11.1 The Discovery of Nucleophilic Substitution Reactions
3 min read•may 7, 2024
are key in organic chemistry. They involve a replacing a , usually a halogen. 's discovery of these reactions in 1896 laid the groundwork for understanding their mechanisms and .
These reactions typically invert the configuration of in primary and . The stereochemical outcome depends on factors like structure and reaction conditions. Multi-step sequences can lead to overall retention or inversion, crucial in synthetic planning.
Discovery and Fundamentals of Nucleophilic Substitution Reactions
Explain the concept of nucleophilic substitution reactions and their discovery by Paul Walden
Top images from around the web for Explain the concept of nucleophilic substitution reactions and their discovery by Paul Walden
9.2. Common nucleophilic substitution reactions | Organic Chemistry 1: An open textbook View original
Is this image relevant?
Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original
Is this image relevant?
Category:Nucleophilic substitution reactions - Wikimedia Commons View original
Is this image relevant?
9.2. Common nucleophilic substitution reactions | Organic Chemistry 1: An open textbook View original
Is this image relevant?
Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original
Is this image relevant?
1 of 3
Top images from around the web for Explain the concept of nucleophilic substitution reactions and their discovery by Paul Walden
9.2. Common nucleophilic substitution reactions | Organic Chemistry 1: An open textbook View original
Is this image relevant?
Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original
Is this image relevant?
Category:Nucleophilic substitution reactions - Wikimedia Commons View original
Is this image relevant?
9.2. Common nucleophilic substitution reactions | Organic Chemistry 1: An open textbook View original
Is this image relevant?
Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original
Is this image relevant?
1 of 3
- reactions involve the replacement of a (typically a halogen) by a nucleophile
- Nucleophile electron-rich species attracted to positively charged or electron-deficient atoms (amines, alkoxides, thiols)
- Leaving group atom or group that departs with a pair of electrons, typically a halogen (Cl, Br, I)
- Paul Walden, a Latvian chemist, discovered nucleophilic substitution reactions in 1896 while studying the stereochemistry of reactions involving optically active compounds
- Walden's work involved the conversion of (-)-malic acid to (+)-chlorosuccinic acid using PCl, followed by the reaction with AgOH to yield (+)-malic acid
- This sequence, known as the , demonstrated the inversion of stereochemistry in nucleophilic substitution reactions and laid the foundation for understanding the mechanism of these reactions
Stereochemistry of Nucleophilic Substitution Reactions
Describe how nucleophilic substitution reactions typically affect the configuration of chiral centers in primary and secondary alkyl halides
- In most cases, nucleophilic substitution reactions result in the at the chiral center due to the backside attack of the nucleophile
- Inversion of configuration the absolute configuration of the chiral center changes from R to S, or vice versa (R-2-bromobutane to S-2-butanol)
- (R-CH-X) undergo substitution with complete inversion of configuration because the nucleophile has unhindered access to the backside of the carbon-halogen bond
- The nucleophile attacks from the opposite side of the leaving group, resulting in a single inversion (1-bromoethane to 1-ethanethiol)
- Secondary alkyl halides (RRCH-X) also typically undergo substitution with inversion of configuration, but the process may be more complex due to steric hindrance
- However, secondary alkyl halides may also undergo through a mechanism (S1 reaction) involving the formation of a planar intermediate (2-bromobutane to 2-butanol via S1$)
- The nature of the substrate (e.g., primary vs. secondary alkyl halides) can influence the stereochemical outcome of the reaction
Analyze the stereochemical outcomes of multi-step reaction sequences involving nucleophilic substitutions, like the interconversion of 1-phenyl-2-propanol enantiomers
- Multi-step reaction sequences involving nucleophilic substitutions can lead to either retention or inversion of configuration, depending on the number of inversions that occur in the overall process
- Even number of inversions (0, 2) results in retention of configuration (R to R, or S to S)
- Odd number of inversions (1, 3) results in inversion of configuration (R to S, or S to R)
