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The Hofmann Elimination
Last updated: June 28th, 2019 |
The Hofmann Elimination Of Alkylammonium Salts: Examples and Mechanism
The Hofmann Elimination is an elimination reaction of alkylammonium salts that forms C-C double bonds [pi bonds]. [note] It proceeds through a concerted E2 mechanism. In contrast with most elimination reactions that yield alkenes, which follow the Zaitsev (Saytzeff) rule, the Hofmann elimination tends to provide the less substituted alkene. In this post we go through the difference between Hofmann elimination and Zaitsev elimination and explain the key features in the Hofmann degradation mechanism that result in its preference for the “less substituted” alkene.
Table of Contents
- Quick Review: Zaitsev’s Rule
- “Non-Zaitsev” Products Can Dominate When Sufficient Steric Hindrance Is Present
- The “Hofmann Degradation”
- The Hofmann Elimination Has An Extremely Bulky Leaving Group, And This Leads To “Non-Zaitsev” Elimination Products
- Summary: The Hofmann Elimination
Conventional elimination reactions that occur via the E2 mechanism follow Zaitsev’s rule. The major product will be the more substituted alkene (that is, the alkene with the most carbons directly attached to the alkene).
For instance in the first example below, the “trisubstituted” alkene is favoured over the “mono-substituted” alkene.
Why? The thermodynamic stability of alkenes increases in the order
mono-substituted < disubstituted < trisubstituted <tetrasubstituted.
The energy differences are quite small – about 2 kcal/mol, but that’s enough to deliver an 80:20 ratio of products! [How do we know this? It can be obtained by plugging 2 kcal/mol into the equation ln K = –ΔG/RT]
Sometimes “non-Zaitsev” products can be obtained through the use of a bulky base for the elimination reaction. A classic example is to use sodium or potassium t-butoxide (KOt-Bu); another is to use lithium di-isopropyl amide (LDA). The idea here is that the bulky base will react more quickly with the least sterically hindered proton on a beta-carbon, which results in formation of the least substituted alkene. [for more, see: Bulky Bases In Elimination Reactions].
You sometimes might see these “non-Zaitsev” products be referred to as “Hofmann products”. Why?
Back to amines.
Back in 1851, not many techniques for analyzing complex molecules were available. One method for determining the structure of an unknown compound was to break it down into simpler pieces and look for clues in the fragments, a process called degradation. August Wilhelm von Hofmann developed a two-step degradation method for amines that was later to bear his name.
The first step is to treat an amine with a vast excess of methyl iodide [CH3I], which results in an ammonium salt [we saw this reaction, “exhaustive methylation”, in a previous post].
The second step is to distill the ammonium salt under low pressure in the presence of a strong base. Silver oxide (Ag2O) is often used.
Heating with strong base results in an elimination reaction: NR3 is lost and and a new alkene is formed.
The interesting observation here is that the alkene product from this process tends to be the least substituted alkene (“Hofmann product”) not the Zaitsev product.
What’s going on?
4. The Hofmann Elimination Has An Extremely Bulky Leaving Group, And This Leads To “Non-Zaitsev” Elimination Products
It’s not that there’s something about the product alkene that makes it more stable than the Zaitsev product (it isn’t).
The answer lies in the relative energies of the transition states leading to the two products.
It might help to look at the mechanism for the reaction again. Recall that the E2 mechanism demands an antiperiplanar (180°) arrangement of the C-H and C-LG bonds.
It really helps to visualize this by drawing out Newman projections. When we do that, what do you notice?
For most elimination reactions, the steric hindrance of the leaving group isn’t a factor we need to consider. Even though leaving groups like I and Br have a large Van Der Waals radius, their bonds to carbon are long, and being single atoms they don’t interfere with adjacent groups.
Contrast that to the NR3 group, which is like a big-ass ceiling fan spinning around its three alkyl groups – and each of the alkyl groups themselves is like a mini-ceiling fan spinning around three hydrogen atoms. It takes up a lot of space!
The conformation that leads to the “Zaitsev” product has a lot more steric hindrance (two gauche interactions!) than the conformation that leads to the “Hofmann” product, because of the extremely bulky N(CH3)3 leaving group!
