Professor notes (CH13, 14, 15, 11, 12, 16, and 17

Chapter 13: Conjugated Unsaturated Systems

• Professor Trevor G. Bolduc

• MSE 0116

• On the traditional, ancestral, and unceded territory of the Cahuilla, Luiseño, Serrano, and Tongva peoples.

Chapter 13: Learning Objectives

• By the end of this chapter, you will be able to:

  • Use retrosynthetic analysis to “think backwards” and plan out a multistep synthesis over two to four steps

  • Rationalize the stability of allylic radicals and allylic cations using resonance and MO theory arguments

  • Recognize conjugated dienes and draw the conformations of a diene

  • Draw the MO diagram of a conjugated diene and identify the HOMO and LUMO

  • Rationalize the product(s) that form from electrophilic addition reactions to conjugated dienes, and draw an arrow-pushing mechanism that shows how the reaction occurs

  • Differentiate between kinetic and thermodynamic control in a reaction and use reaction conditions to predict the product of an electrophilic addition reaction to conjugated dienes

  • Draw the mechanism of the Diels-Alder reaction, using MO, polarity, and steric arguments to rationalize the formation of an endo- or exo-product, as well as stereochemical and regiochemical outcomes

Retrosynthetic Analysis and Multistep Synthesis

• Retrosynthetic Analysis (Chapter 7.18)

• Multistep Synthesis (Ch. 8.20)

Retrosynthetic Analysis: Thinking Backwards

• Retrosynthetic analysis is what you do when you look at a chemical compound, and you envision what reaction(s) could have been performed to form it. In other words, what were the precursors?

  • Compound E: final product

  • Compound D: first synthetic intermediate, made from C

  • Compound C: next synthetic intermediate, made from B

  • Compound B: first synthetic intermediate, made from A

  • Compound A: commercially available starting material

• Retrosynthesis direction (thinking backwards THEMATICALLY)

• Forward synthesis direction (accomplishing each step of the retrosynthesis with ACTUAL REAGENTS AND CONDITIONS)

Retrosynthetic Analysis: Why Do It?

• We do retrosynthetic analysis to create newer, more efficient, safer, more effective, and overall better methods to synthesize known chemical compounds (particularly complex ones).

• We do retrosynthetic analysis to create brand new methods to synthesize chemical compounds that have otherwise never been synthesized before (particularly complex ones).

• Examples:

  • Naloxone (opioid overdose treatment)

  • Phenacetin (FDA-banned former analgesic)

Retrosynthetic Analysis: General Considerations

• Construction of the carbon skeleton (making C–C single bonds)

• Functional group interconversions (FGI)

• Regiochemical control

• Stereochemical control

Retrosynthetic Analysis: “How To” Multistep Synthesis

• Look at the product and identify “disconnections” (find the differences between product and original starting material—which bonds FORMED? Which bonds BROKE?)

• Mark these by “cutting through” the bond you want to “disconnect”

• The thematic fragments you can “stitch together” to form a product are called synthons

• Synthons are not necessarily real chemicals (i.e. you cannot always buy a proposed synthon, but you can buy a real chemical that behaves like the synthon)

• Can you buy a carbocation? No. But you can buy an alkyl halide.

• We call the “real chemical versions” of a synthon, “synthetic equivalents”

Retrosynthetic Analysis: Examples

• Use retrosynthesis to identify a reasonable (and short) synthetic route to achieve the desired multistep syntheses.

• Super important note! If any of these reactions feel unfamiliar to you, you must review your Chem 008A reactions now (TONIGHT)! We are going to use ALL those reactions A LOT in Chem 008B/008C! Weak foundational skills from Chem 008A make Chem 008B/008C unnecessarily difficult.

Retrosynthetic Analysis: More Examples (Homework)

*Use retrosynthesis to identify a reasonable (and short) synthetic route to achieve the desired multistep syntheses.
*Super important note! If any of these reactions feel unfamiliar to you, you must review your Chem 008A reactions now (TONIGHT)! We are going to use ALL those reactions A LOT in Chem 008B/008C! Weak foundational skills from Chem 008A make Chem 008B/008C unnecessarily difficult.

Conjugation in Organic Chemistry

• Conjugation describes an atom with a p-orbital (filled or not) next to a $π$-bond. The p-orbital can be part of another $π$-bond.

