The Conjugate Acid Is A Better Leaving Group

by James

in Alcohols, Alkyl Halides, Organic Chemistry 1

One of the key factors that determines whether a nucleophilic substitution reaction will happen or not is the identity of the leaving group. Previously, we’ve seen that good leaving groups are weak bases. That means that if you see a halogen (Cl, Br, or I) or a tosylate (OTs) or mesylate (OMs) on your molecule, these are all good candidates to be leaving groups, since Cl(–), Br(–), I(–), TsO(–), and MsO(–) are all weak bases.

Here’s the problem. What if we have a functional group on a molecule that we’d like to involve in a substitution reaction, but it isn’t a good leaving group like the ones listed above? For instance, the reactions listed below don’t work, because the leaving group (HO-) is a strong base and thus a poor leaving group.

What can we do to involve OH (and other similar groups) so that they can participate in substitution reactions? Well, we need our leaving group to be a weaker base. How do we make it a weaker base? By removing some of its electron density. The best way to do this is to treat it with acid. This will make the conjugate acid of our leaving group, which will be a weaker base. And then these reactions will proceed nicely.

Here’s an SN2 example:


To put some numbers on it, if you look at a pKa table, you’ll see that the pKa of H2O (water) is about 16 (15.7). Its conjugate base is HO(–). When we add acid, water becomes H3O(+), which has a pKa of –1.7. It’s a much stronger acid, in other words, and therefore its conjugate base (water, H2O) is much weaker. In other words, by adding acid, we’ve made it a better leaving group.

This is a general phenomenon, by the way – the conjugate acid will always be a better leaving group. 

It applies not only to OH, but other functional groups as well. For example, ethers (R–O–R) are some of the most unreactive species you’ll meet. However, if you add a very strong acid to an ether, you can break it open to give an alcohol and an alkyl halide:

We can take advantage of this to make halogens better leaving groups too. Halogens don’t react with H+ as readily as alcohols and ethers do, but they do react with certain Lewis acids [remember – a Lewis acid accepts a lone pair]. One Lewis acid that gets a lot of attention with halides is Ag+ (silver ion). You might see it as AgNO3 or AgBF4  (the counter-ion NO3(-) or BF4(-) is just a spectator here). When Ag+ combines with a halogen such as Cl, the resulting species R-Cl-Ag (+) has a considerably weaker C-Cl bond, meaning it can better participate in substitution reactions. With secondary or tertiary alkyl halides, the result is usually formation of a carbocation. One neat trick is that silver halides are insoluble in water, so if water is chosen as solvent, loss of AgCl is irreversible. The carbocation is then trapped by the water solvent.

In the end, it’s still the same phenomenon here. Whether we use a Brønsted acid or a Lewis acid, the conjugate acid is always a better leaving group, and acid can be helpful for getting substitution reactions to proceed at a much faster rate than they would otherwise.

In the next post, let’s compare the SN1 and SN2 reactions.

Next Post: Comparing The SN1 and SN2 Reactions

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{ 11 comments… read them below or add one }

Jérémy

In the ether cleavage mechanism, along with CH3OH, you rather get CH3Cl instead of HCl, no?

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james

Oh crap. Fixed. Thanks!!!

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SH

Hi,
I think I’m not seeing the bigger picture here — You wrote that halogens can be made into better leaving groups, but aren’t they already good leaving groups in the first place?

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James Ashenhurst

Actually you can make halides into even better leaving groups by using an appropriate Lewis acid. Silver salts (like AgNO3) see some use. Also think about the Friedel Crafts reaction – this uses AlCl3 or FeCl3 to remove a halide from the starting material.

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leanna

For SN2, isn’t the solvent supposed to be aprotic??? Because under protic conditions the acid-base reaction out-competes SN2 and the nucleophile would just grab the proton from OH??

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James Ashenhurst

Not totally clear on the question, but it’s completely possible to do SN2 reactions in protic solvents. It’s also possible to do SN2 reactions under acidic conditions. The only caveat is that the acid cannot *irreversibly* protonate the nucleophile. So yes, trying to do an SN2 under acidic conditions with a strongly basic nucleophile like HO(-) or CH3O(-) would fail due to the acid-base reaction you mentioned. However if the nucleophile was Cl(-) or Br(-) or similar, protonation is reversible.

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sasha

hello! thank you for the great explanation!
My question is: on that very last diagram, the very last step, how come you only drew in one pair of electrons on the oxygen? (it’s the tertiary -OH structure)
Thank you! Have a great day!:)
-orgo college student

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James

Sheer laziness.

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A

in the example you gave which is sn1, hcl will be in the rate law. So is it the case that sn1 can be 2nd order?

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James

Protonation will be quick, relative to loss of leaving group. The rate limiting step is still first order.

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Hinesh

In the reaction where the silver cation is used to make Cl a better leaving group, you have an electron pair moving from the chlorine to the silver ion in the mechanism. In the next step, you then have what looks like a covalent bond between silver and chlorine in silver chloride next to the carbcation. I just wanted to check that this is indeed an ionic compound formed (silver chloride) as I thought.

I also want to ask if the first step of the mechanism for that reaction is Lewis acid-base because a covalent bond is initially formed between the chlorine atom and the silver ion. I’m asking this because I think that ordinarily when silver and chloride ions bond ionically to form silver chloride it is not considered lewis acid-base because an electron pair hasn’t been transferred to form a covalent bond. In this case, however, am I right in thinking that the chlorine is part of a bigger molecule and so the bond it forms is covalent and hence that step can be considered Lewis acid-base?

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