What Makes A Good Nucleophile?

by James

in Organic Chemistry 1, Understanding Electron Flow, Where Electrons Are

If you read the last post, you’ll recall that a nucleophile is a species that donates a pair of electrons to form a new covalent bond. Nucleophilicity is measured by comparing reaction rates; the faster the reaction, the better (or, “stronger”) the nucleophile.

When discussing nucleophilicity we’re specifically talking about donating a pair of electrons to an atom other than hydrogen (usually carbon).  When a species is donating a pair of electrons to a hydrogen (more specifically, a proton, H+) we call it a base.

This post attempts to address one of the most vexing question to students of organic chemistry. What are the factors that make a good nucleophile?

For our purposes, there are at least four key factors contributing to nucleophilicity.

  1. Charge
  2. Electronegativity
  3. Solvent
  4. Steric hindrance

The first two should hopefully be familiar from the discussion of what makes something a strong base. After all, basicity and nucleophilicity essentially describe the same phenomenon, except basicity concerns donation of lone pairs to hydrogen, and nucleophilicity concerns donations of lone pairs to all other atoms.  It’s the third and fourth points where extra factors come into play.

1. The Role of Charge

Since a nucleophile is a species that is donating a pair of electrons, it’s reasonable to expect that its ability to donate electrons will increase as it becomes more electron rich, and decrease as it becomes more electron poor, right? So as electron density increases, so does nucleophilicity.

A handy rule to remember for this purpose is the following: the conjugate base is always a better nucleophile.

2. Electronegativity

Assuming an atom has a pair of electrons to donate, the ability of a species to donate that pair should be inversely proportional to how “tightly held” it is. The key factor for determining how “tightly held” an electron pair is  bound is the familiar concept of electronegativity. Bottom line: as electronegativity increases, nucleophilicity decreases. Note: It’s important to restrict application of this trend to atoms in the same row of the periodic table; for instance, C N O F, or Si P S Cl. Going down the periodic table, another factor comes into play (next)

3. Solvent

Nucleophilicity is not a property inherent to a given species; it can be affected by the medium it’s in (otherwise known as “the solvent”). [For an introduction to the different classes of solvents, click here]

A polar protic solvent can participate in hydrogen bonding with a nucleophile, creating a “shell” of solvent molecules around it like mobs of screaming teenage fans swarming the Beatles in 1962. In so doing, the nucleophile is considerably less reactive; everywhere it goes, its lone pairs of electrons are interacting with the electron-poor hydrogen atoms of the solvent.

The ability of nucleophiles to participate in hydrogen bonding decreases as we go down the periodic table. Hence fluoride is the strongest hydrogen bond acceptor, and iodide is the weakest. This means that the lone pairs of iodide ion will be considerably more “free” than those of fluoride, resulting in higher rates (and greater nucleophilicity).

A polar aprotic solvent does not hydrogen bond to nucleophiles to a significant extent, meaning that the nucleophiles have greater freedom in solution. Under these conditions, nucleophilicity correlates well with basicity – and fluoride ion, being the most unstable of the halide ions, reacts fastest with electrophiles.

[Often asked: why don’t we care about “non polar solvents” here?  Remember “like dissolves like”? If we want a reaction to take place, we need to use solvents that will actually dissolve our nucleophile.  Many nucleophiles are charged species (“ions”) – they don’t dissolve in non-polar solvents.]

4. Steric hindrance

Since, when discussing nucleophilicity, we’re often discussing reactions at carbon, we have to take into account that orbitals at carbon that participate in reactions are generally less accessible than protons are. An effect called “steric hindrance” comes into play.

The bottom line here is that the bulkier a given nucleophile is, the slower the rate of its reactions [and therefore the lower its nucleophilicity].

So comparing several deprotonated alcohols, in the sequence methanol – ethanol – isopropanol – t-butanol, deprotonated methanol (“methoxide”) is the strongest nucleophile, and deprotonated t-butanol (“t-butoxide”) is the poorest (or “weakest”) nucleophile.

