Name: nucleophilic strength in substitution reactions
Uploaded: 2023-04-30T18:28:35.000Z
Duration: 2 min 30 s
Channel: JoVE

In a nucleophilic substitution reaction, the reactant molecule that displaces the leaving group in the substrate is called a nucleophile.
Nucleophiles are electron-rich species and, by definition, Lewis bases.&#160; The nucleophilic atom has a high electron density and donates its electrons to a partially positive, electron-deficient center, thereby making a new bond.
Nucleophilic reagents are either anionic or neutral. Anionic nucleophiles are negative ions containing one or more lone pairs of equal energy, usually on heteroatoms. The non-bonding lone pairs occupy high-energy molecular orbitals, which makes them less stable and more reactive.
For example, the anionic carbon nucleophile, like the cyanide ion, has a lone pair on both the carbon and nitrogen. However, since the carbon&#8217;s sp orbital is higher in energy than the nitrogen&#8217;s, carbon is the nucleophilic center.
Neutral nucleophiles have one or more unshared electron pairs on the highest occupied molecular orbitals of, mostly, heteroatoms.
Furthermore, in species like alkenes that have no lone pairs, a high electron density region &#8212; the pi bond &#8212; functions as the nucleophilic site.
A neutral nucleophile is less nucleophilic than its anionic form, owing to the absence of a negative charge.
In general, pKa values of acids can be used to evaluate the strength of their conjugate bases or nucleophiles. In the case of molecules containing the same nucleophilic atom, the higher the pKas of their conjugate acids, the stronger the nucleophile will be. &#160;&#160;&#160;&#160;
The product of a nucleophilic substitution reaction depends on the type of nucleophile used.
When an anionic nucleophile reacts with the substrate, the covalent bond formed neutralizes the formal charge of the nucleophile, resulting in a neutral product.
In comparison, when a neutral nucleophile reacts with the substrate, the nucleophile gains a positive formal charge. A deprotonation step that follows completes the reaction, resulting in a neutral product.

nucleophiles

Nucleophiles

The word &#8220;nucleophile&#8221; has a Greek root and translates to nucleus-loving. Nucleophiles are either negatively charged or neutral species with a pair of electrons in a high-energy occupied molecular orbital (HOMO). As these species tend to donate electron pairs, nucleophiles are considered Lewis bases as well. Negatively charged species, like OH&#8722;, Cl&#8722;, or HS&#8722;, with one or several pairs of electrons, are typically nucleophiles. Similarly, neutral species such as ammonia, amines, water, and alcohol have non-bonding lone pairs of electrons and can act as nucleophiles. Furthermore, molecules without a lone pair of electrons can still act as nucleophiles, such as alkenes and aromatic rings with bonding &#960; orbitals.
The relative strength of a nucleophile to displace a leaving group in a substitution reaction is called nucleophilicity. The negatively charged species are more nucleophilic than their neutral counterpart species. As an empirical rule, the higher the pKa of a conjugate acid, the better the nucleophile. For example, the hydroxide ion &#8212; a conjugate base of water (pKa 15.7) is a better nucleophile than the acetate ion &#8212; a conjugate base of acetic acid (pKa~5).
Since nucleophilicity is not the inherent property given to a specific species, it is affected by many factors, including the type of solvent in which the reaction is conducted. In polar protic solvents, high solvation of anions reduces the nucleophile&#8217;s availability to participate in substitution reactions.
When comparing halides, fluoride, being the smallest and most electronegative anion, is solvated the strongest, while iodide, the largest and least electronegative ion, is solvated the least. Thus, in polar protic solvents, iodide is the best nucleophile. In polar aprotic solvents, however, anions are &#8220;naked&#8221; due to poor solvation and can participate freely in a nucleophilic attack. In polar aprotic solvents, the nucleophile&#8217;s basicity dictates its nucleophilicity making fluoride the best nucleophile.
Furthermore, the polarizability of atoms affects nucleophilicity. Polarizability describes how easily electrons in the cloud can be distorted. A nucleophile with a large atom has greater polarizability, meaning it can donate a higher electron density to the electrophile compared to a small atom, whose electrons are held more tightly.

