Acid-Base XI. Hard and Soft Acids and Bases (HSAB) Theory in Organic Chemistry

Contents

I. Introduction

II. The HSAB Theory and Hard-Hard Soft-Soft Interaction

III. The HSAB Theory in Organic Chemistry

IV. Application of HSAB Theory: Conjugate Addition

V. Conclusion


I. Introduction

Until now, we have always been talking about acids, bases, and their conjugate pairs; meaning that we have only been talking about Brønsted-Lowry acid-base.

Another well-known acid-base theory is the Lewis theory. This theory defines an acid as an electron pair acceptor and a base as an electron pair donor. We have briefly talked and seen examples of this theory in Acid-Base I.

In Brønsted-Lowry acid-base, we learned about strong and weak acids and bases. Now in Lewis theory, we will learn about hard and soft acids and bases.

Don’t be confused between hard/soft and strong/weak, as they are completely different from each other. Strong/weak is the property related to the Brønsted-Lowry acid-base, whilst hard/soft is the property related to the Lewis acid-base.

The hard and soft acids and bases (HSAB) term and theory was first coined by Ralph G. Pearson about half a century ago (I’m writing this post in 2017). It has proved itself useful in predicting many organic and inorganic reactions and therefore is an important part in understanding organic reactions.

You can read the papers that Pearson himself published in JACS and JCE for the full details, because this post will only talk briefly about the part of the theory that will be useful for students studying organic chemistry.

  • Pearson, R.G. J. Am. Chem. Soc. 1963, 85, 3533-3539 (DOI: 10.1021/ja00905a001)
  • Pearson, R.G. J. Chem. Educ. 1968, 45, 581-587 (DOI: 10.1021/ed045p581)
  • Pearson, R.G. J. Chem. Educ. 1968, 45, 643-648 (DOI: 10.1021/ed045p643)

And like other scientific theories, this theory too has been disputed before. Check out this paper:

  • Mayr, H.; Breugst, M.; Ofial, A. R. Angew. Chem. Int. Ed. 2011, 50, 6470-6505
    (DOI: 10.1002/anie.201007100)

Who’s right or wrong does not concern us here, because the fact is, this theory still remains a big part both in organic and inorganic chemistry and is still taught to students around the world. Hence, I feel the need to talk about this here.

That being said, because this theory concerns Lewis acid-base (hence involves inorganic species), we won’t be going into too much details, we’ll only talk about those useful in organic chemistry.

The hard/soft acid-base is the general name for the theory, but when you learn this theory specificially in organic or inorganic textbooks, you may encounter different terminologies:

  • In organic chemistry textbooks, hard/soft acid-base may sometimes be referred to as hard/soft electrophiles and nucleophiles; in which electrophiles are the Lewis acids whilst nucleophiles are the Lewis bases.
  • In inorganic chemistry textbooks, hard/soft acid-base may sometimes be referred to as hard/soft metal centres and ligands; in which metal centres are the Lewis acids whilst ligands are the Lewis bases.

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II. The HSAB Theory and Hard-Hard Soft-Soft Interaction

First, the qualitative definition of what constitutes the hardness and softness of Lewis acids and bases. Keep in mind that a Lewis acid is an acceptor (of electron pair), and a Lewis base is a donor (of electron pair).

Acid Base
Hard

The acceptor atom:

  • is small
  • has low polarisability
  • has high electronegativity
  • has high charge density

The donor atom:

  • is small
  • has low polarisability
  • has high electronegativity
  • has high charge density
Soft

The acceptor atom:

  • is large
  • has high polarisability
  • has low electronegativity
  • has low charge density

The donor atom:

  • is large
  • has high polarisability
  • has low electronegativity
  • has low charge density

The key point there is size and charge density. I find it useful to just remember this, other than the other characteristics.

In terms of size, you’ll notice that the atom of hard acid/base tends to be small whilst the atom of soft acid/base tends to be large. Usually this correlates to hard species being from the earlier rows of the periodic table (e.g. O, F, and Cl), whilst soft species being from the later rows (e.g. S, I, and P).

And what about charge density?

You’re probably familiar with population density of a country, right?

  • If a country is large and there’s only a small number of people in it, that means it’s a country with low population density.
  • Conversely, if a country is small and there’s a large number of people in it, that means it’s a country with high population density.

It’s just the same with charge density:

  • If an atom (be it an acceptor or a donor atom) is large and is not highly charged, that means the atom has low charge density, and therefore is soft: e.g. I and Ag+.
  • If an atom (be it an acceptor or a donor atom) is small and is highly charged, that means the atom has high charge density, and therefore is hard: e.g. F and Li+.
  • There are also some species in between hard and soft, called ‘borderline’: e.g. Br and Fe2+.

What I’ve shown you so far are inorganic examples because I think they can help you imagine the size and of each atom and their charge density.

Of course, because these are qualitative characteristics, they are at best, approximation. Quantitative measurement of hardness and softness is being carried out by many researchers around the world but that’s not really our concern right now.

So now that you know the definition of hard/soft acid-base, here’s the core of HSAB theory:

Hard acids tend to react with hard bases and soft acids tend to react with soft bases

The hard-hard interaction is governed primarily by electrostatic attraction between the positively-charged acids and negatively-charged bases.

The soft-soft interaction is governed primarily by the mixing (overlap) of orbitals between the LUMO of the acids and the HOMO of the bases.

Keep in mind that the hard-hard and soft-soft interaction is preferable, but is not necessarily the only possible interaction. Hard-soft interaction is also possible, when influenced by external factors. Which is why the theory says ‘tend to react’.

For example, soft Ag+ preferably reacts with soft I to form AgI, and hard Li+ preferably reacts with hard F to form LiF. However, there are also circumstances where AgF and LiI are formed.

