2.4. Effects on Acidity at the Alpha Position
In introductory organic chemistry nucleophilicity and basicity may be considered equivalent: whichever compound is a stronger base is also a stronger nucleophile. This is commonly assessed by considering the acidity of the conjugate acid (the non-deprotonated compound). The exact same approach is used when comparing nucleophilicities of enol(ates). The early parts of this section (2.4.1-2.4.3) are a review of the approach used in introductory courses (see Qualitative Estimates of Acidity).
The functional group itself affects acidity. It is possible to compare acidity at the alpha position of carbonyl-containing functional groups using first principles. However, it is often simpler to compare the electron-donating ability of the atom/group on the opposite side of the carbonyl from the alpha position (Figure 2.8). The more electron density that group donates the more basic an anion at the alpha position would be. By extension, this also makes it a stronger nucleophile. Enolates are shown but the exact same trend applies to the nucleophilicities of enols.
Figure 2.8 – Comparison of Nucleophilicity of Enolates of Different Functional Groups by Evaluation of the Electron-Donating Ability of the Attached Group.
Carboxylic acids are not included in the comparison. Because carboxylic acids are themselves acidic they become carboxylates under the majority of reaction conditions. Although carboxylic acids and carboxylates can undergo some enol/enolate reactions they generally require careful consideration of conditions and may have competitive side-reactions. Likewise, acid halides are not included in the comparison and are generally omitted from introductory discussions. Although acid halides can do some enol reactions, the reactivity is greatly complicated by competitive side-reactions. Acid halide-derived enols and enolates do not feature in this text.
2.4.2. Additional Resonance Stabilization
Recall that having multiple resonance forms provides a large amount of stabilization. When comparing two acids, with other factors being equal, the acid with more delocalization of the anion (more resonance forms) will be more acidic (Scheme 2.5). The more acidic the acid, the less basic the conjugate base, the weaker the nucleophile.
Scheme 2.5 – Example of the Effect of Delocalization on Relative Nucleophilicity of Enolates.
2.4.3. Nearby Electronegative Groups (Induction)
Recall that atoms that are more electronegative are better able to accept additional electron density. As a result, they pull electron density away from other areas of the molecule. This is sometimes called induction. When comparing two acids, with other factors being equal, the acid with more electronegative atoms near the site becoming anionic will be more acidic (Scheme 2.6). The more acidic the acid, the less basic the conjugate base, the weaker the nucleophile.
Scheme 2.6 – Example of the Effect of Induction on Relative Nucleophilicity of Enolates.
Strength of induction is dependent on the electronegativity of the atoms involved, how many atoms are involved, and how close they are to the anionic site (Scheme 2.7). At an introductory level, comparisons that require calculations, such as having two fluorines versus having three chlorines, would not be expected.
Scheme 2.7 – Examples of Factors Affecting Induction on Enolates.
2.4.4. Choosing Bases to Make Enolates
Although carbonyls increase the acidity of hydrogens adjacent to them the alpha hydrogens are still not very acidic. For example, water is more acidic than acetone (Scheme 2.8). As a result, using hydroxide (generally considered a “strong” base) to form the enolate of acetone does not work well. With a 3.5 unit difference in pKa at equilibrium only one molecule of acetone in every ~3,162 (103.5) will be deprotonated.
Scheme 2.8 – Acid-Base Equilibrium of Acetone and Hydroxide Highlighting pKa Values.
For some reactions this is enough. However, the low amount of enolate formed causes problems in the majority of cases. Reaction rates may be (very) slow and/or competitive side-reactions may occur.
2.4.4.1. Lithium Diisopropylamide
Many reactions work best with quantitative enolate formation. This means that all of the carbonyl-containing molecules need to be irreversibly turned into enolates before the electrophile is added. Doing this requires a base that is very basic but NOT very nucleophilic. There are several molecules that work for this purpose. By far the most commonly used is lithium diisopropylamide (LDA; Figure 2.9).
Figure 2.9 – Lithium Diisopropylamide.
The compound’s name, lithium diisopropylamide, is often confusing to introductory students. There is no “amide”, the commonly learned functional group (Figure 2.10). Unfortunately, another functional group (anionic nitrogen attached to alkyl groups) has the same name and is also referred to as an “amide”.
Figure 2.10 – Contrasting Two Functional Groups Referred to as Amides.
LDA is commercially available. However, it requires special considerations and equipment for handling and transport. It can also be synthesized by the reaction of diisopropylamine and butyl lithium (Scheme 2.9).
Scheme 2.9 – Formation of LDA From Diidopropylamine and Butyl Lithium.
Because diisopropylamine is very weakly acidic (pKa = ~36) the conjugate base LDA is very strongly basic. Conversely, unlike butyl lithium LDA is not a strong nucleophile. This is due to the steric bulk of the two isopropyl groups; LDA is too bulky to let the anionic nitrogen get close to any electrophile other than hydrogen. The anionic atom being nitrogen also plays a role, however the reasons for this are complex. The net result is a compound that is a very good base without also being a good nucleophile.
Because diisopropylamine is very weakly acidic (pKa = ~36) the conjugate base LDA is very strongly basic. For example, acetone (propan-2-one) is much more acidic than diisopropylamine (Scheme 2.10). As a result, using LDA to form the enolate of acetone DOES work well. With a ~17 unit difference in pKa there is no equilibrium and the reaction goes to completion, 99.9999999999999% of the molecules will become the enolate.
Scheme 2.10 – Acid-Base Reaction of Acetone and LDA Highlighting pKa Values.
As LDA is highly reactive it typically requires special conditions for its use. The solvent must be polar aprotic (and often contains an ether functional group; e.g. diethyl ether, tetrahydrofuran (THF)) and the temperature is kept as low as possible (e.g. -78 °C). These conditions are likely familiar; they are the same conditions as when Grignard or alkyl lithium compounds are used.
There are a large number of molecules very similar to LDA that are also used to quantitatively form enolates. In general, these are required for specific reactions or types of reactants and are not commonly encountered.
