16.6 Nucleophilic Aromatic Substitution
3 min read•may 7, 2024
swaps out groups on aromatic rings. It's a two-step dance: a nucleophile joins the ring, forming a funky intermediate, then the original group bows out. This process is different from its electrophilic cousin.
Electron-hungry groups on the ring make this substitution easier. Good leaving groups and strong nucleophiles are key players. This reaction is super useful in organic synthesis, helping chemists build complex molecules by tweaking aromatic rings.
Nucleophilic Aromatic Substitution
Mechanism of nucleophilic aromatic substitution
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- () two-step mechanism substitutes on aromatic ring with nucleophile
- Step 1: Nucleophile adds to aromatic ring
- Nucleophile attacks electrophilic carbon with forming new bond
- Forms -stabilized intermediate ()
- structure
- Negatively charged intermediate has nucleophile and leaving group attached to same carbon
- Negative charge delocalized over aromatic ring and electronegative atom of nucleophile
- Resonance structures show negative charge on various ring carbons and nucleophile
- Step 2: Leaving group eliminates
- Leaving group departs Meisenheimer complex restoring to ring
- Forms substituted aromatic product
Nucleophilic vs electrophilic aromatic substitution
- Nucleophilic aromatic substitution (Ar)
- Favored by electron-withdrawing groups (EWGs) on aromatic ring
- EWGs (, , ) stabilize negative charge of Meisenheimer complex
- EWGs activate ring towards nucleophilic attack and facilitate leaving group departure
- Leaving groups typically halides (F, Cl, Br, I) or good leaving groups (, )
- Nucleophiles are strong (-OH, -OR, -NH2, -NHR, -NR2)
- Reaction conditions use polar aprotic solvents (, ) and elevated temperatures
- Favored by electron-withdrawing groups (EWGs) on aromatic ring
- (EAS)
- Favored by electron-donating groups (EDGs) on aromatic ring
- EDGs (-OH, -OR, -NH2, -NHR, -NR2, -alkyl) increase electron density activating ring towards electrophilic attack
- EDGs direct substitution to ortho and para positions
- Electrophiles are electron-deficient species (, , )
- Reaction conditions use Lewis acid catalysts (, ), polar protic solvents, and mild temperatures
- Favored by electron-donating groups (EDGs) on aromatic ring
Applications of nucleophilic aromatic substitution
- Identifying suitable substrates
- with EWGs (-NO2, -CN) ortho or para to leaving group are most reactive
- and chlorides more reactive than and iodides due to better leaving group ability
- Predicting products
- Determine nucleophile and leaving group in reaction
- Substitute leaving group with nucleophile at same position on aromatic ring
- Proposing mechanisms
- Nucleophilic attack
- Identify electrophilic carbon bearing leaving group
- Show nucleophile forming new bond to this carbon resulting in Meisenheimer complex
- Leaving group departure
- Show leaving group departing Meisenheimer complex
- Illustrate restoration of aromaticity in substituted product
- Nucleophilic attack
- Considering potential side reactions
- Elimination () may compete with substitution if strong bases used as nucleophiles and aryl halide has available beta hydrogens
- formation may occur with strong bases and ortho-disubstituted aryl halides
Factors Influencing Nucleophilic Aromatic Substitution
- Resonance: Stabilizes the Meisenheimer complex intermediate
- Aromaticity: Disrupted during the reaction and restored in the product
- : Electron-withdrawing groups enhance reactivity by stabilizing the negative charge
- : Rate-determining step is typically the initial nucleophilic attack
- : Resembles the Meisenheimer complex in structure and energy
Key Terms to Review (38)
-CF3: The -CF3 group, also known as the trifluoromethyl group, is a functional group consisting of three fluorine atoms bonded to a single carbon atom. It is a common substituent in organic chemistry and has significant implications in the context of nucleophilic aromatic substitution reactions.
-CN: -CN, also known as the cyano group, is a functional group consisting of a carbon atom triple-bonded to a nitrogen atom. It is commonly encountered in the context of nucleophilic aromatic substitution reactions, where it can serve as a leaving group or a directing group, influencing the reactivity and regioselectivity of the substitution process.
-NO2: -NO2, also known as the nitro group, is a functional group consisting of a nitrogen atom double-bonded to two oxygen atoms. It is a common substituent in organic compounds and plays a significant role in the context of nucleophilic aromatic substitution reactions.
-OMs: -OMs is a functional group that is commonly encountered in the context of nucleophilic aromatic substitution reactions. It refers to the presence of a sulfonate ester (R-O-SO2-R') group, which can serve as a good leaving group in these types of reactions.