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III. The HSAB Theory in Organic Chemistry

Translating the theory using terms more commonly used in organic chemistry:

Hard electrophiles tend to react with hard nucleophiles and soft electrophiles tend to react with soft nucleophiles

The hard-hard interaction is governed primarily by electrostatic attraction between the positively-charged electrophiles and negatively-charged nucleophiles.

The soft-soft interaction is governed primarily by the mixing (overlap) of orbitals between the LUMO of the electrophiles and the HOMO of the nucleophiles.

Still, keep in mind that the hard-hard and soft-soft interaction is preferable, but is not necessarily the only possible interaction. Hard-soft interaction is also possible, when influenced by external factors.

In organic chemistry, we talk about a wide range of nucleophiles while the electrophiles are usually (though not everytime) carbon. So we can classify the hard/soft and borderline nucleophiles commonly found in organic chemistry:

Hard Nucleophiles
Borderline Nucleophiles
Soft Nucleophiles
H2O, OH
ROH, RO
F, Cl
NH3
R–MgX, R–Li *)
CN
RNH2, R2NH
Br
C5H5N
C6H5NH2
H
RSH, RS
I
C6H6
alkenes

*) This does not mean that all organometallic carbons are hard nucleophiles. Lithium cuprates (R2CuLi) are softer than the Grignard reagent and organolithium. We shall see an example of this in the next section.

On the other hand, there’s only a handful of electrophiles that you need to know:

Hard Electrophiles
Borderline Electrophiles
Soft Electrophiles
H+
R(C=O)+ *)
HX (hydrogen-bonding molecules)
R3C+
C6H5+
I2, I+
Br2, Br+

*) This indicates carbonyl carbon

You can find other hard/soft acids and bases (including inorganic ones) in many other sources such as your textbooks or the papers I previously mentioned in the introdution.

Let’s have a look at the application of HSAB theory in the next section.

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IV. Application of HSAB Theory: Conjugate Addition

The famous application of HSAB theory in organic chemistry is in the nucleophilic addition of α,β-unsaturated carbonyl compounds. The nuclophile can attack either the carbonyl carbon or the β-carbon, both of which are good electrophiles.

When the nuclophile attacks the carbonyl carbon of an α,β-unsaturated carbonyl compound, we get the usual nucleophilic addition reaction. But when it attacks the β-carbon, then we get the conjugate addition reaction.

So how do we decide which carbon that the nucleophile will attack?

Well, there are several factors involved in this reaction, but one of them is the hard/soft nature of the nucleophiles. This is where the HSAB theory comes to play. I will talk about the other factors in another post, and will put the link here once I’ve done so.

The α,β-unsaturated carbonyl compounds are unique because they have both hard and soft carbon electrophiles in one molecule. The carbonyl carbon is a hard electrophile, while the β-carbon is a soft electrophile.

ab-unsaturatedcarbonylcompoundsoftandhard-framed

Therefore, soft nucleophiles (e.g. thiols) tend to react at the soft site (the β-carbon), thereby resulting in a conjugate addition reaction. Here’s the reaction between thiophenol with 3-penten-2-one giving (4-phenylthio)-2-pentanone.

conjugateadditionthiophenol

On the other hand, hard nucleophiles (e.g. Grignard reagents and organolithiums) tend to react at the hard site (carbonyl carbon), resulting in the nucleophilic addition reaction we are all familiar with. Here’s the reaction between ethyl magnesium bromide with 3-penten-2-one giving 3-methyl-4-hexen-3-ol.

nucleophilicadditiongrignard

So, what if we want to add an alkyl group to the β-carbon? Grignard reagents and organolithiums won’t do the job, because they won’t perform the conjugate addition, just like the example shown above. Well, to do this, we can use lithium cuprate reagents (R2CuLi) which are softer. The soft nucleophiles will then perform the conjugate addition, alkylating the β-carbon. Here’s the reaction between lithium diethylcuprate with 3-penten-2-one giving 4-methyl-2-hexanone.

conjugateadditionlithiumcuprate

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V. Conclusion

The HSAB theory states that:

  • Hard electrophiles tend to react with hard nucleophiles and soft electrophiles tend to react with soft nucleophiles.
  • The hard-hard interaction is governed primarily by electrostatic attraction between the positively-charged electrophiles and negatively-charged nucleophiles.
  • The soft-soft interaction is governed primarily by the mixing (overlap) of orbitals between the LUMO of the electrophiles and the HOMO of the nucleophiles.

We have also seen examples of hard/soft electrophiles and nucleophiles, and the role played by HSAB theory in conjugate addition.

Keep in mind that HSAB theory is only one of several factors that determines the outcome of a nucleophilic addition to α,β-unsaturated carbonyl compounds.

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Page last updated: 10iii17
RP


Other Posts in Acid, Base, and pKa Series

Acid-Base
Prologue
Acid-Base I
What are Acids and Bases?
Acid-Base II
What is pKa and Why is It Important?
Acid-Base III
The pKa Table and What Information It Tells You
Acid-Base IV
Factors Affecting the Acidity of Organic Compounds
Acid-Base V
Using pKa to Predict the Course of a Reaction
Part 1
Acid-Base VI
Using pKa to Predict the Course of a Reaction
Part 2
Acid-Base VII
Using pKa to Predict the Course of a Reaction
Part 3
Acid-Base VIII
Acidity, Basicity, and Solvent
Part 1
Acid-Base IX
Acidity, Basicity, and Solvent
Part 2
Acid-Base X
Levelling Effect
Acid-Base XI
Hard and Soft Acids and Bases (HSAB) Theory in Organic Chemistry

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