These extra steric interactions are enough to disfavour the Zaitsev transition state relative to the Hofmann transition state, and lead to the Hofmann product as the major product.
The Hofmann elimination is just another example of how tweaking a single variable in a chemical reaction can flip the outcome. We saw earlier how increasing the steric hindrance of the base can lead to the non-Zaitsev product. Here, we’re increasing the steric hindrance of the leaving group.
A few kcal/mol difference in a transition state might not sound like a lot, but it’s more than enough to change the identity of the major product. This is what makes organic chemistry so frustrating to beginners… yet also so deeply interesting!
00 General Chemistry Review
- Gen Chem and Organic Chem: How are they different?
- How Gen Chem Relates to Organic Chem, Pt. 1 - The Atom
- From Gen Chem to Organic Chem, Pt. 2 - Electrons and Orbitals
- From Gen Chem to Organic Chem, Pt. 3 - Effective Nuclear Charge
- From Gen Chem to Organic Chem, Pt. 4 - Chemical Bonding
- From Gen Chem to Organic Chem, Pt. 5 - Understanding Periodic Trends
- From Gen Chem to Org Chem, Pt. 6 - Lewis Structures, A Parable
- From Gen Chem to Org Chem, Pt. 7 - Lewis Structures
- From Gen Chem to Org Chem, Pt. 8 - Ionic and Covalent Bonding
- From Gen Chem to Org Chem, Pt. 9 - Acids and Bases
- From Gen Chem to Organic Chem, Pt. 10 - Hess' Law
- From Gen Chem to Organic Chem, Pt. 11 - The Second Law
- From Gen Chem to Org Chem Pt. 12 - Kinetics
- From Gen Chem to Organic Chem, Pt. 13 - Equilibria
- From Gen Chem to Organic Chem, Part 14: Wrapup
01 Bonding, Structure, and Resonance
- How Concepts Build Up In Org 1 ("The Pyramid")
- Review of Atomic Orbitals for Organic Chemistry
- How Do We Know Methane (CH4) Is Tetrahedral?
- Hybrid Orbitals
- How To Determine Hybridization: A Shortcut
- Orbital Hybridization And Bond Strengths
- Sigma bonds come in six varieties: Pi bonds come in one
- A Key Skill: How to Calculate Formal Charge
- Partial Charges Give Clues About Electron Flow
- The Four Intermolecular Forces and How They Affect Boiling Points
- 3 Trends That Affect Boiling Points
- How To Use Electronegativity To Determine Electron Density (and why NOT to trust formal charge)
- Introduction to Resonance
- How To Use Curved Arrows To Interchange Resonance Forms
- Evaluating Resonance Forms (1) - The Rule of Least Charges
- Evaluating Resonance Forms (2): Applying Electronegativity
- Evaluating Resonance Forms: Factors That Stabilize Negative Charges
- Evaluating Resonance Forms (4): Positive Charges
- Exploring Resonance: Pi-Donation
- Exploring Resonance: Pi-acceptors
- In Summary: Resonance
- Drawing Resonance Structures: 3 Common Mistakes To Avoid
- How to apply electronegativity and resonance to understand reactivity
02 Acid Base Reactions
- Introduction to Acid-Base Reactions
- Walkthrough of Acid Base Reactions (1)
- Walkthrough of Acid Base Reactions (2): Basicity
- Walkthrough of Acid-Base Reactions (3) - Acidity Trends
- Five Key Factors That Influence Acidity
- Walkthrough of Acid-Base reactions (4) - pKa
- How to Use a pKa Table
- The pKa Table Is Your Friend
- A Handy Rule of Thumb for Acid-Base Reactions
- Acid Base Reactions Are Fast
- pKa Values Span 60 Orders Of Magnitude
- Acid Base Reactions: What's the Point?