- Example Interconversion of enantiomers
- Convert (R)-1-phenyl-2-propanol to (S)-1-phenyl-2-propyl chloride using SOCl (inversion)
- Convert (S)-1-phenyl-2-propyl chloride to (R)-1-phenyl-2-propanol using (inversion)
- Overall, the sequence results in retention of configuration due to two inversions canceling each other out, demonstrating the importance of tracking stereochemistry in multi-step syntheses
- These reactions produce , which are compounds with the same molecular formula but different spatial arrangements of atoms
Factors Affecting Nucleophilic Substitution Reactions
Kinetics and Reaction Mechanisms
- The of nucleophilic substitution reactions can be classified into two main types: S1 and S2
- S2 (bimolecular nucleophilic substitution) follows second-order kinetics, with the rate depending on both nucleophile and substrate concentrations
- S1 (unimolecular nucleophilic substitution) follows first-order kinetics, with the rate depending only on the substrate concentration
- The is influenced by various factors, including the structure of the substrate, the strength of the nucleophile, and the reaction conditions
- play a crucial role in determining the and rate
- Polar protic solvents tend to favor S1 reactions by stabilizing the carbocation intermediate
- Polar aprotic solvents generally promote S2 reactions by increasing nucleophile reactivity
Key Terms to Review (26)
1-phenyl-2-propanol: 1-phenyl-2-propanol is an organic compound consisting of a benzene ring attached to a three-carbon chain with a hydroxyl group on the second carbon. It is an important intermediate in the synthesis of various pharmaceutical and chemical products.
Anti stereochemistry: Anti stereochemistry describes the spatial arrangement in a chemical reaction where two substituents are positioned on opposite sides of a double bond or ring structure after the reaction. It is particularly relevant in the halogenation of alkenes, resulting in products where the added atoms are located across from each other.
Carbocation: A carbocation is a positively charged carbon atom that is part of an organic molecule. These reactive intermediates play a crucial role in various organic reactions, including electrophilic additions, nucleophilic substitutions, and elimination reactions.
Chiral Centers: Chiral centers are atoms within a molecule that have four different substituents attached, resulting in a non-superimposable mirror image. This asymmetry gives rise to the concept of chirality, which is essential in understanding optical activity, meso compounds, and the stereochemistry of various organic reactions and biomolecules.
Double Inversion: Double inversion is a phenomenon that occurs in certain nucleophilic substitution reactions, where the stereochemistry of the product is the same as the starting material. This is achieved through two consecutive inversion steps, resulting in an overall retention of configuration.
Inversion of Configuration: Inversion of configuration refers to the stereochemical change that occurs when a carbon atom bearing four different substituents undergoes a nucleophilic substitution reaction, resulting in the reversal of the spatial arrangement of the substituents around that carbon.
Kinetics: Kinetics is the study of the rates and mechanisms of chemical reactions. It examines how quickly reactions occur and the factors that influence the speed of a reaction, such as temperature, pressure, and the presence of catalysts.
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.
NaOH: NaOH, or sodium hydroxide, is a highly alkaline chemical compound that plays a crucial role in various organic chemistry reactions and processes. It is a strong base that is widely used in a variety of applications, including the discovery of nucleophilic substitution reactions, the SN2 reaction, the E2 reaction, carbonyl condensations, and peptide sequencing through the Edman degradation.
Nucleophile: A nucleophile is a species that donates a pair of electrons to form a covalent bond with another atom or molecule. Nucleophiles are central to understanding many organic reactions, including polar reactions, electrophilic addition reactions, and nucleophilic substitution reactions.
Nucleophilic Substitution: Nucleophilic substitution is a fundamental organic reaction where a nucleophile (a species that donates electrons) replaces a leaving group attached to a carbon atom, resulting in the formation of a new carbon-nucleophile bond. This process is central to many organic transformations and is particularly relevant in the context of alkyl halides, alcohols, carboxylic acids, and amines.