The word &#8220;nucleophile&#8221; has a Greek root and translates to nucleus-loving. Nucleophiles are either negatively charged or neutral species with a ...

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JoVE Core

Organic Chemistry

Unit 1

Nucleophilic Substitution and Elimination Reactions of Alkyl Halides

nucleophilic-substitution-and-elimination-reactions-of-alkyl-halides

KEY TERMS AND CONCEPTS

nucleophilic strength in substitution reactions

Nucleophiles are electron-pair donors that take part in substitution reactions. The word comes from Greek and means nucleus-loving. Because they donate electrons, nucleophiles are also Lewis bases.

Many nucleophiles are negatively charged species, such as hydroxide, chloride, and hydrosulfide. Neutral molecules can also act as nucleophiles when they have lone pairs of electrons. Examples include ammonia, amines, water, and alcohols.

Some molecules without a lone pair can still behave as nucleophiles. Alkenes and aromatic rings can donate electrons from their bonding pi orbitals. The strength of a nucleophile is called nucleophilicity, and it describes how well the species can displace a leaving group in a substitution reaction.

In general, negatively charged species are more nucleophilic than similar neutral species. A useful rule is that a higher pKa of the conjugate acid often means a better nucleophile. For example, hydroxide, the conjugate base of water with a pKa of 15.7, is a better nucleophile than acetate, the conjugate base of acetic acid with a pKa of about 5.

Nucleophilicity also depends on the solvent. In polar protic solvents, anions are strongly solvated, which lowers their ability to react. Among halides in these solvents, fluoride is solvated the most and iodide the least, so iodide is the better nucleophile. In polar aprotic solvents, anions are less solvated and more free to attack, so basicity becomes the main guide and fluoride is the best nucleophile.

Atom size also matters because of polarizability. Polarizability is how easily an electron cloud can be distorted. Larger atoms are more polarizable, so they can donate electron density to an electrophile more easily than smaller atoms with more tightly held electrons.

Nucleophilic Strength in Substitution Reactions

nucleophilic-strength-in-substitution-reactions

alkyl halides

Alkyl Halides: Structure and Reactivity

Alkyl halides are halogen-substituted alkanes. In these compounds, one or more hydrogen atoms in an alkane is replaced by a halogen atom such as fluorine, chlorine, bromine, or iodine. The carbon bonded to the halogen is sp3-hybridized and has a tetrahedral shape. Not every carbon-halogen compound is an alkyl halide. If the halogen is attached to an sp2-hybridized carbon in a carbon-carbon double bond, the compound is a vinyl halide. If the halogen is attached to an sp2-hybridized carbon in an...

nucleophilic substitution reactions

SN1 and SN2 in Organic Substitution

Nucleophilic substitution reactions replace one group in a molecule with another. In these reactions, a nucleophile, which is a Lewis base, reacts with an electrophile, which is a Lewis acid. The nucleophile takes the place of a halogen atom bonded to carbon and releases a stable ion called the leaving group. This reaction pattern is closely related to Lewis acid-base chemistry. The electron-rich species acts as the nucleophile. The electron-deficient species acts as the electrophile. A key...

Nucleophiles are electron-pair donors that take part in substitution reactions. The word comes from Greek and means nucleus-loving. Because they donate electrons, nucleophiles are also Lewis bases. Many nucleophiles are negatively charged species, such as hydroxide, chloride, and hydrosulfide. Neutral molecules can also act as nucleophiles when they have lone pairs of electrons. Examples include ammonia, amines, water, and alcohols. Some molecules without a lone pair can still behave as...

electrophiles

Electrophile Reactivity in Organic Reactions

Electrophile reactivity in organic reactions depends on how a species attracts electrons. Electrophiles are electron-poor and are key partners in nucleophilic substitution reactions. Their charge and orbital structure help explain why they react the way they do. Electrophiles can be positive or neutral species. A positive electrophile such as a proton reacts because it has a vacant, low-energy 1s orbital. Other positive electrophiles, such as carbocations, are reactive because they have an...

