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A Primer On Organic Reactions

By James Ashenhurst

Nucleophilicity vs. Basicity

Last updated: October 9th, 2019 |

Understanding The Differences Between Nucleophilicity vs Basicity

Following up on Nucleophiles and Electrophiles, here’s a common question students have about nucleophilicity:

1. What’s the difference between nucleophilicity and basicity?

Great, great question.

First of all, remember that basicity is a subset of nucleophilicity. All nucleophiles are Lewis bases; they donate a lone pair of electrons. A “base” (or, “Brønsted base”) is just the name we give to a nucleophile when it’s forming a bond to a proton (H+). To summarize, when we’re talking about basicity and nucleophilicity, we’re talking about these two types of events.

Basicity: nucleophile attacks hydrogen

Nucleophilicity: nucleophile attacks any atom other than hydrogen. Because we’re talking about organic chemistry here, for our purposes, this is going to mean “carbon” most of the time.

2. Nucleophilicity vs Basicity: What Is A Base?

So how do reactions of nucleophiles at hydrogen differ from reactions of nucleophiles at carbon? Well, they’re more easily reversible, for one thing. We can measure acidity (and, by extension, basicity) through the measure known as pKa, which is a reflection of the position of the equilibrium between an acid and its conjugate base.

Let’s put it up in a graphic:

Because we can measure the equilibrium constants for reversible acid-base reactions, we can get a fairly good idea of the relative strengths of acids and bases. There’s some complications; solvent effects can play a role in stabilities, for instance*  but overall, the pKa table is our friend. It’s a great “reactivity ladder” to hang our hats on.

We talked about what made species strong bases a few posts ago – it’s here. The bottom line is that the more unstable a lone pair of electrons is, the more basic it will be (and vice versa).

3. Nucleophilicity vs Basicity: What Is A Nucleophile?

And then there’s nucleophilicity. How is nucleophilicity different from basicity? Well, since it’s not limited to simply forming a bond to hydrogen anymore, this leads to some extra complications. Let’s just talk about the measurement problem first.

Many reactions of nucleophiles are not reversible. A bond forms, a bond breaks, and that’s the end of the reaction. The problem with this from a measurement standpoint is that we often can’t determine an equilibrium constant for a reaction. And if we can’t do that, then we can’t develop a reactivity scale based on equilibria.

If we can’t measure equilibria, then what do we do? Well, we use the next best measurement available: to measure reaction rates.

There’s one important thing to remember with reaction rates. They don’t always reflect overall stability. There are a few more variables at play here.

Factor #1: Steric hindrance. Reactions where nucleophiles attack carbon-based electrophiles are significantly more sensitive to steric effects, because empty orbitals on carbon are not as accessible. Steric hindrance is like a fat goalie.

Factor #2: Solvents. The medium (solvent) in which a reaction takes place can greatly affect the rate of a reaction. Specifically, the solvent can greatly attenuate (reduce) the nucleophilicity of some Lewis bases through hydrogen bonding.

Again, let’s go to the graphic:

Here’s another question that comes up. How do you know when something is going to act as a base, and when it’s going to act as a nucleophile? Another great question!

Like the prototypical three-handed economist, I’ll tell you that it depends upon what type of reaction you’re talking about. Acid-base reactions tend to be fast, relatively speaking. But it will greatly depend on the situation. More soon, I assure you.

Next: So what, specifically, makes something a good nucleophile?

Next post: What Makes A Good Nucleophile?


Notes

* Note (for more advanced readers) For instance, alcohols are dramatically less acidic in dimethyl sulfoxide [DMSO] than they are in water, and since many pKa values for less acidic species are given in DMSO, it’s easy to misjudge the acidity of alcohols relative to other species.

Comments

Comment section

46 thoughts on “Nucleophilicity vs. Basicity

  1. Hi. I am wondering about the difference between nucleophicity and basicity,
    but here on your resources i don’t seen such type wondering difference between electrophilicity and acidity, so, give a difference about that….
    Thank you for all great resources.
    Greetings.

