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.

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{ 30 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?

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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?

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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.

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Morgan October 24, 2012 at 10:47 am

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

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james November 5, 2012 at 2:15 pm

Yes it does.

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Garrett December 15, 2012 at 11:15 pm

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

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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.

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mike April 11, 2013 at 2:03 am

THANK YOU!

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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.

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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.

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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…

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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!

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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

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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

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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

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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…

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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].

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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!

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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.

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Abhishek November 14, 2013 at 7:19 am

is boron quadfluoride a nucleophile

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James Ashenhurst November 14, 2013 at 10:14 am

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

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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?

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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.

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Katie January 19, 2014 at 10:33 am

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

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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?

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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 ?

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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 ?

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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.

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liangyy July 17, 2014 at 12:55 am

You mean only hindrance effect make basicity and nucleophilicity different?

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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.

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