Nucleophilic substitution reactions: Nucleophilic substitution reactions are a class of chemical reactions in organic chemistry where an electron-rich nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms to replace a leaving group. The reaction is characterized by the substitution of a nucleophile for a leaving group, which can occur via different mechanisms (SN1 or SN2).
Paul Walden: Paul Walden was a German chemist who made significant contributions to the understanding of nucleophilic substitution reactions in organic chemistry. His work in the early 20th century laid the foundation for the modern concepts of these important reactions.
Primary Alkyl Halides: Primary alkyl halides are organic compounds where a halogen atom (such as fluorine, chlorine, bromine, or iodine) is covalently bonded to the first carbon atom of an alkyl group. These types of halides are important in organic chemistry reactions, particularly in the context of nucleophilic substitution and the alkylation of acetylide anions.
Reaction mechanism: A reaction mechanism is a step-by-step sequence of elementary reactions by which overall chemical change occurs. It outlines the specific way in which reactants convert to products, including the formation and breaking of bonds.
Reaction Mechanism: A reaction mechanism is the step-by-step sequence of elementary reactions by which overall chemical change occurs. It describes the detailed pathway that a reaction follows, including the formation and rearrangement of chemical bonds, the generation of intermediates, and the movement of electrons. Understanding reaction mechanisms is crucial for predicting the products of a reaction, explaining reactivity trends, and designing new synthetic pathways.
Retention of Configuration: Retention of configuration refers to the preservation of the original stereochemical arrangement of atoms during a chemical reaction. It is an important concept in organic chemistry that describes the ability of a molecule to maintain its spatial orientation throughout a transformation.
Secondary Alkyl Halides: Secondary alkyl halides are organic compounds where a halogen atom (such as chlorine, bromine, or iodine) is bonded to a carbon atom that is connected to two other carbon atoms. These compounds are important intermediates in various organic reactions, particularly in the context of nucleophilic substitution reactions and the alkylation of acetylide anions.
SN1: SN1, or Nucleophilic Substitution Reaction, is a type of organic reaction mechanism in which a nucleophile attacks a neutral, trigonal planar carbocation intermediate to displace a leaving group, resulting in the substitution of one functional group for another. This mechanism is characterized by a stepwise process involving the formation of a carbocation intermediate.
SOCl2: SOCl2, or thionyl chloride, is a highly reactive and versatile organic reagent commonly used in various chemical reactions, particularly in the context of nucleophilic substitution reactions and the reactions of alcohols.
Solvent Effects: Solvent effects refer to the influence that the surrounding solvent environment can have on the behavior and properties of chemical reactions, molecules, and spectroscopic measurements. The nature and polarity of the solvent can significantly impact the energetics, kinetics, and outcomes of various organic chemistry processes.
Stereochemistry: Stereochemistry is the study of the three-dimensional arrangement of atoms in molecules and how this arrangement affects the chemical and physical properties of the substance. It examines the spatial orientation of atoms and their relationship to one another, which is crucial in understanding many organic chemistry concepts.
Stereoisomers: Stereoisomers are molecules that have the same molecular formula and connectivity, but differ in the three-dimensional arrangement of their atoms in space. This spatial arrangement of atoms leads to different physical and chemical properties, even though the atoms are connected in the same way.
Substrate: In the context of organic chemistry, a substrate is the molecule or compound that undergoes a chemical reaction, typically catalyzed by an enzyme or a reagent in a laboratory setting. Substrates serve as the starting material for various types of reactions, including biological reactions and laboratory reactions.
Walden Cycle: The Walden cycle is a series of chemical reactions that involve the inversion of stereochemistry during nucleophilic substitution reactions. It is an important concept in understanding the mechanisms of organic reactions, particularly those involving the displacement of leaving groups by nucleophiles.