  • Allylic (charge/radical on the next atom away from the $π$-bond)

  • Benzylic (like allylic, but the $π$-bond is part of a “benzene” core)

  • Vinylic (charge/radical on the $π$-bond, itself)

Allylic Radicals: MO Theory and Resonance

• Allylic radicals are stabilized by electron delocalization with the adjacent $π$-bond

• Result is that allyl radicals are more stable than 1°, 2°, and 3° radicals

• Can show this delocalization using molecular orbitals:

  • Proves that all three carbons are $sp^2$-hybridized

• …and also with resonance:

  • $Sp^2$-character for both terminal carbons further proves that all three carbons are $sp^2$-hybridized

Allylic Cations: MO Theory and Resonance

• Allylic cations are stabilized by electron delocalization with the adjacent $π$-bond

• Result is that substituted allylic carbocations are more stable than 1°, 2°, and 3° carbocations

• Can show this delocalization using molecular orbitals:

  • Proves that all three carbons are $sp^2$-hybridized

• …and also with resonance:

  • $Sp^2$-character for both terminal carbons further proves that all three carbons are $sp^2$-hybridized

Resonance: The Rules (Revisited, Review from Chem 8A)

• What we already know:

  • Resonance structures are a human-made concept and are only a model to help us rationalize chemical properties and behavior (i.e., they do not exist)

  • The hybrid of all resonance structures is the only true representation of a molecule. No single resonance structure can accurately describe a molecule on its own.

  • We can only move electrons that are part of a $π$-system (lone pairs, radicals, double bonds), never electrons in a $σ$-bond (never break/form a single bond), and we can never move an atom.

  • Must be a valid Lewis structure (i.e., no Texas carbons) and the sum of any formal charges must always be the same between structures

Resonance: The Rules (New-ish)

• New rules:

  • All resonance structures must have the same number of unpaired electrons

  • For resonance to occur, the p-orbitals of all atoms that are in resonance must be conjugated and co-planar (0° or 180° dihedral angle), otherwise the p-orbitals are misaligned, and conjugation/resonance is broken

  • Energy of the hybrid is lower than the energy of any single resonance structure

  • Equally “good” resonance structures make equal contributions to the overall hybrid, leading to significant stabilization

  • When one resonance structure is “more stable” than another, it contributes more to the hybrid

Resonance: General Guidelines (Review from Chem 8A)

• Some resonance structures are “better” and “contribute more” to the resonance hybrid than others.

• Maximize bonding interactions and satisfy the Octet “Rule” (full valence) wherever possible

  • Particularly for 2nd row elements

• Minimize charges whenever possible

  • Positive/negative charges on carbon are (generally) not as desirable as neutral charges on carbon

• If you must draw a formal charge:

  • Generally, avoid charge-separation (positive charge on one atom, and a negative charge on the atom next to it), especially for C=C bonds

  • Localize the negative charge on the more electronegative atom

  • Localize the positive charge on the more electropositive atom

Polyunsaturated Hydrocarbons

• Dienes (“two alkenes”):

• Trienes (“three alkenes”):

• Cumulated double-bonds:

• Conjugated double-bonds:

• Isolated double-bonds:

1,3-Butadiene: Conformational Analysis

• 1,3-Butadiene is a conjugated diene and it can adopt two possible conformations while the double bonds are conjugated and delocalized (s-cis and s-trans)

• These conformations are interconvertible, so this is not a cis/trans relationship

• In the Diels-Alder Cycloaddition* (introduced later in this slide deck), we will learn that only the s-cis conformation can undergo the reaction (the s-trans conformation cannot react)

  • *This reaction and the concepts are covered later in this slide deck. For more information on the impact of diene conformational considerations on the reaction, please see the Diels-Alder slides.

1,3-Butadiene: Molecular Orbital (MO) Diagram

• Highest-occupied molecular orbital (HOMO): the MO with the highest energy that contains electrons. Hypothetically nucleophilic (able to donate electron density to a LUMO*).

• Lowest-unoccupied molecular orbital (LUMO): the MO with the lowest energy that contains NO electrons. Hypothetically electrophilic (able to receive electron density from a HOMO*).

• The themes of this analysis work for any length of conjugated poly-ene (poly alkene)

  • *Usually a LUMO or HOMO from a different molecule, except for intramolecular reactions.