    1. Good question. Lewis acidity is essentially electrophilicity. Acidity (Bronsted acidity) is what we call it when the electrophile is a proton.

  2. hi. regarding nucleophilic attack by hydride on aldehydes and ketones, why can’t reaction happen with NaH just because NaH is too basic? What is the link between being too basic and the hydride in NaH not being able to carry out the nucleophilic attack?
    Thank you.

    1. That’s a great question. NaH is generally not observed to add to aldehydes and ketones, although it will add to Lewis acids such as borane (BH3). You can think about the rates of competing reactions – 1) addition of hydride to aldehyde (slow) versus 2) deprotonation of the alpha-carbon by hydride (fast) and the latter reaction prevails.

      1. NaH acts as a non nucleophilic base so basically involves in deprotonation rather in addition of the hydride to the carbonyl.In general all non nucleophilic base acts by the same mechanism.

  3. hi, WHEN comparing the basicities of OH- and CN-, Which is more basic?
    as for my argument the negative charge on oxygen is well stabilised compared to the negative charge on nitrogen as O is more electronegative so it better stabilises the negative charge so CN- is a stonger base?? is this a possible explanation??

    1. The best guide to basicity is by looking at a pKa table. The pka of water is 15.5, the pka of HCN is about 9. The stronger the acid the weaker the conjugate base, and since HCN is a stronger acid, its conjugate base (CN-) will be a weaker base than the conjugate base of H2O (HO-).

      1. it is better to understand why something is a stronger acid/base than to refer to a table of pka. when a student is first learning the subject, if they continuously refer to the table the will never learn that it has to do with electron density, location, and movement. telling them to refer to a table only stunts their growth of knowledge.

        1. This was not a clear cut example where one could point to periodic trends. If the student was asking about -CH3 vs -OH, then that’s clearly a situation where one can mention a factor like increasing electronegativity across the periodic table leads to a decrease in basicity.

          However with nitrogen being coordinated to C in -CN using that principle, they would draw the wrong conclusion.

          Because multiple variables are in play [we are changing the basic atom as well as the substituents connected to that atom] the only recourse is to check a pKa table because the effect of changing two variables at once is not easily predictable.

          This site is not deficient in describing why certain species are stronger acids and bases according to a set of principles.

          I have a whole series of articles where I discuss acidity trends and refer to electronegativity, polarizability, resonance, adjacent electron withdrawing groups, and even aromaticity.

          The point of the current article is to mention that basicity is measured by pKa – it is an equilibrium – whereas nucleophilicity is measured by rate. So only a brief treatment of basicity was given here, with reference to the series on acid-base reactions.

          1. I like your explanation. If pKa is an equilibrium description that makes it thermodynamic in nature; nucleophilicity is a description of a rate, which makes it kinetic behavior. Kinetic and thermodynamic properties tend to push in similar directions- except in those cases where they don’t!

    2. You are correct in all of your assumptions. O being more electronegative would make it the weaker base IF the N was holding the negative charge however, the base you listed actually has the negative charge on the carbon molecule, so in this case your comparison is not applicable. if you change your comparison to NH2- and OH- your logic applies.

  4. To James:

    I think you mean “nucleophillicity is a subset of bases”, since all nucleophiles are bases;
    like {1,2} is a subset of {1,2,3}, since all of {1,2} is a part of {1,2,3}.
    Please check and revert.

    (Apologies if this sounds like nitpicking)

    Parakh

    1. What I meant was that Bronsted basicity is a subset of nucleophilicity, if we consider “nucleophilicity” to be synonymous with Lewis basicity.

        1. I don’t feel comfortable saying there is 100% overlap.

          Nucleophilicity is measured by rate, Lewis basicity can be measured by equilibria given the right conditions.

    1. Going down the periodic table, the electrons will be held more loosely, phosphorus should be more nucleophilic than nitrogen just like sulfur is more nucleophilic than oxygen.

      1. Hi! What about the basicity of R3P and R3N? Also can you please provide examples of species which are good nucleophiles but bad bases and vice versa.

