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The previous article (Part 1) is here. The next article will be released soon.
Recap
In the first part of this article, we discussed three types of nucleophiles: the first type involves nucleophiles with inherited nucleophilic properties; these nucleophiles possess the ability to attack an electrophile because they contain an electronegative atom bonded to a less electronegative atom. This gives the bond some polarity, and allows for one atom to possess a partial negative charge and another to possess a partial positive charge. The partially negatively-charged atom is then the nucleophile. The second type of nucleophile has inherent nucleophilic properties; this means that the nucleophile forms by virtue of the molecule’s structure (usually on the carbon backbone), not because of the existence of a certain substituent that can simply be attached and reattached to the molecule, which dictates the molecule’s nucleophilicity. We have already discussed such nucleophiles previously.
Hydrides
In a continuation of the discussion of the conventional nucleophiles, carbon and oxygen nucleophiles, that we have explained previously, here we will talk about hydrogen nucleophiles. In scientific literature, we do not usually name hydrogen atoms with unshared pairs of electrons as hydrogen nucleophiles; instead, we call them by another name we may already be familiar with, the hydride ion. It works exactly like we expect it to; it will attack electrophilic sites and form a bond with them. It is important for us to distinguish between such reactions and Bronsted-Lowry acid-base reactions. Although both types of reactions involve hydrogen atoms, the acid-base reaction involves the proton while the hydride reaction involves the hydride. As the name suggests, the hydride has two electrons (the unshared electron pair) which it can use to attack electrophiles.
Hydrides usually come from sources of hydrides, of which usually two are discussed: NaBH4 (sodium borohydride) as well as LiAlH4 (lithium aluminum hydride, Fig. 1). Both of these possess negatively-charged hydride anions that are used for attack on the electrophile. We will not cover hydrides in depth as their chemistry is not that interesting at the present.
Fig. 1: Structure of lithium aluminum hydride.
Ambidentates
The second type of molecule that will be discussed in this chapter is ambident nucleophiles. The word ‘ambident’ refers to the fact that two nucleophilic sites exist on a single nucleophilic molecule. Before we delve into the organic chemsitry of the ambident nucleophile, we must discuss the rates of such ambident nucleophiles first. Where an ambident nucleophile takes place in the reaction, there are usually two outcomes ot the rate of formation of a desired product; the first, an increase in the rate of the reaction, although this is relatively rare. The increase in the rate of the reaction will only occur when the nucleophile (molecule on which there are two nucleophilic sites) is symmetrical. In any other case, two different products would be formed from attack by either nucleophilic site, of which only one would be the desired product. Only in the case where two nucleophilic sites are symmetrical to each other would two chemically equivalent products be formed. Even in this case, stereochemical considerations would have to be made to ensure that both the products are exactly the same and not enantiomers.
Now we will study two types of ambident nucleophiles. We have already raised two examples of ambident nucleophiles which possess two nucleophilic sites; these are the carbonyl compounds carboxylic acids and esters, which both contain two nucleophilic oxygen atoms. In this article, we will raise two examples of substituents which possess two carbon nucleophiles, which are already inherently nucleophilic. The first type of substituent is the COC(-)RCO substituent ion, as shown in the 2-structure of Fig. 2. The obvious nucleophiles are the carbonyl oxygens, because the negative charge is delocalized over the them, allowing for more effective attack. The ester oxygens are slightly more interesting because they are not exactly nucleophilic; since they are bonded to two alkyl groups, if there were an attack by these oxygens, the oxygen atom would become positively-charged, which is destabilizing (oxygen is electronegative). In general, attack would only occur via the carbonyl oxygens for malonic esters, and that is why it is termed an ambident nucleophile. Note, however, that instead of two products formed, three products are instead possible, as the two products are formed from the nuceleophilic attack by either oxygen and the last is formed by acylation of the malonic ester.
Fig. 2: Diagram of malonic ester synthesis.
The second type of ambident nucleophile is the CH3COCH2CO- substituent (which becomes 3-oxybutanal, Fig. 3, after protonation), which itself is not as nucleophilic as expected. The carbonyl oxygens are indeed nucleophilic but still not as nucleophilic as the oxygens discussed in the malonic ester, because they do not possess any formal negative charges, even delocalized. However, we should note that there are two acidic hydrogens on the molecule. Due to the presence of resonance forms, the alpha-hydrogens (hydrogens on the carbon bonded to the carbonyl carbon) are weakly acidic. A strong base such as butyllithium is able to deprotonate this substituent by removing the two weakly acidic hydrogens, creating the CH2(-)COCH(-)CO- substituent. In this molecule, the carbons are nucleophilic as they have negative charges and vacant orbitals for nucleophilic attack. Since two carbanions exist, the molecule is an ambident nucleophile and both carbons are able to participate in nucleophilic attack.
Since the carbons are chemically different, there is the inevitable question of which carbon nucleophile would be the most nucleophilic. There is, in fact, a difference between the nucleophilicity of both carbon atoms, due to the fact that one of the deprotonated carbon atoms has two hydrogens, while the other carbon atom only has one. As we should be aware, the CH2 moiety is more basic than the CH moiety. Remember that this does not guarantee that the CH2 moiety is more nucleophilic than the CH moiety; nucleophilicity is not directly related to basicity, as we have noted in a previous article. The basicity of the CH2 moiety makes it more unstable than that of the CH moiety. This thus influences the nucleophilicity and makes the CH2 carbanion more nucleophilic than the CH carbanion.
Fig. 3: Diagram of the structure of 3-oxybutanal.