Electrophilic Addition to Conjugated Unsaturated Systems

• Sueme chemistry from Chem &A Ch. 8 (Additions to Alkenes)

Conjugated Dienes: 1,2- Versus 1,4-Addition

• Addition of HCl or HBr to a conjugated diene has two possible reaction products, due to the formation of an intermediate allylic cation that is stabilized through resonance:
  *Addition of Br2 to a conjugated diene has a similar reaction outcome:

• But how to know which is the major product in each case?

  • Recall from Chem 008A: addition of HCl or HBr to an alkene proceeds via a Markovnikov mechanism (“hydrogen goes with its buddies” and “form the more stable carbocation”).

Conjugated Dienes: Kinetic and Thermodynamic Control

• Reaction temperature may sometimes be used to favor the formation of one product over another.

• A product favoured at lower temperatures (irreversible conditions), is called a kinetic product (faster formed) and the reaction is under kinetic control

• A product favoured at higher temperatures (reversible equilibrium conditions), is called a thermodynamic product (more stable) and the reaction is under thermodynamic control

• 1,2- and 1,4-addition to conjugated dienes can be controlled by the reaction temperature (which product is the more stable one?)

• Transition states ($G^ eq$) of kinetic and thermodynamic:

  • Note that the 1,2-product of any other diene is not always going to be the kinetic one, nor the 1,4-product the thermodynamic. That gets into more complex material than we will cover in our class, but if you would like to know more, please click on this post from Mastering Organic Chemistry. I am happy to explain this in office hours.

Practice: 1,2- Versus 1,4-Addition to Conjugated Dienes

• On your own (~2 min): predict the product(s) of the following reactions. If more than one forms, identify which product is the major product.

• With your neighbour (1–2 min): compare your answers and discuss any differences (politely convince the other person why you are right, if you think you are).

• As a class (1–2 min): We will discuss the strategy to approach this question.

Pericyclic Reactions

• Pericyclic reactions are concerted processes that take place in a single step through a cyclic transition state

• Concerted reactions are those wherein all bond-forming and bond-breaking processes happen simultaneously (i.e., draw all your curved arrows at once)

• Three main types of pericyclic reactions

  • Cycloadditions (Chem 008B)

  • Sigmatropic rearrangements (advanced)

  • Electrocyclic reactions (advanced)

The Diels-Alder Reaction: A [4+2] Cycloaddition

*The reaction of a diene (has $4π$ electrons) and a dienophile (has $2π$ electrons) in a pericyclic reaction is called the Diels-Alder reaction (Nobel Prize in 1950, one of the most powerful and useful reactions in organic chemistry)—a new way to make multiple C–C bonds at once!

• Diene (conjugated di-alkene)

  • Typically electron-rich, EDG (normal-demand D.A.)

  • Can be electron-poor, EWG (inverse-demand D.A.*)

• Dienophile (“diene-loving”, single alkene OR single alkyne)

  • Typically electron-poor, EWG (normal-demand D.A.)

  • Can be electron-rich, EDG (inverse-demand D.A.*)

  • *Beyond the scope of this course. I will not ask you a question on this, nor will we learn about it.
    Keyword: the product of a D.A. reaction is called an “adduct” as it is the addition of two molecules together without any loss of atoms (100% perfect atom economy)

Diels-Alder Reaction: EDG and EWG

• Reaction is favored by dienes with EDG and dienophiles with EWG
  Electron-Donating (EDG) Substituents (Electron-Rich)
  Electron-Withdrawing (EWG) Substituents (Electron-Poor)

• $R$ = alkyl (inductive donation)
  *The $CF_3$ group is strongly inductively withdrawing

The Diels-Alder Reaction: EDG, EWG, and Regiochemistry

*When at least one of the diene and/or dienophile are symmetrical, there is only one possible regiochemical outcome:
*When neither of the diene or dienophile are symmetrical, there are two possible regiochemical outcomes (but only one occurs, using polarity arguments)
*Note that stereochemical considerations have been omitted from this slide, even though they do exist. The focus of this slide is the regiochemistry.

