CHEM 2021: Introductory Organic Chemistry II Chapter 10 Synthesis Using Aromatic Materials PDF

CHEM 2021: INTRODUCTORY ORGANIC CHEMISTRY II Winter 2024 – York University Dr. Lana Hébert  CHAPTER 10 Synthesis Using Aromatic Materials Aromatic Compounds Are Everywhere! Many biomolecules have aromatic rings Aromatic materials are an area of active researc...

CHEM 2021: INTRODUCTORY ORGANIC CHEMISTRY II Winter 2024 – York University Dr. Lana Hébert  CHAPTER 10 Synthesis Using Aromatic Materials Aromatic Compounds Are Everywhere! Many biomolecules have aromatic rings Aromatic materials are an area of active research (2.2)paracyclophane coronene Hexa-peri- hexabenzocoronene Hexa-cata- hexabenzocoronene Many have unique and exciting uses! 3 I’ve made A LOT of Aromatic Compounds! 4 Learning Objectives ❖ Discern and draw the expected products and mechanism for the following electrophilic aromatic substitution (SEAr or EAS) reactions of aromatic rings: Halogenation, nitration, sulfonation, Friedel-Crafts alkylation and acylation ❖ Classify substituents as either ortho/para- or meta-directing and determine whether they will activate or deactivate the ring ❖ Use directing groups to predict the products of electrophilic aromatic substitution on monosubstituted and polysubstituted benzenes ❖ Propose methods to modify the reactivity of strongly activating substituents to help control electrophilic aromatic substitution reactions ❖ Design short syntheses of small aromatic compounds using retrosynthetic analysis 5 π-Bonds Acting as Nucleophiles As described in Chapter 8, the π bond of an alkene can act as a nucleophile: RECALL: RECALL (from Ch. 8): 6 π-Bonds Acting as Nucleophiles When benzene is mixed with bromine in the absence of a catalyst, no reaction happens: Addition of a catalyst can induce reactivity: 7 Electrophilic Aromatic Substitution (EAS or SeAr) All electrophilic aromatic substitution (SEAr or EAS) reactions proceed by a general two-step mechanism: 1. addition of an electrophile (Chapter 8) 2. elimination (explained in detail in Chapter 12) 8 Electrophilic Aromatic Substitution The elimination (second step) restores aromaticity. This drives the reaction toward substitution instead of addition (i.e., nucleophilic attack) 9 Bromination of Veratrole 10 Electrophilic Aromatic Substitution Compare the Gibbs free energies of activation (∆G1‡ and ∆G2‡) for each transition state 11 Halogenation of Aromatics: X2 + Lewis Acid Aromatic rings can be halogenated with bromine or chlorine using a Lewis acid catalyst. The Lewis Acid generates the active electrophile e.g., activation of Br2 by FeBr3 creates highly reactive species (FeBr5) that reacts like Br+ 12 Halogenation of Aromatics: X2 + Lewis Acid The activated, now highly electrophilic halogen reacts with the aromatic ring to form the arenium ion intermediate. 13 Halogenation of Aromatics: X2 + Lewis Acid The halogen present in the Lewis acid most often matches the halogen being substituted in the ring. Molecular Catalyst Reactive Species Reacts Like… Halogen Cl2 FeCl3 or AlCl3 FeCl5 or AlCl5 Cl+ Br2 FeBr3 or AlBr3 FeBr5 or AlBr5 Br+ Fluorine (F2) is reactive enough that no catalyst is needed, although this reaction is not a practical lab procedure hard to handle and control reactivity Iodine (I2) requires an oxidant to generate I+ (like HNO3 or CuCl2) 14  Worked Example Draw a mechanism for the following reaction and show the final product: Nitration of Aromatics: HNO3 + H2SO4 Replacement of an hydrogen atom with a nitro group (–NO2) via SEAr. Overall Reaction: The active electrophile in this reaction is the nitronium ion (NO2+), which is generated by dehydration of HNO3 with H2SO4 16 Nitration of Aromatics: Mechanism Reduction of nitro-substituted aromatics under ‘dissolving metal conditions’ provides a route to aromatic amines, aka anilines (mechanistic details not required) 17  Worked Example Draw a mechanism for the following reaction and show the final product: Sulfonation of Aromatics: H2SO4 (+ SO3) A hydrogen on the aromatic ring is replaced by a sulfonic acid group (–SO3H). ❖ The combination of SO3/H2SO4 is called “fuming sulfuric acid”. ❖ The active electrophile is likely SO3H+ 19 Sulfonation of Aromatics: H2SO4 (+ SO3) Mechanism of formation of SO3H+ from SO3 and H2SO4: Mechanism of sulfonation: 20 De-Sulfonation Of Aromatics Sulfonation can be reversed using a strong acid in water. Because sulfonation is reversible, Ar–SO3H can be used as a temporary directing group (not so important for CHEM 2021) 21 Friedel-crafts Alkylation: Alkyl Halide + AlCl3 Friedel-Crafts Alkylation: a type of SEAr for adding alkyl groups to aromatic rings. AlCl3 is a Lewis acid catalyst used to form a carbocation as the reactive electrophile: 22 Friedel-Crafts Alkylation: Alkyl Halide + AlCl3 Friedel–Crafts alkylation mechanism: 23  Class Question Based on what you know from CHEM 2020 about carbocation stability, what types of alkyl halides would be most suitable for