leaving groups

How Leaving Groups Affect Substitution

Leaving groups affect how nucleophilic substitution reactions happen. In this type of reaction, a nucleophile replaces a functional group on a substrate. The group that leaves is called the leaving group, and it departs when the bond breaks by heterolytic cleavage, taking both electrons with it. A good leaving group is usually a stable weak base. It can leave as an anion or as a neutral molecule. The easier it is for the leaving group to leave, the more it can influence the reaction rate. <br...

carbocations

Carbocation Structure and Stability

Carbocations are reactive carbon species formed during some nucleophilic substitution and elimination reactions. They are electron-deficient intermediates, with the central carbon holding only six electrons and three bonded atoms. Because they are short-lived and highly reactive, they play an important role in many organic reaction pathways. The central carbon in a carbocation is sp2 hybridized and has a trigonal planar shape. It also contains an empty p orbital that sits perpendicular to the...

sn2 reaction: kinetics

SN2 Rate Law and Reaction Mechanism

SN2 reaction kinetics links reaction rate to the concentration of reactants. In a chemical reaction, kinetic studies measure how fast reactants disappear or products appear under fixed conditions such as temperature, pressure, and solvent. These studies help chemists find the rate law, which can give clues about the species involved in the rate-determining step and the reaction mechanism. The rate of a reaction is found experimentally. Scientists withdraw small samples, called aliquots, at...

sn2 reaction: mechanism

SN2 Backside Attack and Inversion

SN2 reactions happen in one step and end with inversion of configuration. The nucleophile and the substrate both take part in the rate-determining step, and no intermediate forms. The substrate contains a polarized carbon-halide bond. The more electronegative halogen pulls the electron cloud toward itself. That leaves the carbon atom electrophilic, or electron-poor, with a partial positive charge. The halide has a partial negative charge. The electrophilic carbon attracts the nucleophile,...

sn2 reaction: transition state

SN2 Reaction: Reactivity and Steric Effects

An SN2 reaction of an alkyl halide happens in one step. The nucleophile forms a bond with the electrophilic carbon while the halide leaves at the same time. No intermediate forms during this process. As the nucleophile approaches with its lone pairs, the leaving group moves away with the electron pair that was bonded to carbon. The transition state is shown with dotted partial bonds and square brackets. This state is very unstable, so it quickly changes into the more favored product state. <br...

sn2 reaction: stereochemistry

SN2 Inversion of Configuration

SN2 reactions cause inversion of configuration at the carbon being substituted. The nucleophile attacks from the back side, while the leaving group departs at the same time. This happens through a transition state, where the carbon changes from tetrahedral to trigonal bipyramidal and then back to tetrahedral. The change in shape helps explain the product stereochemistry. If the substrate is achiral at the alpha-carbon, the inversion is not seen. When the alpha-carbon is chiral, the reversal is...

sn1 reaction: kinetics

SN1 Reaction Rate and Unimolecular Step

SN1 reaction rate depends on the substrate, not the nucleophile. This pattern was identified by Sir Christopher Ingold and Edward D. Hughes while they studied nucleophilic substitution reactions of tertiary alkyl halides. A tertiary alkyl halide can still undergo substitution even when the nucleophile is weak. In their kinetic studies, the rate of product formation stayed the same when the nucleophile concentration changed, as long as the substrate concentration remained constant. That means...

sn1 reaction: mechanism

SN1 Reaction Steps and Carbocation Formation

The SN1 reaction follows a step-by-step pathway that begins with carbocation formation. In a polar protic solvent, a tertiary haloalkane can ionize so that only the substrate takes part in the rate-determining step, which is the slow step. First, the haloalkane undergoes heterolytic cleavage to form a carbocation intermediate and a halide ion. This bond break is highly endothermic and has a large activation energy. The polar protic solvent helps stabilize the ions by solvation, and that makes...

sn1 reaction: stereochemistry

SN1 Pathway and Product Chirality

SN1 reactions can change the chirality of a product because the reaction goes through a carbocation intermediate. First, the bond between the electrophilic carbon and the leaving group ionizes. Then the nucleophile attacks the carbocation. The carbocation formed in an SN1 reaction is sp2 hybridized and has a trigonal planar shape. Its three substituents lie in the same plane, which creates a plane of symmetry. That makes the carbocation achiral, so the nucleophile can approach from either side...

