Korean, Edit

Chapter 7. Alkyl Halides

Recommended Article: 【Organic Chemistry】 Organic Chemistry Table of Contents

1. Overview

2. Nucleophilic Substitution Reactions

3. S_N2 Reaction

4. S_N1 Reaction

5. E2 Reaction

6. E1 Reaction

7. E1cB Reaction

8. Bredt’s rule

9. S_N2 Reaction vs S_N1 Reaction

10. Comparison of S_N2, E2, S_N1/E1 Reactions

11. Carbon-Carbon Coupling Reactions

12. Synthesis method

1. Overview

⑴ Halogenated Alkyl (Alkyl Halide): Compounds in the form of R-X

① Examples: methyl halide, vinyl halide, aryl halide, allylic halide, benzylic halide

② Halogenated alkyl compounds are highly reactive: Due to the high electronegativity of halogen atoms, the halogen atom is easily detached

⑵ Properties According to Structure

① Carbon is a partially positive electrophile, halogen atoms are partially negative

② Reacting reagents are nucleophiles or bases

③ Solvents: H₂O, ROH

⑶ Boiling and Melting Points

① If the number of carbons is the same, the boiling and melting points of halogenated alkyl compounds are higher than those of alkanes: Due to stronger intermolecular forces in halogenated alkyl compounds

② Boiling and melting points of halogenated alkyl compounds increase with larger R groups: Larger R groups lead to increased surface area and stronger intermolecular forces

③ Boiling and melting points of halogenated alkyl compounds increase with larger X atoms: Increased polarity leads to stronger intermolecular forces

⑷ Solubility

① Halogenated alkyl compounds are soluble in organic solvents

② Halogenated alkyl compounds are insoluble in water

⑸ Bond Strength: Decreases with larger X atoms

⑹ General Reaction

① Elimination reactions are predominant upon heating

○ Examples: E1 elimination reaction, E2 elimination reaction, CO₂ elimination, N₂ elimination

2. Nucleophilic Substitution Reactions

⑴ Overview

Figure 1. Nucleophilic Substitution Reaction

R-X: Substrate (S)

Nu:: Nucleophile

R-Nu: Product (P)

X: Leaving Group (L)

⑵ Mechanism Example 1. Simultaneous breaking of reactant bonds and forming of product bonds (S_N2)

Figure 2. Mechanism Example 1 of Nucleophilic Substitution Reaction

⑶ Mechanism Example 2. Reactant bonds break first, then product bonds form (S_N1)

Figure 3. Mechanism Example 2 of Nucleophilic Substitution Reaction

⑷ Mechanism Example 3. Product bonds form first, then reactant bonds break (Not possible)

① Reason: Carbon, a second-period element, can accommodate a maximum of 8 valence electrons, making such a structure impossible

② Intermediate cannot exist; considered to exist as a transition state

Figure 4. Mechanism Example 3 of Nucleophilic Substitution Reaction

3. S_N2 Reaction

⑴ Overview

① Bimolecular Nucleophilic Substitution

② 2^nd order

③ simultaneous reaction, resembles playing with beads

⑵ Reaction Rate Law

⑶ Mechanism

Figure 5. Mechanism of S_N2 Reaction

① Occurs in one step

② Strong nucleophiles substitute weak nucleophiles, making it irreversible

③ MO Theory: σ* antibonding MO of central carbon and orbital of nucleophile interfere, forming a new bond

⑷ Sterechemistry

① Transition State: Trigonal bipyramidal (sp³d)

② Backside attack of nucleophile: Nucleophile attacks from the backside of the leaving group

③ Chiral center inversion

○ RS nomenclature determination remains independent through inversion: RS designation before and after the reaction may stay the same or change

④ Racemization does not usually occur

○ Exception: Iodide ion reversibility

⑸ Rate Factors: Substrate

① Principle: Higher electrophilic nature of α-carbon leads to faster reaction rate

② General trend

○ Trend 1. Increased stability of transition state

○ α-halo carbonyl ＞ R-NH-CH₂-X ＞ R-O-CH₂-X ＞ Ph-CH₂-X, R=C-CH₂-X

Figure 6. Mechanism of α-halo carbonyl stabilizing the transition state of S_N2 reaction