Practice: D.A. Reaction: EDG, EWG, and Regiochemistry

*On your own (~2 min): predict the major product of the following Diels-Alder cycloadditions. Prove to yourself using polarity arguments why the answer is what it is.
*With your neighbor (1–2 min): compare your answers and discuss any differences (politely convince the other person why you are right, if you think you are).
*As a class (1–2 min): We will discuss the strategy to approach this question.
*Note that stereochemical considerations have been omitted from this slide, even though they do exist. The focus of this slide is the regiochemistry.

The Diels-Alder Reaction: Stereochemistry (SYN Addition)

*The stereochemical configuration of the diene and dienophile is retained in the Diels-Alder reaction, and is reflected in the product, making this reaction highly predictable. Since only one type of stereochemical outcome is possible, we can describe the reaction as stereospecific.
*Stereochemistry of the dienophile:

The Diels-Alder Reaction: Endo Versus Exo

*To properly predict any product of the Diels-Alder reaction, we need to consider the 3-dimensional interaction of the diene and dienophile using MO interactions
*Endo product is generally* favoured (kinetically) over the exo product. One argument to explain this is the ability for the endo transition state to form stabilizing (but non-bonding) secondary orbital interactions** (SOI), lowering its energy (a lower energy transition state makes it more kinetically favourable).
* *There are exceptions. You will encounter one exception in the Chem 08LB labs.
* **This is a hotly debated argument, with many chemists supporting and many rejecting SOI. The literature is divided on whether SOI truly even exist, but SOI nonetheless serve as a good model to assist us in rationalizing endo selectivity. Some chemists invoke steric arguments in certain special cases.

Practice: D.A. Reaction: Endo Versus Exo

*On your own (~2 min): predict the product of the following Diels-Alder cycloadditions.
*With your neighbor (1–2 min): compare your answers and discuss any differences (politely convince the other person why you are right, if you think you are).
*As a class (1–2 min): We will discuss the strategy to approach this question.

The Diels-Alder Reaction: Stereochemistry (SYN Addition)

*The diene must be in an s-cis conformation for the reaction to occur. The s-trans conformation cannot react (MO lobes too far apart).
*Stereochemistry of the diene:

Practice: D.A. Reaction: Stereochemistry

*On your own (~2 min): predict the major product of the following Diels-Alder cycloadditions.
*With your neighbor (1–2 min): compare your answers and discuss any differences (politely convince the other person why you are right, if you think you are).
*As a class (1–2 min): We will discuss the strategy to approach this question.

The Diels-Alder Reaction: Practice (Homework)

*Predict the product of the following Diels-Alder cycloadditions. Note that alkynes can also serve as the dienophile (the alkyne will use up only one of its two π-bonds).

Chapter 13: Summary

• Introduction to retrosynthetic analysis and multistep synthesis

  • Thinking backwards

  • Identifying key bonds that were made/broken en route to a product

• Conjugated unsaturated systems

  • Conjugation

  • Stability of allylic radicals and cations

  • 1,2- and 1,4-additions to conjugated dienes

  • Kinetic control versus thermodynamic control, and the impact of reaction temperature

• The Diels-Alder cycloaddition

  • Endo versus exo

  • Regiochemistry

  • Stereochemistry

Chapter 13: To-Do List Before Next Class

• Complete the following before our next class:

  • Chapter 14 assigned readings (will be posted to Canvas soon)

  • Chapter 14 Pre-Lecture Canvas Quiz (go get yourself some credit, woo!)

  • Download Chapter 14 Lecture Notes (will be posted to Canvas soon)

• Recommended practice:

  • Review your lecture notes and watch the lecture recordings

  • Complete textbook practice problems

    • In-chapter problems

    • Recommended practice problems (see “Pre-Class Readings” page on Canvas)

• Recommended self-care:

  • Did you find a cat and hug it? Yes? Have a cookie! No? WTF (what the fluorine) do you not like cats? Omg you monster. No cookie for you.

Chapter 14: Aromatic Compounds

• Professor Trevor G. Bolduc

• MSE 0116

• On the traditional, ancestral, and unceded territory of the Cahuilla, Luiseño, Serrano, and Tongva peoples.

