Nucleophilic attack by hydride on aldehydes and ketones

Nucleophilic attack by the hydride ion, H , is an almost unknown reaction. This species, which is present in the salt sodium hydride, NaH, has such a high charge density that it only ever reacts as a base. The reason is that its filled Is orbital is of an ideal size to interact with the hydrogen atom s contribution to the a orbital of an H-X bond (X can be any atom), but much too small to interact easily with carbon s more diffuse 2p orbital contribution to the LUMO (tc ) of the C=0 group. 

Nevertheless, adding H to the carbon atom of a C=0 group would be a very useful reaction, as the result would be the formation of an alcohol. This process would involve going down from the aldehyde or ketone oxidation level to the alcohol oxidation level (Chapter 2, p. 32) and would therefore be a reduction. It cannot be done with NaH, but it can be done with some other compounds containing nucleophilic hydrogen atoms. 

The most important of these compounds is sodium borohydride, NaBH4. This is a water-soluble salt containing the tetrahedral BH4 anion, which is isoelectronic with methane but has a negative charge since boron has one less proton in the nucleus than does carbon. 

In Chapter 4 we looked at isoelectronic borane BH3 and the cation CHJ. Here we have effectively added a hydride ion to each of them. 

You met this reaction in Chapter 5 but there is more to say about it. The oxyanion produced in the first step can help stabilize the electron-deficient BH3 molecule by adding to its empty p orbital. Now we have a tetravalent boron anion again, which could transfer a second hydrogen atom (with its pair of electrons) to another molecule of aldehyde. 

Any other portions of the molecule that get in the way of (or, in other words, that cause steric hindrance to) the Biirgi-Dunitz trajectory will greatly reduce the rate of addition and this is another reason why aldehydes are more reactive than ketones. The importance of tire Biirgi-Dunitz trajectory will become more evident later—particularly in Chapter 34. 

Steric hindrance not hindrance) is a consequence of repulsion between the electrons in all the filled orbitals of the alkyl substituents. 

Although we now know precisely from which direction the nucleophile attacks the C=0 group, this is not always easy to represent when we draw curly arrows. As long as you bear the Biirgi-Dunitz trajectory in mind, you are quite at liberty to write any of the variants shown here, among others. 

---

Although single-electron transfer is proposed in the reduction of aromatic ketones by AIH3, BH3, and LAH-pyridine [AG2], the reductions of aldehydes and ketones by alumino- and borohydrides and boranes occur mostly by nucleophilic attack of hydride on the carbonyl carbon. This process has been the subject of numerous theoretical [ESI, HWl, N2, W2] and mechanistic [CBl, N5, W2, W4] studies. 

Another standard example is the nucleophilic attack by lithium aluminum hydride (LAH) on a ketone or aldehyde (Scheme 10.8). Each hydrogen in LiAlH4 is partially negatively charged, and therefore the Al-H a bonds are nucleophilic. After the nucleophilic attack by hydride, the resulting alkoxide anion coordinates with the A1 species. These two steps are repeated three more times. Finally, dilute acid is added to supply a proton to the alkoxide anion (electron pushing not shown). 

The reduction of aldehydes and ketones with hydride reagents is a useful way of synthesizing alcohols. This approach would be even more powerful if, instead of hydride, we could use a source of nucleophilic carbon. Attack by a carbon nucleophile on a carbonyl group would give an alcohol and simultaneously form a carbon-carbon bond. This kind of reaction— adding carbon atoms to a molecule— is of fundamental practical importance for synthesizing new compounds from simpler reactants. 

The nucleophilic attack on an acceptor-substituted allene can also take place at the acceptor itself, especially in the case of carbonyl groups of aldehydes, ketones or esters. Allenic esters are reduced to the corresponding primary alcohols by means of diisobutylaluminum hydride [18] and the synthesis of a vinylallene (allenene) by Peterson olefination of an allenyl ketone has also been reported [172]. The nucleophilic attack of allenylboranes 189 on butadienals 188 was investigated intensively by Wang and co-workers (Scheme 7.31) [184, 203, 248, 249]. The stereochemistry of the obtained secondary alcohol 190 depends on the substitution pattern. Fortunately, the synthesis of the desired Z-configured hepta-l,2,4-trien-6-ynes 191 is possible both by syn-elimination with the help of potassium hydride and by anti-elimination induced by sulfuric acid. Analogous allylboranes instead of the allenes 189 can be reacted also with the aldehydes 188 [250]. 

In this section, we will focus primarily on nucleophilic additions to carbonyl groups. The carbonyl substrate may be an aldehyde or ketone, as well as various carboxylic acid derivatives such acid halides and esters. Among the variety of nucleophiles that can participate in these reactions are hydride, hydroxide, alkoxide, and a variety of carbon-based nucleophiles. For carbonyl substrates, attack by a nucleophile typically results in an opening up of the C-O ar-bond, leading to a tetrahedral intermediate, as shown below for the addition of cyanide to a ketone in the presence of water. 

---