Figure 7. Formation of an empty orbital approaching the nucleophile requires overlap between π* and σ*

○ α-halo carbonyl: Combination of π* (C=O) orbital and σ* (C-X) orbital forms lower-energy MO → Nucleophile attacks carbonyl carbon → Intramolecular S_N2 reaction occurs

○ Trend 2. Halogenated alkyl compounds

○ Methyl RX ＞ 1^st RX ＞ 2^nd RX ＞ 3^rd RX ＞ norbornane halide

○ Reason: Due to steric effects, activation energy of transition state varies

○ Trend 3. Halogen atoms bonded to sp² carbons

○ ＞ aryl halide, vinyl halide

○ Backside attack is prohibited by VSEPR

○ Stronger C-X bond makes leaving group harder to detach

⑹ Rate Factors: Nucleophile

① Principle: Strong nucleophiles lead to faster S_N2 reactions

② Weak base nucleophiles (Nu:): NaCN, KN3, RNH2, RCOONa. NaSR, NaBr, KI react with 1^st and 2^nd RX

③ Strong base nucleophiles: NaOR, KC≡CH, NaNH₂, etc., react with 1^st RX, 2^nd RX favors E2 reaction

④ Note, nucleophiles with pK_a greater than 10 are referred to as strong base nucleophiles

⑺ Rate Factors: Solvent

① Polar Protic Solvent,: Solvents with hydrogen bonding

○ Examples: Water, EtOH, MeOH, etc.

② Polar Aprotic Solvent,: Solvents without hydrogen bonding

○ Examples: Acetone, DMSO (dimethyl sulfoxide), DMF (dimethyl formamide), etc.

③ Nonpolar Solvent,: Solvent with low polarity

○ Requires catalysts like 4th ammonium salts, crown ethers for phase transition

④ Case 1: Neutral reactant and charged product

○ Polar protic solvents decrease S_N2 reactivity, thus polar aprotic or polar nonpolar solvents are preferred

⑤ Case 2: Neutral reactant and charged product

○ Polar protic solvents stabilize partial charges better in transition state, thus S_N2 rate increases in polar protic solvents

⑻ Rate Factors: Leaving Group

① S_N2 reaction includes leaving group detachment in reaction rate, making leaving group a rate factor

② Rate increases as leaving group becomes more stable, i.e., as the basicity decreases

③ C-F bond is too strong, making detachment difficult

○ Leaving group trend: C-F < C-Cl, C-Br < C-I

○ Teflon: -(CF₂-CF₂)_n-. Remains stable even with heat

○ Iodine’s high polarity leads to easy C-I bond detachment

⑼ Advanced Theory

① Iodine Ion Reversibility

○ Issue: Iodine ion S_N2 reaction is reversible due to similar basicity of nucleophile and leaving group, leading to coexistence of reactants and products (e.g., CH₃Br + I^- ⇄ CH₃I + Br^-).

○ Solution: To suppress reverse reaction, reaction is conducted in acetone where KBr doesn’t dissolve.

○ Alkyl iodide continuously reacts with iodide ion to form racemic mixture.

Figure 8. Process of alkyl iodide becoming a racemic mixture

② Fluoride ion insolubility

○ Issue: Fluoride ion’s strong ionic nature makes it difficult to dissolve in aprotic solvents.

○ As a result, S_N2 reaction involving fluoride is less likely.

○ Solution: Using phase transition catalysts like crown ethers can introduce chlorine ions into aprotic solvents.