Chapter 14: Learning Objectives (LOs)

• By the end of this chapter, you will be able to:

  • Differentiate between benzene, phenyl groups, and arenes

  • Use Hückel's Rule (4n+2 rule) to identify aromatic and antiaromatic compounds

  • Describe the four qualifiers for a molecule to be classified as aromatic

  • Draw a Frost Circle to predict the relative energies of all π-molecular orbitals for an aromatic compound

  • Explain why certain C–H protons in non-aromatic systems are more acidic than others using aromaticity arguments for the conjugate base

  • Use molecular orbital depictions to rationalize why certain heterocyclic lone pairs are not part of the delocalized π-electron system

  • Further use aromaticity arguments to rationalize the relative basicity of different heterocyclic compounds

General Implications of Aromaticity

.
Chemical Reactivity, Stability, and Properties of Benzene

Benzene and Basic Nomenclature

*“Benzene” describes only the chemical compound, benzene
*It is incorrect to describe the core 6-membered ring of any other arene as “benzene,” but you may describe it as the “benzene core/motif” (arene/aryl/aromatic ring is better)
*Many derivatives of benzene share the root of the word (i.e., benzaldehyde, benzoic acid, methyl benzoate, etc.)

Benzene and More Nomenclature (Take-Home)

*The “benzene core” is found in over 45% of marketed small-molecule pharmaceuticals
*Some common derivatives of the “benzene core” for you to review:

Chemical Reactivity of Benzene and Derivatives

• Alkenes undergo addition reactions (Chem 008A):
  *Benzene and its derivatives do not undergo any of the addition reactions that alkenes can do. They instead undergo substitution reactions.
  *Why? Benzene and its derivatives do not have alkenes (π-bonds).

Kekulé Structure of Benzene and Thermodynamic Stability

• Benzene can be represented by two individual resonance structures (known as the Kekulé structures for benzene). Alone, neither captures the true chemical nature of benzene.

• Kekulé versus resonance: resonance is accurate

Resonance and MO Theory of Benzene

*Resonance theory (correctly) suggests that all six carbon-carbon bonds of benzene should be equivalent
*Benzene contains NO true $σ$-only or $π$ bonds, but instead contains only a hybrid of both
MO theory shows the electron delocalization of the p-orbital system in benzene (all six carbons $sp^2$- hybridized), giving rise to six M)s for benzene

Aromaticity

• Hückel’s Rule (4n+2 Rule) for Delocalized π-Electrons

• Aromaticity, Anti-Aromaticity, and Non-Aromaticity

• Frost Circles

• Ions, Heterocycles, Fused Cycles

Aromaticity: Hückel's Rule (“4n+2” π-Electron Rule)

*For a system to be aromatic, it must meet the following four criteria:
* Cyclic ring
* All atoms in ring are planar (flat ring, not bent)
* Unbroken conjugated π-system of p-orbitals
* The total number of electrons in the π-system must give an integer result for n in Hückel's Rule: $(4n+2)$
* Hückel's Rule: $4n+2$ = (total # of π-electrons)
* If $n = 0,1,2,3…$ (integer) AROMATIC
* If $n = 1/2, 3/2, 5/2…$ (non-interger) ANTI-AROMATIC
cyclo- That lone pair is NOT part of the pi-butadiene system! It is in an $sp^2$-orbital that is 90° (orthogonal) to the pi-system of p-orbitals. I will likely ask this on your midterm/final exam.

Aromaticity: Aromatic, Anti-Aromatic, and Non-Aromatic

• Aromatic compounds ($4n+2 π$-electron compounds): cyclic, planar, unbroken conjugated π-system of p-orbitals, $n$ = integer (0,1,2,3…) by Hückel's rule ($4n+2$ = # $π$- electrons). Pi electron delocalization leads to significant stabilization.

• Anti-aromatic compounds ($4n π$-electron compounds): cyclic, planar, unbroken conjugated π-system of p-orbitals, $n$ = non-integer (1/2, 3/2, 5/2…) by Hückel's rule ($4n+2$ = # π-electrons). Pi electron delocalization leads to significant DE-stabilization.

• Non-aromatic compounds: fail to obey one or more of the above requirements. Usually acyclic, non-planar, or not fully conjugated. Some (not all) anti-aromatic compounds will BEND and become non-planar to relieve anti-aromatic destabilization, becoming non-aromatic.

Practice: Aromatic, Anti-Aromatic, and Non-Aromatic

• On your own (~2 min): determine if each of the following compounds is aromatic, anti-aromatic, or non-aromatic.

