

Nitrogen reacts with itself faster.  It inverts sp² carbon, which can be done from both sides.  sp³ carbon requires more energy because bond lengths change more. CN activation energy is 70 kj/mol smaller than the thermodynamic product.  If the electrophile has SN1 character, then a larger portion of the product distribution will be it.  Usually, this is reversible, however.  When its not, the kinetic product can even lead to the major product.  For an example of an eneamine, look at the jpg.  The activation energy difference in an enamine is 50kj/mol. Source: DOI 10.1002/anie.201007100