Miss anything? Any further questions? Leave a comment below!

Next Post: What Makes A Good Leaving Group?

Note: Are there other factors? Yes. This list of four covers the basics, but several other factors are worth noting. 1) the identity of the electrophile 2) atoms with lone pairs adjacent to the nucleophile 3) in the case of ions, the identity of the counter-ion [i.e. positively charged species] can be significant.

Related Posts:

{ 35 comments… read them below or add one }

Doug Borgman June 28, 2012 at 1:49 am

My understanding with I>F in polar protic solvents wasn’t because F has MORE hydrogen bonding but rather that it is more affected by the hydrogen bonding due to being smaller in size. Roughly, the larger I ion has the same hydrogen bonds but can still “wiggle” the electron pair through them since it is a “looser coat” of hydrogen bonds…
is this correct?

Reply

james June 29, 2012 at 9:23 am

It’s correct in that fluoride, being smaller, has a larger charge density, and the interactions with the partial positive charges on the hydrogen of water will be stronger. Iodide, being larger, will have a lower charge density and interactions with hydrogen will be weaker. Does that make sense to you?

Reply

Joseph December 17, 2012 at 8:04 am

Its actually the opposite. Since flourine is smaller, its charge is confined to a smaller space and it therefore has a higher electron density. Florine is effected by hydrogen bonding more than Iodine (in polar protic solvents) but the reason is because Florine’s smaller size makes it more easily solvated (surrounded by solvent molecules) than iodine so it can’t react as well. Remember that nucleophilicuty is a measure of how well/fast something reacts, while basicity is a measure of how “willing” an atom is to give up a lone pair. They are correlated most of the time but not always.

Reply

Morgan October 24, 2012 at 10:47 am

With the “bulkiness,” does that have to do with Beta-branching?

Reply

james November 5, 2012 at 2:15 pm

Yes it does.

Reply

Garrett December 15, 2012 at 11:15 pm

How is polarizability related to nucleophilic strength? Would it fit into any of these categories?

Reply

Joseph December 17, 2012 at 7:59 am

Polarizability plays a role when you take the solvent into account. In polar protic solvents, hydrogen bonding occurs between the partial positive hydrogen (H attached to N or O usually) and the nucleophile. Smaller nucleophiles become more solvated than larger nucleophiles, which means that smaller nucleophiles in polar protic solvents will not be able to react as well and thus are poorer nucleophiles.

For example, Florine anions become so heavily solvated in polar protic solvents that they wont even react, but Iodine, being much larger, is much less solvated and can still react.

In aprotic solvents, hydrogen bonding does not occur to any significant extent and the stronger base is usually the stronger nucleophile.

Reply

mike April 11, 2013 at 2:03 am

THANK YOU!

Reply

PaladinQ March 31, 2013 at 10:34 pm

Excellent post, but…

If this list does not take into account all the factors that make a good nucleophile, where is a more detailed treatment of the ones that are remaining?

Also, in the case of polar aprotic solvents, one may mention the idea of the cation being solvated, while the anion (nucleophile) less so, and so it is more reactive.

Once again, excellent post.

Reply

james April 1, 2013 at 3:05 pm

What’s missing is hard-soft acid base (HSAB) theory which involves discussion of molecular orbitals. I’ve chosen to defer that discussion for now. One example is the differing selectivity of enolates for C vs. O alkylation; depending on the nature of the solvent, counter-ion, and electrophile, either dominant O vs. C alkylation can be achieved. For a discussion I’d refer to Carey and Sundberg but there are many other online sources which discuss HSAB.

Reply

PaladinQ March 31, 2013 at 10:37 pm

Also, I think “Polarizability” was a factor that may have been missed, or perhaps stated in a more subtle manner…

Reply

Jessica April 2, 2013 at 12:51 am

Hi, I was wondering why (CH3)2N- is better nucleophile than CH3NH- which is better than H2N-, when (CH3)2N- and CH3NH- has more steric hindrance? I understand that the presence of electron donating groups (eg. methyl groups) would increase the nucleophilicity, but how do I know which factor is more important?