• With your neighbor (1–2 min): compare your answers and discuss any differences (politely convince the other person why you are right, if you think you are).

• As a class (1–2 min): We will discuss the strategy to approach this question.

Aromaticity: Frost Circles as a Model for MO Diagram

• The MO diagram of π-electron aromatic system can be quickly shown using a Frost circle

  1. Draw a circle. Orient the polygon shape of the aromatic system with one “point” (atom) pointed straight down within the circle. All “points” (atoms) of the ring must touch the circle.

  2. Draw a horizontal dashed line halfway up the circle (above = antibonding, below = bonding, on the line = non-bonding orbitals)

  3. Draw a dot on each “point” that touches the circle. These are the energy levels of each MO. Fill the MOs using the Aufbau, Pauli, and Hund rules.

• Why does this matter? Proof that anti-aromatic systems are destabilized by their own π-electron systems!

Practice: Frost Circles as a Model for MO Diagram

• On your own (~2 min): use a Frost circle to draw a complete MO diagram for furan, shown below. Use this MO diagram to prove to yourself that furan is aromatic with three bonding MOs. Hint: are both of those lone pairs part of the π-system of delocalized electrons, or not?

• With your neighbor (1–2 min): compare your answers and discuss any differences (politely convince the other person why you are right, if you think you are).

• As a class (1–2 min): We will discuss the strategy to approach this question.

Aromaticity: Ions (Cations and Anions)

• Anionic and cationic systems can be aromatic or anti-aromatic (think about the four requirements)

• Can and does impact the acidity of certain C–H protons

• Can and does impact the ease of hydride abstraction of certain C–H hydrides

Aromaticity: Heterocycles

• Aromaticity is not limited to carbon-only cycles (carbocycles). Heterocycles can also be aromatic, anti-aromatic, and non-aromatic, and they obey the same rules as carbocycles.

• Many heteroatoms will either have a lone pair of electrons. The lone-pair can ONLY contribute to a delocalized π-system of electrons if the lone pair is in a p-orbital that is conjugated in the system. If the lone pair is in an sp2-hybridized orbital (which is automatically 90° , orthogonal, to the π-system), it does NOT participate in aromaticity. You MUST check for this with heterocycles. Common error by students on MT2!

• Impact: some lone pairs are basic (not participating in aromaticity, localized), while others are not (participating in aromaticity means it cannot be to deprotonate anything).

Aromaticity: Fused Cycles

• Benzoids: fused aromatic hydrocarbons (may or may not be based on the benzene motif)

  • If unsure, draw a resonance structure

• Non-benzoids can also be aromatic (draw resonance structures to check)

Practice: Ions, Heterocycles, and Fused Cycles

• On your own (~2 min): are the following compounds aromatic, anti-aromatic, or non-aromatic. For any heteroatom lone pairs, identify whether the lone pair can operate as a base or not.

• With your neighbor (1–2 min): compare your answers and discuss any differences (politely convince the other person why you are right, if you think you are).

• As a class (1–2 min): We will discuss the strategy to approach this question.

Chapter 14: Summary

• Benzene and aromaticity: leads to alternative chemical reactivity (to be covered in Chapter 15)

• Frost circles and MO representations

• Hückel's Rule for aromaticity:

  • Cyclic

  • Planar

  • Conjugated π-system of p-orbitals

  • $4n+2 π$-electrons, leading to $n$ = integer

• Aromatic vs anti-aromatic vs non-aromatic

• Heterocyclic, fused, and ionic aromaticity

• Effects on acidity and basicity

Chapter 14: To-Do List Before Next Class

• Complete the following before our next class:

  • Chapter 15 assigned readings (will be posted to Canvas soon)

  • Chapter 15 Pre-Lecture Canvas Quiz (go get yourself some credit, woo!)

  • Download Chapter 15 Lecture Notes (will be posted to Canvas soon)

• Recommended practice:

  • Review your lecture notes and watch the lecture recordings

  • Complete textbook practice problems

    • In-chapter problems

    • Recommended practice problems (see “Pre-Class Readings” page on Canvas)

• Recommended self-care:

  • Go buy a succulent. Name it George. You forgot to water George. Now George is dead. What I’m trying to say is go drink more water.