03 Alkanes and Nomenclature
- Summary Sheet - Alkane Nomenclature
- Meet the (Most Important) Functional Groups
- Condensed Formulas: Deciphering What the Brackets Mean
- Hidden Hydrogens, Hidden Lone Pairs, Hidden Counterions
- Don't Be Futyl, Learn The Butyls
- Primary, Secondary, Tertiary, Quaternary In Organic Chemistry
- Branching, and Its Affect On Melting and Boiling Points
- The Many, Many Ways of Drawing Butane
- Common Mistakes: Drawing Tetrahedral Carbons
- Common Mistakes in Organic Chemistry: Pentavalent Carbon
- Table of Functional Group Priorities for Nomenclature
- Organic Chemistry IUPAC Nomenclature Demystified With A Simple Puzzle Piece Approach
04 Conformations and Cycloalkanes
- Newman Projections
- Putting the Newman into ACTION
- Introduction to Cycloalkanes (1)
- Geometric Isomers In Small Rings: Cis And Trans Cycloalkanes
- Calculation of Ring Strain In Cycloalkanes
- Cycloalkanes - Ring Strain In Cyclopropane And Cyclobutane
- Cyclohexane Conformations
- Cyclohexane Chair Conformation: An Aerial Tour
- How To Draw The Cyclohexane Chair Conformation
- The Cyclohexane Chair Flip
- The Cyclohexane Chair Flip - Energy Diagram
- Substituted Cyclohexanes - Axial vs Equatorial
- Ranking The Bulkiness Of Substituents On Cyclohexanes: "A-Values"
- The Ups and Downs of Cyclohexanes
- Cyclohexane Chair Conformation Stability: Which One Is Lower Energy?
- Fused Rings - Cis-Decalin and Trans-Decalin
- Naming Bicyclic Compounds - Fused, Bridged, and Spiro
- Bredt's Rule (And Summary of Cycloalkanes)
05 A Primer On Organic Reactions
- The Most Important Question To Ask When Learning a New Reaction
- The 4 Major Classes of Reactions in Org 1
- Learning New Reactions: How Do The Electrons Move?
- How (and why) electrons flow
- The Third Most Important Question to Ask When Learning A New Reaction
- 7 Factors that stabilize negative charge in organic chemistry
- 7 Factors That Stabilize Positive Charge in Organic Chemistry
- Common Mistakes: Formal Charges Can Mislead
- Nucleophiles and Electrophiles
- Curved Arrows (for reactions)
- Curved Arrows (2): Initial Tails and Final Heads
- Nucleophilicity vs. Basicity
- The Three Classes of Nucleophiles
- What Makes A Good Nucleophile?
- Leaving Groups Are Nucleophiles Acting In Reverse
- What makes a good leaving group?
- 3 Factors That Stabilize Carbocations
- Three Factors that Destabilize Carbocations
- What's a Transition State?
- Hammond's Postulate
- Grossman's Rule
- Draw The Ugly Version First
- Learning Organic Chemistry Reactions: A Checklist (PDF)
- Introduction to Addition Reactions
- Introduction to Elimination Reactions
- Introduction to Free Radical Substitution Reactions
- Introduction to Oxidative Cleavage Reactions
06 Free Radical Reactions
- Bond Dissociation Energies = Homolytic Cleavage
- Free Radical Reactions
- 3 Factors That Stabilize Free Radicals
- What Factors Destabilize Free Radicals?
- Bond Strengths And Radical Stability
- Free Radical Initiation: Why Is "Light" Or "Heat" Required?
- Initiation, Propagation, Termination
- Monochlorination Products Of Propane, Pentane, And Other Alkanes
- Selectivity In Free Radical Reactions
- Selectivity in Free Radical Reactions: Bromination vs. Chlorination
- Halogenation At Tiffany's
- Allylic Bromination
- Bonus Topic: Allylic Rearrangements
- In Summary: Free Radicals
- Synthesis (2) - Reactions of Alkanes
07 Stereochemistry and Chirality
- On Cats, Part 4: Enantiocats
- On Cats, Part 6: Stereocenters
- The Single Swap Rule
- Introduction to Assigning (R) and (S): The Cahn-Ingold-Prelog Rules
- Assigning Cahn-Ingold-Prelog (CIP) Priorities (2) - The Method of Dots
- Types of Isomers: Constitutional Isomers, Stereoisomers, Enantiomers, and Diastereomers
- Enantiomers vs Diastereomers vs The Same? Two Methods For Solving Problems
- Assigning R/S To Newman Projections (And Converting Newman To Line Diagrams)
- How To Determine R and S Configurations On A Fischer Projection
- The Meso Trap
- Optical Rotation, Optical Activity, and Specific Rotation
- Optical Purity and Enantiomeric Excess
- What's a Racemic Mixture?
