Home / The Hofmann and Curtius Rearrangements
The Hofmann and Curtius Rearrangements
Last updated: September 21st, 2022 |
Here’s the thing about the coverage of “amines” in Org 2: there’s no narrative.
Unlike most chapters, it doesn’t start with a set of concepts and then build up to a series of examples you can then apply those concepts to.
No. A typical chapter on amines in an introductory textbook is essentially just a hodge-podge of seemingly random topics thrown together that didn’t fit anywhere else. The only unifying thread is that they contain nitrogen in some way.
Case in point: today’s random amine post is about the Hofmann and Curtius rearrangements.
What prompts this, you might ask? No good answer. Most courses cover them at some point, and they’ve got to fit in somewhere. So what the hell. Why not now?
Table of Contents
- The Hofmann and Curtius Rearrangements
- The Mechanism of the Hofmann and Curtius Rearrangements, Part One – Setting Up The Rearrangement
- Part Two: The Key Rearrangement Step In The Hofmann And Curtius Rearrangements
- Part Three: Formation of the Isocyanate
- Putting The Steps Together
- The Fate of the Isocyanate: Formation of Carbamates, Amines, And Ureas
- Summary: The Hofmann and Curtius Rearrangements
- (Advanced) References and Further Reading
The Hofmann and Curtius rearrangements are two examples of a whole family of rearrangement reactions that share a common mechanistic step. [as do the Beckmann and Wolff rearrangements – see bonus topic 2]
In the Hofmann rearrangement, an amide is treated with bromine and base (usually NaOH or KOH). Upon heating, an intermediate isocyanate is formed, which is not isolated. In the presence of water, the isocyanate loses carbon dioxide (“decarboxylates”) to give an amine.
The key bond that forms in the Hofmann is the C2–N bond. Note how the carbonyl group (C1) is lost, forming carbon dioxide (CO2). (note: this isn’t IUPAC numbering, just numbering to facilitate discussion)
In the Curtius rearrangement, an acyl azide is heated, and an isocyanate is formed. In the Curtius, the isocyanate can be isolated, but is usually transformed further into other species such a carbamate, a urea, or (via decarboxylation, as in the Hofmann) to an amine (more on those below).
The key observation to note in both cases is that the C1-C2 bond has broken, and a new C2-N bond has formed.
The question is HOW?
There are four important parts to the mechanism of the Curtius and Hofmann rearrangements, and we’re going to walk through them all.
- Prelude (straightforward)
- The key migration step (tricky, but less tricky if you realize you’ve seen a variant of it in Org 1 !)
- Formation of the isocyanate (straightforward)
[interlude: steps 2 and 3 actually happen at the same time, so we’ll show how to put them together]
4. Epilogue: Transformations of the isocyanate
Part 1: Prelude
- The Hofmann rearrangement occurs with an amide.
- The Curtius rearrangement occurs with an acyl azide.
Both are conveniently prepared from acyl halides through an addition-elimination reaction. If you’re covering amines now, then carbonyl reactions are likely familiar territory. The acyl halides can be prepared from carboxylic acids through using a reagent like thionyl chloride (SOCl2) or phosphorus pentachloride (PCl5).
Setting up the Hofmann
In the Hofmann rearrangment, the amide is treated with bromine (Br2) and a base such as NaOH. This results in the breakage of N-H and the formation of N-Br, resulting in the installation of a good leaving group on the nitrogen. We call this an “N-bromo amide”.
The Curtius needs no “setting up”, as the acyl azide already has a splendid built-in leaving group: N2. This is why organic azides should be treated with care, as rough treatment can lead to explosions.
Now we get down to business.
The key step in the Hofmann and Curtius rearrangments is migration of a carbon atom to displace a leaving group on an adjacent nitrogen.
This requires two curved arrows to draw, which are shown in the structure on the far left (below).
- In the first curved arrow, the C-C bond breaks, and a new C-N bond forms.
- In the second curved arrow, the N–LG (leaving group) bond breaks.
However, it isn’t always easy to go directly from the structure on the far left to the structure on the far right (which is drawn nice and tidy! ).
Countless points are needlessly lost in exams every year by students who get the curved arrows right but end up drawing the wrong structure! That’s why I encourage students to draw an “ugly version” first, which looks like crap but at least has all the bonds in the right place. There’s always time to redraw it and make it look pretty later.
At first this rearrangement probably looks… odd. But it’s actually a reaction you’ve seen before! (but in disguised form).
Anyone remember the mechanism for the “oxidation” step in hydroboration-oxidation?
It’s basically the same thing!
Here’s a refresher:
Let’s visit the specific rearrangement step in the Hofmann and Curtius rearrangements with concrete examples.
Here’s the key step in the Hofmann, where heating results in breakage of C-C , formation of C-N, and breakage of N-Br.
If you follow all the arrows, you should end up with a weird-looking carbocation (above right) which we’ll deal with in a minute.
In the Curtius, heating the acyl azide results in rearrangement. The leaving group is nitrogen gas (N2).
(A subtle difference between the Curtius and the Hofmann is that there is no hydrogen attached to N in the Curtius, so we end up with a negative charge on the nitrogen in the rearranged species.)
The next step is going from our rearranged species to the isocyanate. For anyone accustomed to drawing resonance forms, this shouldn’t be too difficult.