predicting products: sn1 vs. sn2

SN1 and SN2 Reaction Factors

Nucleophilic substitution of alkyl halides can follow an SN1 or SN2 pathway. In an SN2 reaction, the nucleophile attacks as the leaving group leaves at the same time. In an SN1 reaction, the substrate first splits to form a carbocation, which is a positively charged intermediate. The structure of the alkyl halide helps decide which mechanism is more likely. As alkyl substitution increases, steric hindrance also increases, which makes backside attack harder for SN2. More substituted alkyl...

elimination reactions

E2 vs E1 in Alkyl Halide Elimination

Elimination reactions of alkyl halides form alkenes by removing groups from adjacent carbons. A base can act on the substrate instead of causing substitution. It deprotonates the neighboring carbon, and the reaction creates at least one pi bond. The carbon bonded to the halogen is the alpha carbon, and the adjacent carbon is the beta carbon. These are also called beta elimination or 1,2-elimination reactions. Strong bases help drive this process. Common examples include hydroxides, alkoxides,...

e2 reaction: kinetics and mechanism

E2 Elimination: Rate, Base, and Solvent

E2 elimination is a concerted reaction of alkyl halides that forms an alkene. In this mechanism, the base removes a beta hydrogen as the halide leaves from the alpha carbon. The two bonds change at the same time, so the products are formed in one step. The rate-limiting transition state has partially broken carbon-hydrogen and carbon-halogen bonds. It also has a partially formed pi bond between the alpha and beta carbons. Because the beta hydrogen and the halide are eliminated together, the...

e2 reaction: stereochemistry and regiochemistry

e2-reaction-stereochemistry-and-regiochemistry

E2 Elimination: Major and Minor Products

E2 elimination reactions of alkyl halides can form one or more alkenes, and the product mix depends on regiochemistry and stereochemistry. Regiochemistry controls where the double bond appears. Stereochemistry controls the shape of the alkene that forms. When a substrate has two different beta hydrogens, a strong base can remove either one. That can give two regioisomeric alkenes. The more substituted alkene is the major product and is called the Zaitsev product. The less substituted alkene is...

e1 reaction: kinetics and mechanism

E1 Elimination: Carbocation Stability and Rates

E1 elimination depends on carbocation stability and reaction rate. It follows a two-step path. The first step is the rate-limiting loss of the leaving group. The second step is the abstraction of the beta hydrogen by a weak base. Experimental support for the E1 mechanism comes from kinetic studies and isotope studies. Kinetic studies show first-order kinetics, which means the rate depends only on substrate concentration. Isotope studies show that hydrogen is removed only in the second step. <br...

e1 reaction: stereochemistry and regiochemistry

e1-reaction-stereochemistry-and-regiochemistry

E1 Elimination: Zaitsev Product and Carbocation

E1 elimination often gives the most substituted alkene, called the Zaitsev product. In the example, water acts as a weak base and favors elimination over substitution, so two alkene products can form. The Zaitsev alkene is usually more stable than the Hofmann product because it has more alkyl groups attached to the double bond. The lower-energy pathway also helps explain why the Zaitsev product is favored. Its transition state has lower energy, so this product is both thermodynamically stable...

predicting products: substitution vs. elimination

predicting-products-substitution-vs-elimination

Choosing Products in Substitution and Elimination

Substitution and beta-elimination compete when a nucleophile reacts with an alkyl halide. The major product depends on the substrate, the nucleophile, the temperature, and the solvent. Because more than one pathway can happen at once, a reaction often gives a product mixture. The structure of the alkyl halide helps predict which mechanism is more likely. Methyl halides and 1° halides usually favor bimolecular reactions, especially SN2. SN1 and E1 are disfavored for 1° halides because the 1°...

key terms and concepts

Learn how nucleophiles donate electron pairs, why charge and pKa matter, and how solvent and polarizability change nucleophilic strength.

Nucleophilic Strength in Substitution Reactions | JoVE K12

organic chemistry

JoVE Core Organic Chemistry explains basic concepts of stereochemistry, reactions, and mechanisms using concise and easy-to-understand animated video lessons. Additionally, the scientist-in-action videos demonstrate the application of related concepts in classical and original research experiments performed in today's laboratories worldwide.

Nucleophilic Strength in Substitution Reactions

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