- Chiral Allenes And Chiral Axes
08 Substitution Reactions
- Introduction to Nucleophilic Substitution Reactions
- Walkthrough of Substitution Reactions (1) - Introduction
- Two Types of Substitution Reactions
- Common Blind Spot: Intramolecular Reactions
- Why the SN2 Reaction Is Powerful
- The SN1 Mechanism
- The Conjugate Acid Is A Better Leaving Group
- Comparing the SN1 and SN2 Reactions
- Polar Protic? Polar Aprotic? Nonpolar? All About Solvents
- Steric Hindrance is Like a Fat Goalie
- The SN2 Mechanism
- The Conjugate Base is Always a Stronger Nucleophile
09 Elimination Reactions
- Elimination Reactions (1): Introduction And The Key Pattern
- Elimination Reactions (2): The Zaitsev Rule
- Elimination Reactions Are Favored By Heat
- Two Types of Elimination Reactions
- The E1 Reaction
- The E2 Mechanism
- Comparing the E1 and E2 Reactions
- The E2 Reaction and Cyclohexane Rings
- Bulky Bases in Elimination Reactions
- Comparing the E1 and SN1 Reactions
- Elimination (E1) Reactions With Rearrangements
11 SN1/SN2/E1/E2 Decision
12 Alkene Reactions
- Addition Reactions: Elimination's Opposite
- Selective vs. Specific
- Regioselectivity In Alkene Addition Reactions
- Stereoselectivity In Alkene Addition Reactions: Syn vs Anti Addition
- Markovnikov Addition Of HCl To Alkenes
- Alkene Hydrohalogenation Mechanism And How It Explains Markovnikov's Rule
- Curved Arrows and Alkene Addition Reactions
- Addition Pattern #1: The "Carbocation Pathway"
- Rearrangements in Alkene Addition Reactions
- Bromination of Alkenes
- Bromination of Alkenes: The Mechanism
- Alkene Addition Pattern #2: The "Three-Membered Ring" Pathway
- Hydroboration - Oxidation of Alkenes
- Hydroboration Oxidation of Alkenes Mechanism
- Alkene Addition Pattern #3: The "Concerted" Pathway
- Bromonium Ion Formation: A (Minor) Arrow-Pushing Dilemma
- A Fourth Alkene Addition Pattern - Free Radical Addition
- Alkene Reactions: Ozonolysis
- Summary: Three Key Families Of Alkene Reaction Mechanisms
- Synthesis (4) - Alkene Reaction Map, Including Alkyl Halide Reactions
13 Alkyne Reactions
- Acetylides from Alkynes, And Substitution Reactions of Acetylides
- Partial Reduction of Alkynes To Obtain Cis or Trans Alkenes
- Hydroboration and Oxymercuration of Alkynes
- Alkyne Reaction Patterns - Hydrohalogenation - Carbocation Pathway
- Alkyne Halogenation: Bromination, Chlorination, and Iodination of Alkynes
- Alkyne Reactions - The "Concerted" Pathway
- Alkenes To Alkynes Via Halogenation And Elimination Reactions
- Alkynes Are A Blank Canvas
- Synthesis (5) - Reactions of Alkynes
14 Alcohols, Epoxides and Ethers
- E and Z Notation For Alkenes (+ Cis/Trans)
- Alcohols (1) - Nomenclature and Properties
- Alcohols Can Act As Acids Or Bases (And Why It Matters)
- Alcohols (3) - Acidity and Basicity
- The Williamson Ether Synthesis
- Williamson Ether Synthesis: Planning
- Ethers From Alkenes, Tertiary Alkyl Halides and Alkoxymercuration
- Alcohols To Ethers via Acid Catalysis
- Cleavage Of Ethers With Acid
- Epoxides - The Outlier Of The Ether Family
- Opening of Epoxides With Acid
- Epoxide Ring Opening With Base
- Making Alkyl Halides From Alcohols
- Tosylates And Mesylates
- PBr3 and SOCl2
- Elimination Reactions of Alcohols
- Elimination of Alcohols To Alkenes With POCl3
- Alcohol Oxidation: "Strong" and "Weak" Oxidants
- Demystifying Alcohol Oxidations
- Intramolecular Reactions of Alcohols and Ethers
- Protecting Groups For Alcohols
- Thiols And Thioethers
- Calculating the oxidation state of a carbon
- Oxidation and Reduction in Organic Chemistry
- Oxidation Ladders
- SOCl2 Mechanism For Alcohols To Alkyl Halides: SN2 versus SNi
- Alcohol Reactions Roadmap (PDF)
- What's An Organometallic?