Friedel-Crafts alkylations? A) 3° alkyl halides C) 1° alkyl halides B) 2° alkyl halides D) I don’t know Friedel-Crafts: Carbocation Rearrangements Carbocations tend to rearrange via an alkyl or hydride shift, if a more stable carbocation is accessible. This often leads to product mixtures (less useful). RECALL: Relative stabilities of carbocations 25  Worked Example Provide a mechanism for the formation of the major and minor products: Alternative Conditions for Alkylation Alternative way to alkylate a benzene rings involves the use of an alkene and a strong acid, such as HF or H2SO4 Acid protonates the alkene to form a carbocation (the active electrophilic species) that then reacts with the aromatic ring in the usual SEAr mechanism 27 Friedel-Crafts Acylation: Acyl chloride + AlCl3 Very similar to Friedel–Crafts alkylation but adds an acyl group instead. This involves the formation of an acylium ion (the active electrophilic species) 28  Worked Example Draw a mechanism for the following reaction and show the final product: Friedel-Crafts Acylation: Variations Friedel–Crafts acylation can also use an anhydride instead of acid chloride: It cannot produce aromatic aldehydes: 30 Friedel-Crafts Acylation: Variations Gatterman–Koch reaction: synthesis of aromatic aldehydes: Mechanism: 31 Directing Groups in EAS Existing substituents affect the outcome of SEAr reactions with respect to: Reaction Rate is the reaction slower or faster due to the substituent? as compared to the unsubstituted aromatic (i.e., benzene) Regioselectivity Is the new substituent ortho, meta, or para to the original substituent? 32 Directing Groups in EAS Aromatic substituents are classified according to particular properties: Activating Groups vs. Deactivating Groups refers to reaction rates Activating = faster reaction than benzene Deactivating = slower reaction than benzene 33 Directing Groups in EAS 2. Directing Groups: Ortho/para vs. meta directors refers to regioselectivity Ortho/para directors: favour the formation of both ortho and para regioisomers Meta directors: favour the formation of the meta regioisomer 34  Class Question Based on the Hammond postulate, the first transition state structure should most closely resemble… A) Starting materials B) Arenium ion C) The second transition state D) Products E) I don’t know Impact of Directing Groups on Reaction Rate Generally: Electron-donating groups stabilize the arenium ion, making the reaction faster and are therefore considered activating groups Electron-withdrawing groups destabilize the arenium ion, making the reaction slower and are therefore considered deactivating groups 36 Activating Ortho/Para Directing Groups Electron-donating groups are activating They also tend to direct regioselectivity toward ortho and/or para products. Observed regioselectivity is governed by the lowest energy pathway 37 Strongly Activating Directing Groups: ortho/para Directors i) Strongly activating ortho/para directors contain heteroatoms with lone pairs 38 Activating Groups: Ortho Substitution Mechanism Ortho substitution leads to an arenium ion intermediate that can be stabilized by resonance with the heteroatom lone pair 39 Activating Groups: Para Substitution Mechanism Para substitution also leads to an arenium ion intermediate that can be stabilized by resonance with the heteroatom lone pair 40 Activating Groups: meta-Substitution Disfavoured However, if initial addition occurs at the meta position, the lone pair cannot stabilize arenium Meta substitution leads to a less stable arenium ion intermediate fewer resonance contributors → less resonance stabilization → higher energy pathway! 41 Moderately Activating Directing Groups ii) Moderately activating ortho/para directors contain a heteroatom that is engaged in cross-conjugation (i.e., lone pair delocalized into a different π-system) 42 Weakly Activating Directing Groups iii) Weakly activating ortho/para directors Consist of electron-rich groups that do not have a lone pair that can delocalize into the benzene ring Alkyl groups Can only donate electron-density through σ-bonds (inductive effects), therefore considered weak donors 43 Activating Ortho/Para Directing Groups b) Aromatic Rings Aromatic group can stabilize the arenium ion through resonance, but this is not a favourable process due to loss of aromaticity and increased steric strain 44 Deactivating Ortho/Para Directing Groups Halogens are deactivating → electronegative, withdraw electron-density by induction Halogens are ortho/para directors have lone pairs that can donate into the ring Resonance effect is weak poor orbital overlap between 2p ring orbitals and lone pair p orbitals for Cl and Br 45 Deactivating Meta Directing Groups Electron-withdrawing groups typically: deactivate an aromatic ring toward EAS favor meta regioisomer With an EWG present, pathways involving ortho/para substitution lead to a less stable arenium ion because one resonance form has the positive charge next to an