  5. Trying to make my daughter to understand organic chemistry (being a student in pharmacy) it was a great help.Thank you.
    Dennis

  6. You can describe basicity as a thermodynamic process (acid-base equilibrium exists and an equilibrium constant can be measured) while nucleophilicity is considered a kinetic process where rate of reaction can be evaluated.

  7. Pls tell the order of nucleophilicity of the anions and mention the reason : PhO-, PhS- , o-,p- dinitroPhO-, p-nitroPhO-

  8. In some reactions a good nucleophile is desired while in other a good base….
    Give me the reason Also tell why is hydroxyl ion a good base but not a good nucleophile?????

  9. Hi ! In your first example why is N in NH3 donating its lone pair to water? Why can’t water donates its lone pair to bond with H in NH3 ?

    1. Very conceptual question… Hopefully this will clear it up!

      O being more electronegative than N, makes the lone pair in water less available for donation as compared to the lone pair in NH3. This makes NH3 a better base than H2O. Conversely, H2O is a stronger acid than NH3, because O is more electronegative than N, thereby making the O-H bond easier to break as compared to the N-H bond. The two facts combined make sure that NH3 de-protonates H2O and not the other way around.

  10. Hi, im wondering how to order these nucleophiles here: NEt3, PEt3 and pyridine. As you already told, PEt3 is surely more nucleophile than NEt3. But what about pyridine? Is it more nucleophile than PEt3 due to steric hindrance?

    1. the nitrogen in pyridine is sp2 hybridized, which means it has a higher effective electronegativity and thus should be less nucleophilic than NEt3. The order is PEt3 > NEt3 > pyridine

  11. Great help .. I have a question that in secondary alkyl cyanide can substitution or elimination can occur in the presence of CH3COONa+CH3COOH? Plz give me good explanation for it. I m counting on you. Plzzzzzzz

  12. Does basicity of a compound has anything to do with its size or steric factor? Because anything it has to do is just to take out a proton from a molecule.?

  13. Hi there. Can you please help me in my confusion? In a case, where I am given a tertiary alkyl and H2O. How do I know if the H2O will be acting as a base and undergo elimination or, acting as a nucleophile and undergo substitution? Thanks!

    1. I assume you mean that you have a tertiary alkyl halide, in the presence of H2O. The first step will be loss of halide ion to give a carbocation. What happens next could either be attack of the carbocation by water (SN1) or deprotonation adjacent to the carbocation to give an alkene (elimination – E1). Both pathways will occur. However in my experience the elimination pathway is generally only going to be the major product if the reaction also mentions “Heat”.

  14. In very first line , you start with saying ‘Basicity is subset of Nucleophilicity’…And in the next line you wrote ‘All Nucleophiles are Lewis base’…..Your both statements produce contradiction against each other.

  15. Indicate which reagents in the pair is expected to be more nucleophilic towards ch3br in ethanol and why ?
    1) ch3oh or ch3sh

  16. What if the two groups, -OH alcohol (tert position) and -COOH (primary position), present on the same molecule, then which one would be better nucleophile?
    I think, in aprotic solvents, -OH group would be good nucleophile than -COOH.

    1. If we are comparing neutral OH with neutral COOH, with equal steric hindrance, then the stronger nucleophile would be the group that is the most basic.

      It is easier to protonate R-OH to R-OH2 (+) than it is to protonate R-CO2H to R-CO2H2 (+). We know this because the pKa of protonated R-OH is about -2.2 (CH3-OH2+) and the pKa of protonated R-CO2H is about -7.7 (Ph-CO2H2 + ) Source: http://evans.rc.fas.harvard.edu/pdf/evans_pKa_table.pdf

      If there is significant difference in steric hindrance then this would affect the relative nucleophilicity to some extent. You are correct that protic solvent would retard the nucleophilicity of both these species, and polar aprotic solvent would augment it.

    1. Hard to generalize too much, but generally speaking the most activating substituent will “win”. Also, putting a substituent on a C-H ortho to two substituents tends to be disfavored. Can’t be more specific other than to say the old, “it will be mixture of steric and electronic facgtors”.

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