Thanks!

Reply

james April 3, 2013 at 12:02 pm

Great question. These types of tradeoffs are what can make organic chemistry difficult. In advance, it’s hard to know exactly which factor is most important until you actually see the results from experiment.

Good discussion here:
http://wavefunction.fieldofscience.com/2010/11/why-are-secondary-amines-most-basic.html

Reply

Rashika April 8, 2013 at 9:00 am

How do we decide that from anisole, nitrobenzene and benzene, what will be the correct order of rate of electrophillic substitution? And can you possibly link me to an article related to it?
PS AMAZING site! You are soon gonna get a lot of Indian visitors. :D

Reply

Jim2013 July 31, 2013 at 7:47 pm

Hello,
Is it accurate to say that primary amines are more strongly nucleophilic than carboxylic acids? I presume this is so given the charge delocalization in COO- and the steric hindrance in COOH. Do you happen to know of a reference in the literature that compares these two species’ nucleophilicity?
Many thanks for your help and time.
Jim

Reply

Matheus October 10, 2013 at 11:41 am

“Bottom line: as electronegativity increases, nucleophilicity decreases”

“Under these conditions, nucleophilicity correlates well with basicity – and fluoride ion, being the most unstable of the halide ions, reacts fastest with electrophiles.”

Which one is it? It seems to me that you are contradicting yourself and making me more confused than I was previous to visiting this page…

Reply

James Ashenhurst November 14, 2013 at 10:20 am

Maybe I should have made this clearer. It’s consistent if you consider that nucleophilicity increases with basicity EXCEPT in the case of polar protic solvent, in which nucleophilicity increases with polarizability.
Basicity: CH3(-) > NH2(-) > HO(-) > F(-) and F(-) > Cl(-) > Br (-) > I(-) [in polar aprotic solvents].

Reply

Anna Moravec May 21, 2014 at 5:33 pm

I don’t understand why F(-)>Cl(-)>Br(-)>I(-)

Electronegativity decreases down a group, so shouldn’t nucleophilicity increase down the group?

SO CONFUSED!

Reply

Frances August 28, 2014 at 5:29 am

The “electronegativity decreases, nucleophilicity increases” rule applies only to atoms within the SAME ROW in the periodic table. Also, that rule only applies for polar protic solvents. F(-) tends to H-bond with the solvent more, making it less reactive as a nucleophile, as compared to a nucleophile containing carbon.

The reverse of the rule is what actually applies in polar aprotic solvents. Since the solvent does not H-bond to the halide nucleophiles, fluorine basically becomes the most reactive among the halides.

It took me way too long before I finally understood this whole nucleophile thing, but I hope my answer helped.

Reply

Abhishek November 14, 2013 at 7:19 am

is boron quadfluoride a nucleophile

Reply

James Ashenhurst November 14, 2013 at 10:14 am

What do you think? What atom(s) on BF4(-) could donate a pair of electrons?

Reply

sarah December 23, 2013 at 6:33 am

Hi,

This was very helpful, but I’m still confused about 1 thing, how is fluorine a better base than iodine but a worse nucleophile?

Reply

James Ashenhurst December 27, 2013 at 12:55 am

In polar protic solvents (and only in polar ptotic solvents) fluorine’s strong Lewis basicity helps it form very strong hydrogen bonds with the solvent. The resulting “shell” of solvent molecules around fluorine acts to “hinder” fluorine and therefore makes it a poorer nucleophile. Iodine does not form strong hydrogen bonds and therefore is not accompanied by a large solvent shell, so it is less “hindered” in polar protic solvents and thus a better nucleophile.

Reply

Katie January 19, 2014 at 10:33 am

Does good nucleophilies have anything to do with hard/soft base?

Reply

Bk February 19, 2014 at 10:14 am

Hi, I came across a question asking ‘Which is the stronger base? Pyridine or Morpholine?’ Is it the same as asking which is the stronger nucleophile? Anyway, I think the answer is morpholine but I do not know how to explain it. Could anyone please help me on this?

