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A Primer On Organic Reactions

By James Ashenhurst

What makes a good leaving group?

Last updated: March 29th, 2019 |

A leaving group is a nucleophile acting in reverse; it accepts a lone pair as the bond between it and its neighbor (usually carbon for our purposes) is broken.

So what makes a good leaving group?

The “happier” and more stable that lone pair is, the better a leaving group it will be. The most predictive rule for leaving group ability is….

Good leaving groups are weak bases.

Why?

Think about the dissociation of an acid H–A to give H+  and A– . The species A– is the conjugate base of HA. It accepts a pair of electrons from the H-A bond. It’s a base acting in reverse.

The more stable A- is, the greater the equilibrium constant will be that favors dissociation to give A- .

This turns out to be the very definition of acidity! The negative log of the equilibrium constant is the familiar pKa.

In other words pKa is a direct measurement of how “happy” and stable a lone pair of electrons is – the very definition of what we should be looking for when trying to quantify leaving group ability.

So it should be no surprise to find that very weak bases such as  halide ions (I-, Br-, Cl-) water (OH2), and sulfonates such as p-toluenesulfonate (OTs) and methanesulfonate (OMs) are excellent leaving groups.

These are the conjugate bases of strong acids. (Recall that the stronger the acid, the weaker the conjugate base).

[One word of caution: pKa measures an equilibrium (think “differences in energy”), whereas leaving group ability is based on reaction rates. So although the correlation is very good, it isn’t perfect.]

On the other hand, strong bases are bad leaving groups. This is why alcohols don’t participate in SN2 reactions very much! the hydroxyl group (HO-) is a terrible leaving group.

If you’re not sure where a reaction is going to happen on a molecule, look for a good leaving group. That’s usually where the action is!

The trend is pretty clear – in general, the weaker the base, the better the leaving group. Furthermore, note how we (almost) never see alkanes or hydrogens as leaving groups. That’s because they’re strongly basic anions – and very unstable.

You might note that I have carefully avoided discussing fluorine. Fluorine tends to be a very poor leaving group for SN1/SN2/E1/E2 reactions. In Org 2, you may see some examples where F can act as a leaving group when it is attached to a carbonyl carbon or an aromatic ring. These reactions (addition-elimination reactions) are a little bit different in that the rate determining step is not so related to loss of the leaving group. There are some extra factors at work in these situations that we can discuss if you’re curious.

Next Post: Leaving Groups Are Nucleophiles Acting In Reverse

00 General Chemistry Review
01 Bonding, Structure, and Resonance
02 Acid Base Reactions
03 Alkanes and Nomenclature
04 Conformations and Cycloalkanes
05 A Primer On Organic Reactions
06 Free Radical Reactions
07 Stereochemistry and Chirality
08 Substitution Reactions
09 Elimination Reactions
10 Rearrangements
11 SN1/SN2/E1/E2 Decision
12 Alkene Reactions
13 Alkyne Reactions
14 Alcohols, Epoxides and Ethers
15 Organometallics
16 Spectroscopy
17 Dienes and MO Theory
18 Aromaticity
19 Reactions of Aromatic Molecules
20 Aldehydes and Ketones
21 Carboxylic Acid Derivatives
22 Enols and Enolates
23 Amines
24 Carbohydrates
25 Fun and Miscellaneous

Comments

Comment section

72 thoughts on “What makes a good leaving group?”

      1. Procedure for you figuring this out for yourself: Go to a pKa table and figure out the pKa of Phenol (PhOH) and HCl. Which is a stronger acid? Now: the stronger the acid, the weaker the conjugate base. . So which of these would have the weaker conjugate base? The weaker the base, the better the leaving group.

        Reply

        1. phenol has a pKa of about 16 and HCl has a pKa of about -5 so “strong acid weak conjugate base” would imply that Cl- is the better leaving group.

          Reply

          2. hcl is a strong acid and it is the better leaving group

            how did you get through general chemistry not knowing that?!

        2. phenol at about 10 pka, HCl at about -7 pka. So HCl is the stronger acid=weaker conj. base = more stable as an anion = better leaving group. Do I have this thought process correct?

          Reply

  9. Awesome blog!!!

    I have my MCAT exam in 2 days, (well 1.5 days if you start counting from now), wish I stumbled on your blog 3 months ago! well, still 1.5 x 12 hours left! :)

    Reply

  10. Yes, please discuss the extra factors you mentioned regarding F- in a-e rxns.

    Thanks so much for always making it clear and interesting!

    Reply

  12. This is just what I need,Organic chemistry has been a part of chemistry that seemed to be impossible to understand. But with the help of your explanations I see my self getting a straight A,beyond the shadow of doubt. Thanks to you James.

    Reply

  14. Thanks for this amazing resource to help me through orgo. It’s people like you who need to be in Universities teaching students because anyone can see based off this website you’ve made, that you actually care about the people learning and understanding orgo….thank you.

    Reply

  15. Just wanted to say thank you. Wish I had found this website months ago. All the information is so accessible and very well organized. Keep up the tremendous work. You’ve gained a loyal visitor to your website. I’ll be back next semester for organic II as well.

    Reply

  17. There is a mistake in the second paragraph, I think. An atom can never be neutral and charged at the same time. A neutral atom’s atomic number(number of protons) is the same as the number of electrons. I recommend you to say an atom becomes an ion(negatively charged) to reach the full octect.