③ Intermolecular and Intramolecular S_N2 Reactions

○ Competing relationship between intermolecular and intramolecular reactions

○ Generally, intramolecular reactions proceed faster than intermolecular reactions: Intramolecular reactions increase entropy

○ Conditions favoring intramolecular reactions: Low molecular concentrations, formation of 5-membered or 6-membered rings

⑽ Conclusion: S_N2 reactions occur rapidly in substrates with minimal steric hindrance, strong nucleophiles, and polar aprotic solvents

4. S_N1 Reaction

⑴ Overview

① Unimolecular Nucleophilic Substitution

② 1^st order

③ Remove and react, leading to carbocation

⑵ Introduction to Mechanism Background

① Reaction of t-butyl bromide with KOH: E2 reaction occurs

Figure 9. Reaction of t-butyl bromide with KOH

② Reaction of t-butyl bromide with H₂O

Figure 10. Reaction of t-butyl bromide with H₂O

○ 3^rd RX faces significant steric hindrance, making S_N2 nucleophilic attack difficult

○ Reaction rate is proportional only to t-butyl bromide concentration, making S_N2 explanation unsuitable: Only possible when reactant bonds break and product bonds form

⑶ Reaction Rate Law

⑷ Mechanism: 2-step reaction

Figure 11. Mechanism of S_N1 Reaction

① Carbocation formation: A type of solvolysis reaction

○ Rate-determining step: Formation of carbocation in 1st step

② Vibrations of solvents can break C-Br bonds due to Boltzmann energy distribution

⑸ Sterechemistry

① In the above mechanism, water can add to the front or back of carbocation, allowing racemization for chiral substances

② In other words, chiral molecules can form through racemization via achiral intermediates

③ However, actual reactions favor inversion over retention: Perfect S_N1 reactions are rare, and S_N2 reactions also occur simultaneously

④ Carbocation rearrangement reaction may occur to a more stable carbocation

Figure 12. An example of a S_N1 reaction involving ring expansion due to a rearrangement reaction.

⑹ Reaction rate factors: Substrate

① Increase in the carbon degree of CX → stabilization of carbocations → decrease in activation energy of rate-determining step → increase in reaction rate

② Resonance stabilization causes stabilize carbocation intermediates, leading to faster S_N1 reaction compared to the same degree of simple carbocation.

③ 1^st alkyl halide: S_N1 reaction doesn’t occur due to the extreme instability of carbocations

⑺ Reaction rate factors:** Nucleophile

① General S_N1 reaction conditions: Reaction between tertiary RX and weak nucleophiles such as H₂O, ROH, RCOOH, excluding amines, etc.

② Strong nucleophile conditions: Especially in tertiary RX, E2 reactions occur

③ S_N2 reaction is the major reaction under weak nucleophile conditions like H₂O, ROH (excluding RCOOH) even in 2^nd RX

④ Solvolysis reaction: Generally, solvent is used as a nucleophile

⑻ Reaction rate factors: Solvent

① Polar protic solvents: Stabilize the carbon cation, leading to an increase in reaction rate

⑼ Reaction rate factors: Leaving group

① The weaker the bond between carbon and the leaving group, or the more stable the departing anion, the faster the leaving group ability, resulting in a faster S_N1 reaction.

② Leaving ability is inversely proportional to the basicity of the leaving group

⑽ Reaction rate factors: Catalyst

① Ag⁺ forms a complex with the leaving group, promoting the dissociation of the leaving group and increasing the rate of the S_N1 reaction.

5. E2 Reaction

⑴ Overview

① Bimolecular elimination

② 2nd order, hence a simultaneous reaction

⑵ Competition Reaction with Nucleophilic Substitution Reaction

Figure 13. Competition Reaction between E2 Reaction and S_N2 Reaction

⑶ Reaction Kinetics

⑷ Mechanism: One-step reaction, the bonds of reactants break simultaneously with the formation of bonds in products

Figure 14. Mechanism of E2 Reaction

① Alkali attacks the beta hydrogen, forming an intermediate which then reacts with X^- and HB⁺ detaching.

⑸ Sterechemistry

① Position-selective reaction: Saytzeff’s rule (Zaitsev’s rule)

Figure 15. Example of Zaitsev’s Rule

○ The more substituents there are, the more stabilized the alkene becomes.

○ Explanation 1. Interaction between anti-π (π*) bonding orbitals and adjacent σ orbitals through hyperconjugation.

○ Explanation 2.

○ sp² hybridized carbons have a large s-character (33%), resulting in higher electronegativity.

○ sp³ hybridized carbons have a small s-character (25%), resulting in lower electronegativity.

