Nucleophile: What is Nucleophile?, Periodic Trends and Solvent Effects in Nucleophilicity, Resonance Effect on Nucleophilicity, Steric Effects on Nucleophilicity, Practice Problems and Frequently Asked Questions(FAQs)

If you want to buy a house, what will you do to pay the builder such a large amount of money?

Obviously, we shall seek a loan from a bank.

Similarly to how a bank offers loans to those in need and approaches them, there are some molecules in chemistry that are electron rich and provide electrons to molecules that require electrons; we refer to these molecules as Nucleophiles.

Let us start with "nucleophiles" (derived from "nucleus loving" or "positive-charge loving"). A nucleophile is a species that gives up a pair of electrons in order to form a new covalent bond.

Does this sound familiar? This is exactly what a Lewis base does.

Nucleophiles, in other terms, are Lewis bases.

Table of content:

• What is a nucleophile?
• Periodic trends and solvent effects in nucleophilicity
• Resonance effect on nucleophilicity
• Steric effects on nucleophilicity
• Practice problems
• Frequently asked questions(FAQs)

What is a nucleophile?

Nucleophilic functional groups are electron-rich atoms that can donate a pair of electrons to form a new covalent bond. In both laboratory and biological organic chemistry, the most important nucleophilic atoms are oxygen, nitrogen, and sulphur, whereas the most common nucleophilic functional groups are water, alcohols, phenols, amines, thiols, and rarely carboxylates.

In particular, halide and azide (N3-) anions are frequently found acting as nucleophiles in laboratory processes.

When considering nucleophiles, the first thing to remember is that the same 'electron-richness' that makes something nucleophilic also makes it basic: nucleophiles can be bases, and bases can be nucleophiles.

A nucleophilic atom's protonation state has a significant impact on its nucleophilicity. This makes logical sense: a hydroxide ion is substantially more nucleophilic (and basic) than a water molecule because the negatively charged oxygen on the hydroxide ion carries more electron density than the neutral water molecule's oxygen atom. In practice, this means that a hydroxide nucleophile will react with methyl bromide much faster (approximately 10,000 times faster) than a water nucleophile in an SN2 reaction.

Periodic trends and solvent effects in nucleophilicity:

Nucleophilicity has predictable periodic trends. As one proceeds horizontally across the second row of the table, the trend in nucleophilicity follows the trend in basicity:

The cause for the horizontal nucleophilicity trend is the same as it is for the basicity trend: more electronegative components firmly keep their electrons and are less able to transfer them to create a new bond.

Despite the fact that both groups frequently act as nucleophiles in laboratory and biological activities, this horizontal trend shows that amines are more nucleophilic than alcohols.

As we move vertically down the periodic table, keep in mind that the basicity of atoms decreases. For instance, thiolate ions are less basic than alkoxide ions, and bromide ions are less basic than chloride ions, which are less basic than fluoride ions. It's important to keep in mind that this trend can be explained by taking into consideration the expanding "electron cloud" that surrounds larger ions: because the inherent electron density of the negative charge is spread out over a broader region, it tends to increase stability (and thus reduce basicity).

The vertical periodic trend for nucleophilicity is slightly more complicated than that for basicity: the nucleophilicity trend might go in either direction depending on the solvent in which the reaction is taking place. Let us consider the simple example of SN2 reaction below:

where Nu- is one of the halide ions fluoride, chloride, bromide, or iodide, and I* is a radioactive iodine isotope (which allows us to distinguish the leaving group from the nucleophile in that case where both are iodide). If this reaction takes place in a protic solvent (one that has a hydrogen bonded to an oxygen or nitrogen atom - water, methanol, and ethanol are the most common examples), the reaction will proceed fastest when iodide is the nucleophile and slowest when fluoride is the nucleophile, reflecting the relative strength of the nucleophile.

The vertical periodic trend for basicity, in which iodide is the least basic, is obviously violated by this. What precisely is happening here? Given that its unbonded valence electrons are more reactive, shouldn't the stronger base be the greater nucleophile?

As was already stated, the solvent is the key. Keep in mind that the reaction we are discussing right now is occurring in ethanol, a protic solvent. The negatively charged nucleophile and protic solvent molecules interact through extraordinarily strong ion-dipole interactions to surround the nucleophile in a "solvent cage":

The nucleophile must at least partially escape from its solvent cage in order to attack the electrophile. In contrast to the smaller, more basic fluoride ion, whose lone pair electrons are more tightly bound to the cage's protons, the larger, less basic iodide ion interacts less strongly with the protons on the protic solvent molecules, allowing the iodide nucleophile to escape the solvent cage more readily.

A molecular dipole is present in a polar aprotic solvent like acetone, but there are no hydrogens linked to oxygen or nitrogen, so the situation changes. Iodide is currently the least efficient nucleophile, while fluoride is the most efficient.

The reason for the reversal is because the ion-dipole interactions between the solvent and the nucleophile are significantly less in an aprotic solvent: the positive end of the solvent's dipole is hidden in the interior of the molecule and sterically crowded. Due to steric crowding and repulsions aprotic solvents won't be able to solvate or form the solvent cage structures.

The weaker the solvent-nucleophile interaction, the weaker the solvent cage for the nucleophile to break through, so the solvent effect is much less important, and the more basic fluoride ion is also the better nucleophile.