EWG 46 Deactivating Meta Directing Groups 47 Deactivating Meta Directing Groups These groups usually contain polar π bonds connected to electronegative atoms and conjugated to the ring In this course we will not distinguish between “moderate” and “strong” deactivators (all meta directors will be considered strong deactivators) 48  Class Question Which compound would react the fastest in an electrophilic aromatic substitution reaction? Summary of Directing Group Effects in EAS Note: Special conditions may need to be applied for strongly activating groups, such as anilines and phenols 50 Limitations of EAS Reactions 1. Strongly activating groups (-OH, -NH2) will often lead to poly-substituted products Another example: phenol + Br2 immediately gives 2,4,6-tribromophenol even without a catalyst 51 Limitations of EAS Reactions 2. NH2 groups can be protonated under strongly acidic conditions Becomes an EWG instead of EDG due to positive charge on nitrogen 52 Limitations of EAS Reactions Anilines should be temporarily converted to amides to conduct EAS reactions → reduces polyfunctionalization and forces o/p-selectivity 53  Worked Example Phenols can be temporarily converted to esters to reduce chances of poly- substitution Limitations specific to Friedel-Crafts Reactions 1. A Friedel-Crafts reaction will not occur if a meta-directing deactivator is present on the ring. Carbocations are not electrophilic enough to react with deactivated rings. e.g., NO2 is a strong EWG e.g., NH2 is Lewis basic and will react with Lewis acid to form an EWG (can be solved by conversion to amide group) 55 Limitations specific to Friedel-Crafts Reactions 2. Possible carbocation rearrangements (see slides 19-21) 3. Overalkylation can occur in Friedel-Crafts alkylations since electron-donating groups often make the product more reactive towards additional EAS reactions 56 Limitations specific to Friedel-Crafts Reactions To synthesize an equivalent alkyl benzene product, use two-step procedure: (1) Friedel-Crafts acylation; (2) reduction of ketone to alkane Either Clemmenson (Zn/HCl) or Wolff-Kischner (NH2NH2/KOH) conditions can be used Why are we not worried about poly-acylation here? 57 Strength of activation on polysubstituted benzenes When multiple substituents are present, the collective effects of directing groups must be considered. Directing effects reinforce each other Directing effects oppose each other 58 Strength of activation on polysubstituted benzenes When comparing two opposing activating (or deactivating) groups, the stronger one will direct the regiochemistry Activating groups will more strongly direct the regiochemistry compared to deactivating groups If there is >1 site of reactivity, the reaction will preferentially take place at the less sterically crowded position. 59  Class Question Pick the major product that would form in the following reaction. Retrosynthetic Analysis in Aromatic Synthesis Synthesis: assembling new substances by reacting different molecules to combine in a controlled manner Retrosynthesis: ▪ technique for planning synthesis in which the target is analyzed in reverse ▪ What could the target be made from? ▪ What could that compound be made from? etc. Disconnection: a retrosynthetic step, an imaginary “reverse” reaction 61 Retrosynthetic Analysis in Aromatic Synthesis Retrosyntheses for p-nitroisopropylbenzene: Forward synthesis: 62 Using Synthons in Retrosynthetic Analysis Synthon: ▪ an imaginary component that captures the overall reactivity pattern of a series of compounds 63 Order of Synthetic Operations Often, the order you perform the EAS reactions is important depending on the desired product When performing a synthesis, you can assume o/p products can be separated easily Provide a synthesis of the following aromatic compound: 64 Worked Example Worked Example  Class Question How would you perform the following synthesis? A) 1. Br2 , FeBr3 2. HNO3, H2SO4 C) 1. HNO3, H2O 2. Br2 , HBr B) 1. HNO3, H2SO4 2. Br2 , FeBr3 D) 1. HBr 2. HNO3, H2SO4 Worked Example  Worked Example Synthesise the below compound using only benzene as your source of aromatic carbons.  Summary Know the reactions! Halogenation, nitration, sulfonation, de-sulfonation Friedel-Crafts alkylation Friedel-Crafts acylation Esterification/Amidation (protecting phenols/anilines) Ester hydrolysis/Amide hydrolysis Recognize the similarities between the mechanisms Know the directing abilities of the different substituents! Better to understand, rather than purely memorize Practice, practice, practice! 70 Patterns in EAS Reactions General reaction mechanism for EAS: The only difference between the mechanisms is how E+ is generated and the identity of the base! In General: electron-donating groups are activating and ortho/para-directing electron-withdrawing groups are deactivating and meta-directing, Halogens are the exception, and are ortho/para-directing 71 Patterns in Electrophilic Aromatic Substitution Reactions Reaction Recap 73