○ sp³ hybridized carbons tend to donate electrons to sp2 hybridized carbons, hence more substituents lead to the stabilization of sp2 hybridized carbons.

○ Hammond’s Postulate

○ Definition: The transition state structure resembles the structure closer in energy.

○ For endothermic reactions, the energy order is reactants ＜ products ＜ transition state, so the transition state structure resembles the products.

○ For exothermic reactions, the energy order is products ＜ reactants ＜ transition state, so the transition state structure resembles the reactants.

○ Application: The rate of elimination reactions increases with more substituents on the product.

○ According to Hammond’s Postulate, transition state energy is lower for products with more substituents.

○ The path leading from reactants to a more stable product in cases with many substituents has a lower transition state energy, resulting in a faster reaction rate.

○ Hammond’s Postulate doesn’t apply to all reactions beyond E2 reactions.

Figure 16. Other Reactions where Hammond’s Postulate doesn’t apply

○ Judging the major product when two or more alkenes are formed

○ Alkyl halides or bases with steric hindrance: Consider the path involving steric hindrance to determine the major product.

○ E2 elimination reactions by EtO^- or OH^- generally follow Zaitsev’s rule.

○ Exceptions

○ When concomitant conformational stability is more favorable than the number of substituents, e.g., 4-chloro-5-methyl-1-hexene.

○ Alkyl fluoride, e.g., 2-fluoropentane.

○ Hofmann elimination reaction

○ When C-X bonds are rigid

Figure 17. Position-selective reactions of E2 mechanism depending on the C-X bond.

○ When the C-X bond is strong (e.g., X = F): Follows path ⒜. ㈎ is more stable than ㈏ due to steric hindrance.

○ When the C-X bond is weak (e.g., X = I, OTs): Follows path ⒝. The intermediate of the multi-substituted alkene is more stable due to thermodynamics.

② Stereoselective Reaction: Selective in terms of stereochemistry for a single reactant

Figure 18. E2 Elimination Reaction and Stereoselective Reaction

○ Particularly, when there are two beta hydrogens, stereoselective reactions can occur.

○ Example: trans alkene as the major product, cis alkene as the minor product.

③ Stereospecific Reaction

Figure 19. anti-Periplanar Rule in E2 Reaction (X and Ha are departing in the reaction)

○ Periplanar arrangement: Geometric arrangement with four atoms in the same plane.

○ Case 1: anti-addition

○ anti-periplanar arrangement: C-H and C-L(L: leaving group) have a 0° dihedral angle in the periplanar arrangement.

○ In this case, the anti-periplanar arrangement means that H and X atoms are arranged on opposite sides of the molecule.

○ When the leaving group and acidic hydrogen have a 180° dihedral angle (anti), E2 elimination reaction can occur.

○ anti-periplanar arrangement is a staggered conformation, thus anti-addition occurs frequently.

○ Dihedral angles between 175-179° are sufficient for anti -addition.

○ E2 reaction of cyclohexane halides: The major product is when the anti-addition occurs with chair-form.

○ Case 2: syn-addition

○ syn-periplanar arrangement: C-H and C-L(L: leaving group) have a 0° dihedral angle in the periplanar arrangement.

○ In this case, the syn-periplanar arrangement means that H and X atoms are arranged on the same side of the molecule.

○ When the leaving group and acidic hydrogen have a 0° dihedral angle (eclipsed), E2 elimination reaction can occur.

○ syn-periplanar arrangement is an eclipsed conformation, thus syn-addition doesn’t occur frequently.

○ E2 elimination reactions related to cyclopentane mostly follow syn-addition.

○ Caution

○ anti-periplanar rule takes precedence over Saytzeff’s rule.

○ Complex problems involve the application of stereospecific reactions in nine out of ten cases.

⑹ Reaction Rate Factors

① Substrate: Reaction rate increases as the degree of the substrate increases (∵ Zaitsev’s rule).

○ CH₃-X ＜ 1° RX ＜ 2° RX ＜ 3° RX

○ Reason: Transition state involves partial secondary bonding, stabilizing the transition state with increased substituents through hyperconjugation.