Chapter 15: Reactions of Aromatic Compounds

• Professor Trevor G. Bolduc

• MSE 0116

• On the traditional, ancestral, and unceded territory of the Cahuilla, Luiseño, Serrano, and Tongva peoples.

Chapter 15: Learning Objectives (LOs)

• By the end of this chapter, you will be able to:

  • Predict the products of an electrophilic aromatic substitution (SEAr) reaction

  • Identify the pros and cons of Friedel-Crafts alkylation and acylation reactions

  • Identify how and when to use the Wolff-Kishner and Clemmensen reductions

  • Differentiate between ortho/para- (activating) groups, and meta- (deactivating) groups

  • Identify and show how ortho/para- and meta-directing groups operate using an arrow-pushing mechanistic justification

  • Show how to chemically convert between different types of directing groups

  • Predict the product of a multi-step reaction sequence of SEAr reactions, considering different directing groups

Electrophilic Aromatic Substitution (SEAr)

• Electrophilic Aromatic Substitution (SEAr) Reactions

• The General Mechanism

Electrophilic Aromatic Substitution (SEAr): General

• Aromatic systems undergo substitution reactions, instead of addition reactions

• The aromatic system is the nucleophile

• The reagent that is added is the electrophile

SEAr: A General Mechanism

• SEAr proceeds via a two-step mechanism, similar in concept to the $SN<em>1/E</em>1$ mechanisms

• We can describe the SEAr mechanism as an addition-elimination mechanism

• The loss of aromaticity in the first reaction incurs a heavy energetic cost

• Re-aromatization in second step is highly thermodynamically favoured

SEAr: The Arenium Cation Intermediate

• The arenium cation intermediate is stabilized through significant resonance

• Not aromatic

• Key concept: stabilization of the arenium cation speeds up the SEAr reaction (see “ortho/para- directing activating groups later in this slide deck)

• Key concept: de-stabilization of the arenium cation slows down the SEAr reaction (see “meta- directing de-activating groups later in this slide deck)

SEAr: The Reactions to Know and Learn (Summary)

• The following reactions will be the core of this chapter and will be used extensively throughout Chem 08LB and 08LC

SEAr: Halogenation (X2 and FeX3)

*We can chlorinate or brominate an aromatic ring with a Lewis acid catalyst
*Best practice is to match the halogens of the X2 and the Lewis acid catalyst
*The X2 alone is not sufficiently electrophilic. Activation of X2 by the Lewis acid catalyst is required, otherwise the first step cannot occur.
Fluorination is a challenging reaction and a major area of modern research. Fluorination will not be covered. Iodination requires a special reaction that we will not cover.

SEAr: Nitration ($HNO<em>3$ and $H</em>2SO_4$)

*Nitration can be performed with nitric acid (source of the active nitronium ion, $NO_2$ +) and sulfuric acid as a catalyst
*Mechanism (via nitronium ion):

SEAr: Sulfonation ($SO<em>3$ and $H</em>2SO_4$)

*Sulfonation can be performed with sulfur trioxide ($SO_3$) and concentrated sulfuric acid as a catalyst
*Mechanism (via acid activation):

SEAr: Friedel-Crafts Alkylation (R–X and $AlCl_3$)

• Alkylation (installation of an alkyl chain) can be performed with an alkyl chloride and aluminum trichloride as a catalyst

• (Limited) method to form C–C bonds

• Mechanism (via acid activation):

SEAr: Friedel-Crafts Alkylation, Limitations

• Carbocation rearrangements can (and will) occur, complicating syntheses

  • Just like in $SN<em>1$ and $E</em>1$
    *F.C. alkylations (and acylations) fail in the presence of powerful EWG (see “deactivating groups” later in this slide deck)

  • The aromatic ring is not nucleophilic enough with powerful EWG
    *Fails for amine-substituted aromatic rings too

SEAr: Friedel-Crafts Alkylation, Limitations

*Cannot perform with aryl or vinyl ($sp^2$) halides (must be an $sp^3$-hybridized carbon-halide centre)
*The product of a F.C. alkylation is more reactive than the starting material, so uncontrollable polyalkylations are very likely to occur (alkyl groups are EDG and make the ring MORE nucleophilic)
*F.C. acylations do not suffer from this!

SEAr: Friedel-Crafts