    Reply

  19. That’s so helpful! You made very simple. Are there other factors beside PKa? what about the bond strength effect in case of a hydroxy gp attched to a carbon…
    Thank James

    Reply

    1. The more stable the leaving group the better it’s ability to leave right? So, if the base is weak, it will not be in a hurry to accept protons and react. Hence, as the base is not readily reacting, it is stable and a good leaving group.

      Reply

    2. Weak bases are very stable as anions in solution on their own. A weak base has a strong conjugate acid (e.g. HCl is the strong conjugate acid of the weak base Cl-). In the acid, you can think of the base as being a “leaving group” that allows the H+ to go off on it’s own (Like Cl- rapidly leaving H+ in aqueous solution). Since the acid is strong, we know that the base must very readily leave.

      Conversely, if the acid is weak (like CH3COOH), we know that it holds the H+ relatively tightly. The base (CH3COO-) is relatively unstable in solution, so it doesn’t want to leave the H+. It’s very similar when that same base is attached to a carbon skeleton. Cl will leave the carbon skeleton readily because it’s fairly happy just being Cl- in solution, whereas CH3COO- is not so happy to do so. Moderately strong bases, like NH3 are poor leaving groups, and strong bases like OH- are terrible leaving groups. If you take a very strong base like CHC- (acetylide) it will never leave, so we don’t even consider that a leaving group.

      Reply

  24. By far the most coherent explanation of nucleophiles and leaving groups I have seen so far. Better than Youtube and most text books for that matter!

    Reply

  25. What if there are two identical leaving groups on different parts of the molecule? Say, two bromines. What factors do you look at when choosing the leaving group then?

    Reply

    1. Then you would examine the carbon that the leaving groups are attached to. Primary, secondary, or tertiary? Then you would look at the reaction conditions (i.e. what nucleophile is present?). This then leads into the SN1/SN2/E1/E2 decision. You might want to check my “Quick N’ Dirty Guide to SN1/SN2/E1/E2 for more information there because it’s a lot to summarize in a blog comment.

      Reply

  28. Minor fix needed on the first image: the reactants side is neutral while the products side is positive (need to either add a negative formal charge to Nu or take off the negative formal charge from L).

    Reply

    1. Yes, F- is an OK leaving group in those situations (nucleophilic aromatic substitution) because the rate limiting step is attack of the aromatic ring (disrupting aromaticity). Loss of the leaving group is slow compared to that step. Also, because F- is so electron withdrawing, F actually helps to accelerate the reaction by removing electron density from the ring and making it easier to attack.

      Reply

      1. James, someone mentioned the difference for F- between protic and aprotic solvents, do you mind shedding some light and clarity on this, please?

        Thank you in advance

        Reply

        1. Question was answered in a round about encompassing way here: https://forums.studentdoctor.net/threads/nucleophiles.752905/

          “In polar protic solvents, the nucleophile, which is typically an anion, is strongly solvated by the hydrogen bonding solvent. While you do want the entire reaction to occur in one solution, you don’t want such a strong solvation, because that blocks the anion from reacting quickly with the electrophile. This effect is biggest for fluorides because they are so small and not easily polarisable. In a polar aprotic solvent, this anion solvation doesn’t occur to the same extent, and thus fluoride, which is more reactive than the iodide (think basicity), will be a stronger nucleophile.”

          Good read if anyone needs it.

          Reply

  30. this is a great website which is helping for my exams very much clarifies my doubts in organic chemistry can you tell me why flurine is a exeption and in a carbonyl carbon or an aromatic ring acts as a good leaving group compared to other halogens

    Reply

  31. I- is a BLG than F- in aprotic solvents.
    F- is a BLG than I- in protic solvents .
    If something is a poor nucleophile it has to be BLG.
    I am right , right ?

    Reply

    1. asking this because I read poor bases are BLG which I accept ,but I think that it should differ in solvents.
      (Ex:F- in protic is much more stable than I- due h bond.)
      someone please tell me if I am right or not.

      Reply

  37. Oh. My. Goodness. This is absolutely amazing. I will never be able to thank you enough or express how much this has helped me. Seriously, you are a god in my eyes right now.

    Reply

  38. Awesome website, explains the any topic with ease. Whenever I have any doubt I refer MOC, it helps me a lot. Thank you Mr. James for your remarkable efforts. You have made learning organic chemistry interesting through this website.

    Reply

    1. “The conjugate acid is always a better leaving group”. So H2O is a better leaving group than HO-, HOR is better than RO- , NH3 better than NH2 (-). It’s hard to generalize if you combine multiple factors. For instance Cl- is a better leaving group than NH3.
      That’s why it’s useful to have a pKa table.

      Reply

  41. in which solvent is this pka table given.

    Q. does the leaving tendency depend upon solvent for example if F- leaves in polar protic medium it would stabilize its charge through hydrogen bonding which might not be possible in polar aprotic medium

    Reply

    1. Think about what’s happening in a reaction where a leaving group is created. You need to break a bond and to form a relatively stable species. So if the bond is too strong (e.g. C-F) or if the leaving group is not very stable by itself (stongly basic) then the activation energy for this process will be too high for it to happen.

      Reply

  43. I’m confused about HF and its conjugate base. Does F- make an excellent leaving group? So for an E2 reaction it would leave?

    Reply

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