Figure 20. Transition State with Partial Secondary Bonding in E2 Reaction

② Nucleophile: Reaction rate increases with higher nucleophilicity.

③ Solvent

○ Rate comparison: Polar protic solvent ＜ Nonpolar solvent ＜ Polar aprotic solvent

○ Polar positive solvents stabilize nucleophiles and decrease reaction rates.

④ Leaving Group: Reaction rate increases with more stable leaving groups.

⑤ Deuterium Substitution

○ Assume that deuterium is heavier, making it less likely to dissociate a carbon-deuterium bond.

○ Since hydrogen elimination is the rate-determining step (RDS) for E2 reactions, the presence of deuteriums slows down the E2 reaction rate.

⑥ In cases where E2 reaction conditions and -OH groups coexist in a molecule, H⁺ elimination by strong bases from -OH takes precedence.

○ Reason: Terminal acid-base reactions are very fast reactions.

6. E1 Reaction

⑴ Overview

① Unimolecular Elimination

② Break the molecule into parts since it’s first-order, forming a carbocation

⑵ Reaction Kinetics

⑶ Mechanism: Two-step reaction, the formation of a carbocation in the first step is the rate-determining step.

Figure 21. Mechanism of E1 Reaction

① Formation of a carbocation: A kind of solvolysis reaction

○ Rate-determining step: Formation of a carbocation in the first step

② If H₂O acts as a strong base and attaches to C+, the reaction becomes S_N1 reaction in the mechanism.

③ S_N1 and E1 reactions occur competitively under similar conditions, always in competition.

⑷ Stereochemistry

① E1 reactions also follow Zaitsev’s rule like E2 reactions.

② Due to the involvement of carbocation intermediates, rearrangement reactions to more stable carbocation can occur.

⑸ Reaction Rate Factors

① Substrate

○ 3° benzyl ≃ 3° allyl ＞ 2° benzyl ≃ 2° allyl ≃ 3° alkyl ＞ 1° benzyl ≃ 1° allyl ≃ 2° alkyl ＞ 1° alkyl ＞ methyl ＞ vinyl carbocations

○ Influenced by the stability of intermediate carbocations

○ Reaction that forms carbocation is the rate-determining step (rate-determining step)

○ Carbocation stabilizes with more substituents

○ Energy difference in transition states is smaller than the energy difference in intermediate carbocations.

② Solvent

○ Reaction rate significantly influenced by the extent of carbocation stabilization.

○ Nonpolar solvent ＜ Polar aprotic solvent ＜ Polar protic solvent

7. E1cB Reaction

⑴ Overview

① Definition: Elimination reaction occurring when the substrate is β-halo carbonyl or β-hydroxy carbonyl.

② unimolecular elimination conjugate base

③ Condition 1: Presence of acidic hydrogen.

④ Condition 2: Presence of poor leaving group.

⑵ Mechanism

① Step 1: Strong base removes acidic hydrogen.

② Step 2: Hydrogen removal leads to resonance with ketone, forming an oxygen anion.

③ Step 3: Resonance of the oxygen anion leads to the departure of the leaving group and formation of a double bond.

⑶ Carbonyl α-Reaction

8. Bredt’s Rule

⑴ Bredt’s Rule

① Rule

○ ** In bridged bicyclic compounds, double bonds (π-bonds) cannot be present at bridgehead carbons.

○ Bridgehead carbons in bridged bicyclic compounds cannot be carbocations.

② Reason

○ Sterically hindered trigonal planar geometry of sp² cannot form due to structural constraints.

○ Three carbons linked to the bridgehead carbon cannot lie in the same plane, preventing p-orbital overlap and making a trigonal planar arrangement unstable.

③ Application

○ S_N2 reactions on bridgehead carbons are impossible: Backside attack is impossible.

○ S_N1 reactions on bridgehead carbons are impossible: Carbocation formation is impossible.

○ E2 and E1 reactions on bridgehead carbons are impossible: Formation of double bonds is impossible.

○ For other carbons, S_N2, S_N1, E2, and E1 reactions are possible.