-OTs: -OTs is a functional group commonly encountered in the context of nucleophilic aromatic substitution reactions. It refers to the presence of a leaving group, typically a sulfonate ester, attached to an aromatic ring, which can be displaced by a nucleophile during the substitution process.
$AlCl_3$: $AlCl_3$, or aluminum chloride, is a Lewis acid that plays a crucial role in nucleophilic aromatic substitution reactions. It serves as an electrophilic catalyst, activating the aromatic ring and facilitating the substitution of a nucleophile in place of a leaving group.
$Br^+$: $Br^+$ is a positively charged bromine cation that is a key intermediate in nucleophilic aromatic substitution reactions. It serves as an electrophile that can attack and displace substituents on aromatic rings, facilitating the substitution of new functional groups.
$FeBr_3$: $FeBr_3$, or ferric bromide, is an inorganic compound composed of iron and bromine. It is a key term in the context of nucleophilic aromatic substitution reactions, as it can act as a Lewis acid catalyst in these transformations.
$NO_2^+$: $NO_2^+$ is a positively charged nitro group, which is an important intermediate in nucleophilic aromatic substitution reactions. It is a key electrophilic species that can undergo substitution with various nucleophiles on aromatic rings.
$S_N$Ar: $S_N$Ar, or nucleophilic aromatic substitution, is a type of aromatic substitution reaction where a nucleophile replaces a leaving group on an aromatic ring. This reaction is particularly important in the context of understanding the reactivity and stability of aromatic compounds.
$SO_3H^+$: $SO_3H^+$ is the sulfonic acid functional group, which is a key intermediate in the nucleophilic aromatic substitution reaction. It is formed when a sulfur trioxide molecule ($SO_3$) reacts with an aromatic compound, creating a strong electrophilic species that can be further substituted by a nucleophile.
Addition-Elimination Mechanism: The addition-elimination mechanism is a type of nucleophilic aromatic substitution reaction in which a nucleophile first adds to the aromatic ring, followed by the elimination of a leaving group, resulting in the substitution of the original functional group on the aromatic ring.
Aromaticity: Aromaticity is a fundamental concept in organic chemistry that describes the unique stability and reactivity of certain cyclic compounds with delocalized pi electron systems. This term is central to understanding the structure, stability, and reactivity of a wide range of organic compounds, including benzene and other aromatic heterocycles.
Aryl Bromides: Aryl bromides are organic compounds containing a bromine atom attached directly to an aromatic ring. They are an important class of compounds in organic chemistry, particularly in the context of nucleophilic aromatic substitution reactions.
Aryl Chlorides: Aryl chlorides are a class of organic compounds that contain a chlorine atom bonded directly to an aromatic ring. They are widely used in various chemical reactions and processes due to their unique reactivity and versatility.
Aryl Fluorides: Aryl fluorides are organic compounds where a fluorine atom is directly attached to an aromatic ring structure. They are an important class of compounds in organic chemistry, particularly in the context of nucleophilic aromatic substitution reactions.
Aryl Halides: Aryl halides are organic compounds that consist of a halogen atom (fluorine, chlorine, bromine, or iodine) bonded directly to an aromatic ring, such as a benzene ring. These compounds are important in organic synthesis and have various applications in chemistry.
Aryl Iodides: Aryl iodides are a class of organic compounds that consist of an aromatic ring (aryl group) bonded to an iodine atom. These compounds are important in the context of nucleophilic aromatic substitution reactions, where the iodine atom can be replaced by a nucleophile.
Benzyne: Benzyne is a highly reactive intermediate species in organic chemistry, characterized by the presence of a triple-bonded carbon-carbon unit within a benzene ring. This reactive intermediate plays a crucial role in various organic reactions, particularly in the context of nucleophilic aromatic substitution and the formation of benzyne-derived compounds.
Carbanion: A carbanion is a negatively charged species that contains a carbon atom with three bonds and a lone pair of electrons, giving it a formal negative charge. This species is crucial in various organic reactions, as it acts as a strong nucleophile and can participate in forming new bonds by attacking electrophiles.
DMF: DMF, or dimethylformamide, is a versatile organic solvent that has applications in various chemical reactions and processes. It is a polar aprotic solvent that is widely used in organic chemistry, particularly in the context of nucleophilic substitution reactions, nucleophilic aromatic substitution, and the preparation of ethers and crown ethers.
DMSO: DMSO, or dimethyl sulfoxide, is a highly polar organic solvent known for its ability to dissolve both polar and nonpolar compounds. Its unique properties make it a valuable reagent in various chemical reactions, particularly in nucleophilic substitution processes, where it enhances the solubility of reactants and facilitates the formation of intermediates.