Reply

Hamada Abulkhair November 14, 2014 at 11:11 am

I expect that, in pyridine nitrogen atom surrounded by three bons all of them with carbon atoms while in morpholine there are three bonds two of them with crbon and the thired one with hydrogen which is lower electronegative than carbon so the availability of unshered electron pair in morpholine more than that in pyridine.

Reply

Hawers March 9, 2014 at 12:28 pm

in sn2 reaction ı know why we use polar aprotic solvent, but under which conditon the reaction may retard? I mean which polar aprotic solvent may retard reaction ?

Reply

Mannat May 26, 2014 at 2:36 am

Can u explain finkelstein’s reaction on the basis of the effect of polar Aprotic solvents on Nu ?

Reply

James May 26, 2014 at 3:41 pm

No, Finkelstein’s reaction goes forward because NaI is soluble in acetone, whereas NaCl precipitates out. That drives the equilibrium forward.

Reply

liangyy July 17, 2014 at 12:55 am

You mean only hindrance effect make basicity and nucleophilicity different?

Reply

James July 22, 2014 at 10:00 pm

Not quite. Acidity/basicity is measured by equilibrium constant, whereas nucleophilicity is measured by reaction rate (since the vast majority of substitution reactions are not reversible). But steric hindrance (due to the fact that a sigma star orbital is being attacked on carbon, versus an S orbital on hydrogen) is the key difference.

Reply

Lauren September 20, 2014 at 4:19 pm

Hello!
My question is why flouride ion behaves as a strong nucleophile in aprotic polar solvent when nucleophilisity is related to polarizability. any specie that is more polarizable tends to be a good nucleophile. Then why not iodide is a strong nucleophile in aprotic polar solvent and also iodide is less electronegative than fluoride so it should easily donate its lone pair of elctron

Reply

symara October 11, 2014 at 10:25 am

Hi! It says in my textbook that in methanol, RS- is a better nucleophile than iodide. This is something I didn’t get it. I mean, sulfur is smaller and the R group is probably making it more basic by electron-donating effect, thus making it a stronger base. This means that RS- should be the most solvated one and therefore less nucleophilic. But according to Ms. Paula Bruice, no, RS- is the better one.
By the pka table, HI is a stronger acid than RSH. So, RS- would still have the stronger base, that would still be more solvated. I really don’t get it. When I think I got it, I didn’t. I used to like Ochem a lot, but now I think I will never undestand it and it bums me out.
Another thing, in a SN2 reaction, ammonia is the nucleophile and it is asked which solvent will make the reaction faster: ether or ethanol. I would say ethanol, because it would stabitize the transition state by solvation, right? But, no, according to my professor, ether would be the best one because it would not make hydrogen bonds to ammonia. Now I don’t know if I must consider transition states, and solvents stabilizing carbocations or just the nucleophile and hydrogen bonding.
Please, help.

Reply

James October 12, 2014 at 1:53 pm

Hi Symara – there are many factors involved in nucleophilicity. It’s not a simple, one-variable equation.

Hydrogen bonding is most important for atoms O, N, and F (because of the large difference in electronegativity between these atoms and H). When you compare that to S (electronegativity 2.6) there just isn’t much hydrogen bonding going on so it shouldn’t affect nucleophilicity. So the above answer (RS- beats I-) and ether being a better solvent than ethanol probably makes the most sense.

As an aside, when talking about different variables like basicity or polarizability it is much clearer if you are going across a row or up and down a column of the periodic table. For example, compare polarizability going down (F- Cl- Br- I- ) or basicity going across (H3C- H2N- HO- F- ). Comparing both at once (e.g. Cl- and H2N- ) really requires looking at experimental evidence.

Reply

Seung October 11, 2014 at 6:16 pm

Being challenged, need reasons why H2O instead of Br- became nucleophiles. Textbooks with huge price tags just presents drawings of kind of skeletons, H2O and arrows.
Here I get it.
Thank you James.

Reply

Leave a Comment