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Introduction
The first part of this article, this page, will explain solely nucleophiles; electrophiles will be discussed in a later part. Due to the broad definition given for nucleophiles, there is a large number and diverse variety of them. A nucleophile is generally given as any atom that has a unshared pair of electrons, which it can use to attack an atom with a vacant orbital that can be used for bonding (this is an electrophile). The strengths of the nucleophile and electrophile are highly relative; it may be that every atom the nucleophile attacks is termed an electrophile. Nucleophiles may have a neutral or negative charge, while electrophiles may have a neutral or positive charge, but never any other charge. Furthermore, the nucleophilic-electrophilic interaction may also be compared to a Lewis acid-base reaction. Since the electrophile has vacant orbitals for bonding, it is a Lewis acid, and since the nucleophile has electrons available for attack, it is a Lewis base. The nucleophilic substitution can thus be compared successfully to a Lewis acid-base reaction.
Types
We will begin with the ‘conventional’ nucleophiles; these refer to common molecules containing nucleophilic atoms that are very common, such as the hydroxide anion (OH) or the halogens (I, Br, Cl and F). Before we begin, note that we classify molecules with nucleophilic atoms on them as ‘nucleophiles overall’. This means that for example, we consider alcohols as nucleophiles because they contain electronegative oxygen atoms (which are nucleophilic). Such a definition will allow us to discuss a wider scope of molecules, not simply the atoms themselves, as sometimes different molecules with the same type of nucleophilic atoms will nevertheless have different reactivities, due to the presence of other substituents on a molecule as well. For instance, tert-butoxide (Fig. 1), typically existing as a salt with potassium ions, is sterically hindered and this gives it a lower nucleophilicity than would be expected for a negatively-charged oxygen atom.
Fig. 1: Structure of potassium tert-butoxide.
The first class of conventional nucleophiles which exist are molecules which possess negatively-charged atoms. This also happens to be the largest class of nucleophiles. While nucleophiles are expected to have a unshared pair of electrons, this does not necessarily mean that this will give the nucleophile a ‘complete’ negative charge, as the nucleophile could be neutral as well. In a majority of cases, however, a negatively-charged nucleophile would be more nucleophilic than a neutral nucleophile; the reason is because the negative formal charge would result in greater attraction between the nucleophile and electrophile, speeding up the rate of the reaction and thus higher nucleophilicity. Many negatively-charged atoms, nucleophilic or not, can exist as a negatively-charged nucleophile. For electronegative atoms, they are typically nucleophilic with or without the negative charge, while for more electropositive atoms, it is generally more likely to only be electronegative when they possess the negative charge (because they usually do not have an ‘extra’ unshared pair of electrons).
Now, more on the types of molecules that contain these nucleophilic atoms. We will first begin with the most important atom in organic chemistry, the carbon atom. The carbon atom, if it is bonded to one or more protons, can be subsequently deprotonated, which would result in a negative charge for this carbon, making it nucleophilic. In this case only is basicity linked to nucleophilicity. In general, any type of molecule with a carbon atom (that also must have protons bonded to it) can be nucleophilic. Of course, other types of carbon nucleophiles exist without any deprotonation. We note that the carbonyl carbon (C=O bond) is electrophilic due to the electron-withdrawing properties of the oxygen it is bonded to. However, the polarity can be reversed in carbonyl umpolung, a term that refers to the inversion of polarity which is not as expected. Such a case will occur when the carbonyl oxygen is converted to another functional group, most prominently a thioacetal. The carbonyl oxygen is first converted to a thioacetal in a way similar to that of acetals themselves, by reaction with a dithiol, resulting in the formation of the dithiane (Fig. 2). Reaction of the ‘carbonyl’ carbon bonded to two sulfur atoms with n-butyllithium (a strong base) deprotonates it, making it negatively-charged and thus nucleophilic. At the same time, the sulfur atoms are electronegative and withdraw electron density from the negatively-charged carbon, stabilizing it.
Fig. 2: Structure of the dithiane.
Next, we will look at oxygen nucleophiles. Oxygen itself is already a nucleophile since it is electronegative and contains a pair of unshared electrons. Many substituents containing oxygen are electronegative such as OH and OR. Since we ended the previous paragraph by discussing carbonyl umpolung, we will explain carbonyl oxygens in this paragraph first. Although carbonyl oxygens do still have unshared pairs of electrons, we note that attack by the carbonyl oxygen is rarely seen. This is attributed to a number of reasons. The main reason is a very simple one: the nucleophilic attack by a carbonyl oxygen is not more favorable than a different mechanism, which we will explain now. In this other mechanism, the electrophilic carbonyl carbon is first attacked by a nucleophile (likely the solvent), breaking its pi bond with the oxygen atom. The pi electrons from this bond goes to the oxygen, making it negatively-charged and an even better nucleophile (as seen in the Hell-Volhard-Zelinsky reaction, Fig. 3). This makes subsequent reactions more energetically favorable; as such, this mechanism usually occurs over direct attack by the carbonyl oxygen, explaining why we rarely see the carbonyl oxygen ‘directly’ attacking (it does happen in some cases, for example, in the conversion of carboxylic acid to acid chloride).
Fig. 3: Mechanism of the Hell-Volhard-Zelinsky reaction.
There are also other types of oxygen nucleophiles. But before we completely move away from carbonyl oxygens, we have to first discuss two more types of nucleophiles, carboxylic acids and esters. These nucleophiles can be further classified into ambident nucleophiles; this is because there are two nucleophilic atoms on carboxylic acids and esters, both of which are oxygen atoms. We will discuss carboxylic acids first. For one we must note that both the oxygen atoms are able to participate in nucleophilic attacks; for the carbonyl oxygen, it sometimes participates in reactions by nucleophilic attack on an electrophile, such as in the case we have already raised before, in the case of reaction between a carboxylic acid and SOCl2, thionyl chloride (where the sulfur atom is the carbonyl carbon position, making it interestingly electrophilic), eventually resulting in an acid chloride as the product. As for the oxygen at the alpha position relative to the carbonyl carbon (adjacent to the carbonyl carbon), it is also electronegative in the case of both the carboxylic acid and the ester. This is relatively similar to that of conversion of alcohols or alkoxides to esters, respectively.
Conclusion
In this article, we discussed only two types of nucleophiles, which also happen to be the most common atoms in organic chemistry: carbon nucleophiles and oxygen nucleophiles. In the next articles, we will be talking about more types of nucleophiles as well as electrophiles, which are chemically more unique, rather than conventional nucleophiles.
Part 2 of this article is here (released on 31 Oct).