- Formation of Grignard and Organolithium Reagents
- Organometallics Are Strong Bases
- Reactions of Grignard Reagents
- Protecting Groups In Grignard Reactions
- Grignard Practice Problems: Synthesis (1)
- Grignard Reactions And Synthesis (2)
- Organocuprates (Gilman Reagents): How They're Made
- Gilman Reagents (Organocuprates): What They're Used For
- Common Mistakes with Carbonyls: Carboxylic Acids... Are Acids!
- The Heck, Suzuki, and Olefin Metathesis Reactions (And Why They Don't Belong In Most Introductory Organic Chemistry Courses)
- Reaction Map: Reactions of Organometallics
- Degrees of Unsaturation (or IHD, Index of Hydrogen Deficiency)
- Conjugation And Color (+ How Bleach Works)
- Introduction To UV-Vis Spectroscopy
- UV-Vis Spectroscopy: Absorbance of Carbonyls
- UV-Vis Spectroscopy: Practice Questions
- Bond Vibrations, Infrared Spectroscopy, and the "Ball and Spring" Model
- Infrared Spectroscopy: A Quick Primer On Interpreting Spectra
- IR Spectroscopy: 4 Practice Problems
- Homotopic, Enantiotopic, Diastereotopic
- Liquid Gold: Pheromones In Doe Urine
- Natural Product Isolation (1) - Extraction
- Natural Product Isolation (2) - Purification Techniques, An Overview
- Structure Determination Case Study: Deer Tarsal Gland Pheromone
17 Dienes and MO Theory
- What To Expect In Organic Chemistry 2
- How Concepts Build Up In Org 2
- Are these molecules conjugated?
- Conjugation And Resonance In Organic Chemistry
- Bonding And Antibonding Pi Orbitals
- Molecular Orbitals of The Allyl Cation, Allyl Radical, and Allyl Anion
- Pi Molecular Orbitals of Butadiene
- Reactions of Dienes: 1,2 and 1,4 Addition
- Thermodynamic and Kinetic Control
- More On 1,2 and 1,4 Additions To Dienes
- s-cis and s-trans
- The Diels-Alder Reaction
- Cyclic Dienes and Dienophiles in the Diels-Alder Reaction
- Stereochemistry of the Diels-Alder Reaction
- Exo vs Endo Products In The Diels Alder: How To Tell Them Apart
- HOMO and LUMO In the Diels Alder Reaction
- Why Are Endo vs Exo Products Favored in the Diels-Alder Reaction?
- Diels-Alder Reaction: Kinetic and Thermodynamic Control
- The Retro Diels-Alder Reaction
- Regiochemistry In The Diels-Alder Reaction
19 Reactions of Aromatic Molecules
- Electrophilic Aromatic Substitution: Introduction
- Activating and Deactivating Groups In Electrophilic Aromatic Substitution
- Electrophilic Aromatic Substitution - The Mechanism
- Ortho-, Para- and Meta- Directors in Electrophilic Aromatic Substitution
- Understanding Ortho, Para, and Meta Directors
- Why are halogens ortho- para- directors?