○ In the case of E2 elimination reactions occurring in other carbons, the anti elimination reaction is not favored, but rather the syn elimination reaction.

Figure 22. When bridgehead carbon becomes a carbocation (impossible)

⑵ Anti-Bredt’s rule

① Rule

○ When a ring with 8 or more carbons is present, Bredt’s rule cannot be applied.

○ Example 1: bicyclo[3.3.1]non-1-ene: The smallest compound where double bonds can form on bridgehead carbons under normal conditions.

② Reason

○ In cycloalkenes, starting from an 8-membered ring, trans can exist.

③ Application

○ S_N2 reactions are still impossible ( ∵ backside attack is impossible).

○ S_N1, E2, and E1 reactions can occur.

⑶ Grignard reactions can occur even when Bredt’s rule is applicable.

① Reason: Because bridgehead carbons become sp3 carbon cations.

9. S_N2 Reaction vs S_N1 Reaction

⑴ 1^st step reaction vs 2^nd step reaction

⑵ Bimolecular reaction vs Unimolecular reaction

⑶ Substrate

① S_N2 Reaction: Reaction rate increases as steric hindrance decreases. Methyl group > 1° > 2°

○ Reaction does not occur with 3° carbons.

○ Exception: In the case of neopentyl bromide, due to steric hindrance, although it’s 1°, the reaction is about 500 times slower than 2°.

② S_N1 Reaction: Reaction rate increases as carbocation stability increases. 3° > 2°

○ Reaction does not occur with methyl and 1° carbons.

⑷ Nucleophile

① S_N2 Reaction: Strong nucleophiles are favored.

② S_N1 Reaction: Nucleophilicity does not significantly affect reaction rate. Mild nucleophiles are used to increase reaction selectivity.

⑸ Stereochchemistry

① S_N2 Reaction: Inversion of configuration.

② S_N1 Reaction: Both inversion and retention of configuration occur simultaneously, leading to racemization.

10. Comparison of S_N2, E2, S_N1/E1 Reactions

⑴ Determining Mechanism

Table. 1. Method of Mechanism Determination ​ E1cB reaction is similar in nature to E2 elimination.

① Very weak base: H₂O, ROH, etc.

② Weak base: X^-, SR^-, CN^-, N₃^-, RCO₂^-, NR₃, PR₃, etc.

○ S_N2 reactions dominate with 2° RX.

○ Neutral nucleophiles (e.g., NR₃, PR₃) are weak bases, but ammonia and amines are classified as strong nucleophiles.

③ Strong base + Steric hindrance ×: OH^-, RO^-, NH₂^-, etc.

④ Strong base + Steric hindrance ○: LDA, DBN, DBU, t-BuO^-

○ E2 reactions dominate with 1° RX.

○ DBN (1,5-diazabicyclo[4.3.0]non-5-ene)

○ DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)

⑵ Solvent

⑶ Substrate

① 1° RX primarily undergo S_N2 reactions, but if the substrate has severe steric hindrance or a non-nucleophilic strong base is present, E2 reactions occur.

② 2° RX competitively undergo S_N2 and E2 reactions.

○ When the pK_a of the leaving group is below 12, S_N2 products are major products. However, clear distinction is not always possible.

○ When the pK_a of the leaving group is above 12, E2 products are major products. However, clear distinction is not always possible.

③ 2° RX forms products through all mechanisms, so the strength of the nucleophile (or base) should be considered.

○ 2-bromoheptane + NaOCH₃ + CH₃OH: Strong nucleophile is present. Therefore, S_N2 and E2 reactions occur.

○ 2-bromoheptane + CH₃OH + heat(Δ): Reaction conditions favor solvent reaction conditions. Therefore, S_N1/E1 reactions occur.

④ 3° RX undergo E2 reactions under strong base conditions, and S_N1/E1 reactions under mild base conditions.

⑷ Nucleophile

① Neutral nucleophiles like ammonia and amines perform S_N2 or E2 reactions.

② Preferred nucleophiles for S_N2: X^-, SR^-, CN^- ( Important ), RCO₂^- ( Important ), NH₃, Et₃N

③ Preferred bases for E2: OH^- ( Important ), RO^-, NH₂^- ( Important ), LDA, DBN, DBU, t-BuOK( Important )

○ Zaitsev’s rule (Saytzeff’s rule): Thermodynamically stable alkene is obtained.