E2: E2 (Elimination, bimolecular) is a type of organic reaction mechanism where a base removes two atoms, typically a hydrogen and a leaving group, from adjacent carbon atoms in a single step, resulting in the formation of a new carbon-carbon double bond.
Electron-Withdrawing Group: An electron-withdrawing group is a functional group or substituent in a molecule that has the ability to attract or withdraw electrons from the surrounding atoms, thereby stabilizing or destabilizing certain reaction intermediates or transition states. This property plays a crucial role in understanding carbocation stability, nucleophilic aromatic substitution, and nucleophilic addition reactions of aldehydes and ketones.
Electrophilic aromatic substitution: Electrophilic aromatic substitution is a chemical reaction in which an atom, typically hydrogen, attached to an aromatic system, such as benzene, is replaced by an electrophile. This process preserves the aromaticity of the compound while introducing a functional group.
Electrophilic Aromatic Substitution: Electrophilic aromatic substitution is a fundamental organic reaction in which an electrophile (a species that is attracted to electrons) replaces a hydrogen atom on an aromatic ring, resulting in the formation of a new carbon-electrophile bond. This reaction is crucial in understanding the behavior and reactivity of aromatic compounds, which are prevalent in many organic molecules and have widespread applications.
Leaving group: A leaving group in organic chemistry is an atom or group that detaches from the parent molecule during a nucleophilic substitution (SN2) reaction, forming a lone pair or negative ion. The ease with which a leaving group departs affects the rate and success of the reaction.
Leaving Group: A leaving group is a functional group or atom that is displaced or removed from a molecule during a chemical reaction. It is a key component in many organic reactions, particularly substitution and elimination reactions, as it facilitates the formation of a new bond or the creation of a new product.
Meisenheimer complex: A Meisenheimer complex is an intermediate formed during the nucleophilic aromatic substitution process when a nucleophile attacks and temporarily bonds to an aromatic ring, resulting in a negatively charged complex. This intermediate is stabilized by electron-withdrawing groups attached to the aromatic system.
Meisenheimer Complex: A Meisenheimer complex is a type of intermediate formed during nucleophilic aromatic substitution reactions. It involves the addition of a nucleophile to an aromatic ring, creating a negatively charged, tetrahedral intermediate that is stabilized through resonance.
Nucleophilic aromatic substitution: Nucleophilic aromatic substitution is a reaction where an electron-rich nucleophile selectively replaces a leaving group, such as a halide, attached to an aromatic ring. This process contrasts with electrophilic aromatic substitution by involving the attack of a nucleophile instead of an electrophile.
Nucleophilic Aromatic Substitution: Nucleophilic aromatic substitution is a reaction in organic chemistry where a nucleophile replaces a leaving group on an aromatic ring, typically a halogen or nitro group. This process is crucial in understanding the reactivity and synthesis of various aromatic compounds, including heterocyclic systems and polysubstituted benzenes.
Nucleophilic aromatic substitution reactions: Nucleophilic aromatic substitution reactions are a class of chemical reactions where an electron-rich nucleophile selectively replaces a leaving group (usually a halogen) on an aromatic ring. This reaction differs from the more common electrophilic aromatic substitution by involving a nucleophile attacking an aromatic system that typically contains an electron-withdrawing group to facilitate the substitution.
Reaction Kinetics: Reaction kinetics is the study of the rates and mechanisms of chemical reactions. It examines the factors that influence the speed and efficiency of a reaction, such as temperature, pressure, and the presence of catalysts. This concept is crucial in understanding organic reactions, as the rate and pathway of a reaction can have a significant impact on the products formed and the overall efficiency of the process.
Resonance: Resonance is a fundamental concept in organic chemistry that describes the ability of certain molecules to exist in multiple equivalent structures or resonance forms. This phenomenon arises from the delocalization of electrons within the molecule, leading to the stabilization of the overall structure and the distribution of electron density across multiple atoms.
Substituent Effects: Substituent effects refer to the influence that specific functional groups or atoms have on the chemical and physical properties of a molecule. These effects can significantly impact the reactivity, stability, and behavior of organic compounds in various contexts, including conformational analysis, electrophilic and nucleophilic substitutions, and acidity determination.
Transition state: In organic chemistry, the transition state is a high-energy, temporary condition where reactants are transformed into products during a chemical reaction. It represents the point of maximum energy on the energy diagram before the formation of products.
Transition State: The transition state is a key concept in organic chemistry that describes the highest-energy intermediate along the reaction pathway. It represents the point where the reactants are being converted into products, with the system at its most unstable and energetically unfavorable configuration.