- Disubstituted Benzenes: The Strongest Electron-Donor "Wins"
- Electrophilic Aromatic Substitutions (1) - Halogenation of Benzene
- Electrophilic Aromatic Substitutions (2) - Nitration and Sulfonation
- EAS Reactions (3) - Friedel-Crafts Acylation and Friedel-Crafts Alkylation
- Intramolecular Friedel-Crafts Reactions
- Nucleophilic Aromatic Substitution (NAS)
- Nucleophilic Aromatic Substitution (2) - The Benzyne Mechanism
- Reactions on the "Benzylic" Carbon: Bromination And Oxidation
- The Wolff-Kishner, Clemmensen, And Other Carbonyl Reductions
- More Reactions on the Aromatic Sidechain: Reduction of Nitro Groups and the Baeyer Villiger
- Aromatic Synthesis (1) - "Order Of Operations"
- Synthesis of Benzene Derivatives (2) - Polarity Reversal
- Aromatic Synthesis (3) - Sulfonyl Blocking Groups
- Synthesis (7): Reaction Map of Benzene and Related Aromatic Compounds
20 Aldehydes and Ketones
- Weird Nomenclature In Carbonyl Chemistry
- Aldehydes and Ketones: 14 Reactions With The Same Mechanism
- Wittig Reaction
- Imines and Enamines
- On Acetals and Hemiacetals
- Carbonyl Chemistry: 10 Key Concepts (Part 1)
- Carbonyls: 10 key concepts (Part 2)
- Acid Catalysis Of Carbonyl Addition Reactions: Too Much Of A Good Thing?
- Breaking Down Carbonyl Reaction Mechanisms: Anionic Nucleophiles (Part 1)
- Breaking Down Carbonyl Reaction Mechanisms: Reactions of Anionic Nucleophiles (Part 2)
21 Carboxylic Acid Derivatives
- Simplifying the reactions of carboxylic acid derivatives (part 1)
- Carbonyl Mechanisms: Neutral Nucleophiles, Part 1
- Carbonyl chemistry: Anionic versus Neutral Nucleophiles
- Proton Transfers Can Be Tricky
- Let's Talk About the [1,2] Elimination
- Carbonyl Chemistry: Learn Six Mechanisms For the Price Of One
- Summary Sheet #5 - 9 Key Mechanisms in Carbonyl Chemistry
- Summary Sheet #7 - 21 Carbonyl Mechanisms on 1 page
- How Reactions Are Like Music
- Making Music With Mechanisms (PADPED)
- The Magic Wand of Proton Transfer
- The Power of Acid Catalysis
22 Enols and Enolates
- The Amide Functional Group: Properties, Synthesis, and Nomenclature
- Basicity of Amines And pKaH
- 5 Key Basicity Trends of Amines
- The Mesomeric Effect And Aromatic Amines
- Nucleophilicity of Amines
- Alkylation of Amines (Sucks!)
- Reductive Amination
- The Gabriel Synthesis
- Some Reactions of Azides
- The Hofmann Elimination
- The Hofmann and Curtius Rearrangements
- The Cope Elimination
- Protecting Groups for Amines - Carbamates
- The Strecker Synthesis of Amino Acids
- Introduction to Peptide Synthesis
- Reactions of Diazonium Salts: Sandmeyer and Related Reactions
- D and L Notation For Sugars
- What is Mutarotation?
- Reducing Sugars
- Pyranoses and Furanoses: Ring-Chain Tautomerism In Sugars
- The Big Damn Post Of Carbohydrate-Related Chemistry Definitions
- The Haworth Projection
- Converting a Fischer Projection To A Haworth (And Vice Versa)
- Reactions of Sugars: Glycosylation and Protection
- The Ruff Degradation and Kiliani-Fischer Synthesis
25 Fun and Miscellaneous
- Organic Chemistry and the New MCAT
- A Gallery of Some Interesting Molecules From Nature
- The Organic Chemistry Behind "The Pill"
- Maybe they should call them, "Formal Wins" ?
- Planning Organic Synthesis With "Reaction Maps"
- Organic Chemistry Is Shit
- The 8 Types of Arrows In Organic Chemistry, Explained
- The Most Annoying Exceptions in Org 1 (Part 1)
- The Most Annoying Exceptions in Org 1 (Part 2)
- Org 1 Review Quizzes
- Screw Organic Chemistry, I'm Just Going To Write About Cats
- On Cats, Part 1: Conformations and Configurations
- On Cats, Part 2: Cat Line Diagrams
- The Marriage May Be Bad, But the Divorce Still Costs Money
- Why Do Organic Chemists Use Kilocalories?
- What Holds The Nucleus Together?
- 9 Nomenclature Conventions To Know