Why not use a totally nonpolar solvent, such as hexane, for this reaction to completely eliminate the solvent cage? The answer is simple: the nucleophile must be in solution in order to react with the electrophile at a significant rate, and a solvent such as hexane will not solvate a charged (or highly polar) nucleophile at all. That is why chemists use polar aprotic solvents in the laboratory for nucleophilic substitution reactions: they are polar enough to solvate the nucleophile but not so polar that it is trapped in an impenetrable solvent cage. In addition to acetone, three other polar aprotic solvents that are often employed are acetonitrile, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

The most important implication of the periodic trends in nucleophilicity in biological chemistry, where the solvent is protic (water), is that thiols are more strong nucleophiles than alcohols. The thiol group in a cysteine amino acid, for example, is a powerful nucleophile that frequently serves as a nucleophile in enzymatic reactions, and negatively charged thiolates (RS-) are even more nucleophilic. This is not to say that the hydroxyl groups on serine, threonine, and tyrosine do not act as nucleophiles, they do.

Resonance effect on nucleophilicity:

Resonance effects also affect how various compounds differ in their inherent nucleophilicity. The same logic is applied to understand resonance effects on basicity. Resonance causes the electron lone pair on a heteroatom to become less reactive, less nucleophilic, and less basic. An alkoxide ion is more nucleophilic and basic than a carboxylate group, despite the fact that the nucleophilic atom in both instances is a negatively charged oxygen. While the negative charge in the carboxylate ion is delocalized over two oxygen atoms through resonance, the negative charge in the alkoxide is concentrated on a single oxygen atom.

Steric effects on nucleophilicity:

A crucial aspect to take into account when evaluating nucleophilicity is steric hindrance. For instance, tert-butanol has a lower nucleophilicity than methanol. This is due to the fact that the bulkier methyl groups in the tertiary alcohol effectively block the nucleophilic oxygen's path of attack, greatly delaying the reaction.

Practice problems:

Q.1. Which of the following statements about NH₃ and H₂O is correct?

(A) NH₃ is more basic and more nucleophilic than H₂O
(B) NH₃ is less basic and less nucleophilic than H₂O
(C) NH₃ is more basic but less nucleophilic than H₂O
(D) NH₃ is less basic but more nucleophilic than H₂O

Answer: (A)

Solution: Because oxygen is more electronegative than nitrogen, it is less likely to contribute its lone pairs to form a covalent bond with a carbon atom during a nucleophilic attack.

Q.2. Among the following, which is not a nucleophile?

(A) CH₃NH₂
(B) (CH₃)₂NH
(C) (CH₃)₃N
(D) (CH₃)₄N+

Answer: (D)

Solution: The nucleophile donates electrons to the electrophiles, and because nitrogen (CH₃)₄N+ lacks a lone pair in this tetramethyl amine, electron donation is not possible.

Q.3. Which of the following statements about nucleophiles is false?

(A) donates an electron pair to an electrophile to form a chemical bond
(B) all molecules or ions with a free electron pair or at least one bond can act as nucleophiles
(C) nucleophile are Lewis acids by definition
(D) Ammonia is a nucleophile

Answer: (C)

Solution: Because nucleophiles are electron donors , they are by definition Lewis bases.

Q.4. Which of the following statements about the two anionic molecules is correct?

C₆H₅O^-, C₆H5S^-

(A) C₆H₅O^- is more basic and more nucleophilic than C₆H₅S^-
(B) C₆H₅O^-is less basic and less nucleophilic than C₆H₅S^-
(C) C₆H₅O^- is more basic but less nucleophilic than C₆H₅S^-
(D) C₆H₅O^- is less basic but more nucleophilic than C₆H₅S^-

Answer: (C)

Solution: Due to polarizability, larger atoms make better nucleophiles, so C₆H₅S^- containing S will be more nucleophilic than C₆H₅S^- but less basic.

Frequently asked questions(FAQs):
 

1. What is an ambident nucleophile?
Answer: Ambident nucleophile is an anionic nucleophile with a delocalized negative charge over two dissimilar atoms. Ambident derives its name from the Latin words 'ambi' (on both sides) and dens (tooth).

Ambient nucleophiles have two nucleophilic centres, or two (-ve) sites, and the negative charge is delocalized due to resonance. As a result, they can attack a substrate from two sides.

Nitrite ion is an example of an ambident nucleophile. It can attack through the 'O' atom, producing alkyl nitrites, or it can attack through the 'N' atom, producing nitroalkanes.

2. What exactly is solvolysis?
Answer: Solvolysis is defined as a chemical reaction in which solvents such as water or alcohol are present in large quantities. It is a substitution reaction in which an atom or group of atoms in a molecule is replaced by another atom or group of atoms. In this case, the solvents produce electron-rich atoms that serve as nucleophiles, displacing an atom or group of atoms from the substrate molecule.

3. Why CN- is stronger nucleophile than OH-?
Answer: Smaller molecules are more effective nucleophiles than larger molecules (because they are not as sterically hindered). Because nitrogen is less electronegative than oxygen, CN- is a stronger nucleophile than OH- (Look for the lower electronegativity on the atom holding the lone pair of electrons). As a result, the lone pair of electrons on nitrogen are not as stable as those on oxygen and will readily donate their pair of electrons to another species.

4. What is the role of alkenes as nucleophiles?
Answer: The pi electrons are loosely bound because they are relatively far away from the nucleus. An electrophile will attract those electrons and will be able to pull them away to form a new bond. One carbon is left with only three bonds and a positive charge (carbocation). The nucleophile is the double bond (attacks the electrophile).