○ Hofmann rule: Kinetically favored product is obtained.

○ Preferred bases for Zaitsev’s rule: OH^-, MeO^-, EtO^-

○ Preferred bases for Hofmann rule: t-BuOK, LHMDS, LDA, DBN, DBU, or sterically hindered bases

⑸ Other

① S_N1 and E1 reactions both involve carbocation intermediates, resulting in a mixture of substitution and elimination products.

○ Generally, S_N1 is more dominant than E1.

○ Example: tert -Bu-Br + EtOH yields 81% S_N1 product and 19% E1 product.

② Substitution reactions are favored with mild bases, while elimination reactions are favored with strong bases.

③ As temperature increases, E1 elimination reactions are favored, and as temperature decreases, S_N1 substitution reactions are favored.

○ ΔG = ΔH - TΔS, as temperature increases, the entropy factor is enhanced, favoring elimination reactions.

○ S_N1 Substitution Reaction

○ Carbocation intermediate + :Nu^- → Product

○ 2 reactants, 1 product

○ Δn = -1, entropy decreases

○ E1 Elimination Reaction

○ Carbocation intermediate + :B → Product + HB⁺

○ 2 reactants, 2 products

○ Δn = 0, negligible change in entropy

○ Considering temperature for determining major product in S_N1/E1 reactions is rare.

④ AgNO₃ conditions: Removes the eliminated halide.

○ Effect 1: Increases S_N1 reaction rate.

○ Effect 2: 1° RX also follows S_N1 mechanism.

11. Carbon-Carbon Coupling Reactions

⑴ Grignard Reagents: RMgX (e.g., H₃C-MgX)

① Preparation: R-X + Mg (solvent: anhydrous ether or anhydrous THF) → R-MgX

② (Mechanism) Mg becomes δ⁺ in RMgX, and R has a strong negative charge. Find electrophilic carbon starting from R and connect.

Figure 23. Example of Grignard reagent reaction with an ester

③ Reacts with: Ketones, Aldehydes, Acyl Chlorides, Acid Anhydrides, Esters, Phosgene

④ Does not react with: Carboxylic Acids

⑵ Alkyl Lithium Reagents: RLi (e.g., H₃C-Li)

① Preparation: R-X + 2Li (solvent: anhydrous ether) → R-Li + Li-X

② (Mechanism) Li becomes δ⁺ in RLi, and R has a strong negative charge. Find electrophilic carbon starting from R.

③ Reacts with: Ketones, Aldehydes, Carboxylic Acids

⑶ Gilman Reagents: R₂CuLi (e.g., (H₃C)₂CuLi)

① Preparation: 2RLi + CuI (solvent: anhydrous ether) → R₂CuLi + LiS(s) ↓

② (Mechanism) CuLi becomes δ⁺ in R₂CuLi, and R has a strong negative charge. Connect only one R starting from R₂CuLi.

③ Reacts with: Alkyl Halide (S_N2), Enone (Michael Addition), Acyl Chlorides

④ Does not react with: Ketons, Aldehydes

⑷ Summary

① Alkyl groups in organic reagents are δ^-

② The δ- part of the molecule attaches to electrophilic carbon.

12. Synthesis Methods

⑴ Methods via Addition of HX to Alkenes

⑵ Methods via Addition of X₂ to Alkenes for vic -dihalides

⑶ Methods via Addition of HX to Alkynes for gem -dihalides

⑷ Methods via Addition of X₂ to Alkynes for tetrahalides

⑸ Alkane Radical Substitution Reactions

⑹ Allylic Radical Halogenation Reactions

⑺ Benzylic Radical Halogenation Reactions

⑻ Substitution Reactions of Alcohols with HX

⑼ Substitution Reactions of Alcohols with SOCl₂, PBr₃, etc.

⑽ Decomposition Reactions of Ethers with HX

Input: 2019.01.10 15:12

Modified: 2022.02.01 16:36