(As we’ll discuss below, studies have determined that isocyanate formation occurs at the same time as migration. But for our teaching purposes, I think it helps to treat this step in isolation. We can put it all together in a minute).
As you might recall from waayyyy back in Org 1, a resonance form with full octets is superior to one without (quick review). Our weird-looking product from rearrangement has a carbocation adjacent to a nitrogen containing a lone pair. So the first step is to draw the formation of a new C-N pi bond. This is essentially just a resonance form.
The Hofmann rearrangement occurs in the presence of base. So after drawing the resonance form, the next step is deprotonation of the N–H bond giving the neutral isocyanate.
There’s no hydrogen on the nitrogen in the Curtius. So isocyanate formation is achieved merely by donation of a lone pair from nitrogen to the carbocation. You can just look at it as drawing a resonance form.
Studies into the mechanism of the Hofmann and Curtius rearrangements have determined that these two steps do not happen sequentially; they actually happen at the same time! (how do we know this? see Note 1 )
That is, the migration happens at the same time as isocyanate formation.
We need to redraw the mechanisms of the Hofmann and Curtius to reflect that, incorporating both steps.
Here’s the Hofmann (note that the deprotonation event is actually separate).
And the Curtius:
Both the Hofmann and Curtius give rise to an isocyanate. You likely haven’t encountered isocyanates before. At first glance, they are pretty strange-looking species, but their chemistry is not so different from that of other carbonyl species such as esters, amides, and acyl halides.
The isocyanate structure closely resembles that of carbon dioxide, CO2. The carbon is pi-bonded to two strongly electronegative atoms. This makes the carbon an excellent electrophile.
By adding various nucleophiles, isocyanates can be transformed into other useful species.
• Adding an alcohol results in formation of a carbamate
• Adding an amine results in a urea
• Adding water results in a carbamic acid, which is unstable. Carbamic acids quickly lose carbon dioxide to give an amine.
In particular, the decarboxylation pathway presents a nifty way to make amines. We’ve learned tons of ways to make carboxylic acids, but not too many ways of making amines (besides nucleophilic substitution and reductive amination). The Hofmann is a good trick to have in your back pocket in situations where neither of those situations might apply – like making substituted anilines, for example.
Mechanisms? See Note 2.
The mechanism of these rearrangments is tricky at first glance, but is made considerably easier once you realize that you’ve seen a variant of the migration reaction before (i.e. in hydroboration-oxidation).
I highly recommend drawing the ugly version first, because it will help you focus on seeing the bonds that form and break, before trying to redraw it into a more aesthetically appealing structure. This also goes for the Beckmann and Wolff rearrangements, which have a similar step.(see below)
- The Cope Elimination
- Draw The Ugly Version First
- Some Reactions of Azides
- Rearrangement Reactions (1) – Hydride Shifts
- More Reactions on the Aromatic Sidechain: Reduction of Nitro Groups and the Baeyer Villiger
- Hydroboration Oxidation of Alkenes Mechanism
- Curtius Rearrangement of Acyl Azides to Isocyanates
- Hofmann Rearrangement of Amides to Amines
- Amine Practice Questions
If the Curtius was stepwise, the loss of nitrogen would lead to a nitrene. Nitrenes undergo a host of interesting reactions, such as insertion into C-H bonds (!). So one can design an experiment to test this: if one tries the following Curtius rearrangement, one could look for evidence of formation of a five-membered ring.
The absence of such products, along with other evidence, points to a concerted mechanism.
The most important mechanism of isocyanates is electrophilic addition (i.e. adding a nucleophile to the central, electrophilic carbon). In the mechanism below I showed the nucleophile adding to the carbon so as to form an anion on the nitrogen, although this is is likely not the best resonance form (the oxygen is better at stabilizing negative charge than is nitrogen). Proton transfer from oxygen to nitrogen results in a neutral species. (I used the Magic Wand of Proton Transfer here, because it’s faster).
Note that the decarboxylation step in 1) doesn’t need to be preceded by deportation of the oxygen, although it definitely needs to occur such that nitrogen is protonated during the step (you don’t want to form a strongly basic amide ion, for instance).
But wait, there’s more!
There’s a 1,2-shift with loss of a leaving group in the Beckmann rearrangement. The key step is essentially the same as we saw in the Hofmann and Curtius.
And in the Wolff rearrangement, which is commonly also covered, you might also recognize the same key step.
And that’s not all! There’s a reaction called the Schmidt rearrangement, which is like the Curtius, but comes from adding HN3 to an acyl chloride (or carboxylic acid). And there’s another one called the Lossen rearrangement that occurs with hydroxyamic acids. No prizes for guessing the key step in those two processes. And we haven’t even mentioned the Baeyer-Villiger, which doesn’t involve nitrogen, but is pretty much the same type of process.
When I learned the hydroboration-oxidation step in Org 1, many moons ago, I certainly never expected that I would see the same reaction pattern repeat itself in so many different guises.
The bottom line is that there are a lot of reactions that go by different names that proceed through the same mechanistic process. This highlights the importance of learning the key patterns in organic chemistry, because they sure do repeat themselves a lot.
- Ueber die Einwirkung des Broms in alkalischer Lösung auf Amide
Chem. Ber. 1881, 14, 2725-2736
Original paper by A. W. Hofmann (who was a very productive chemist and has his name attributed to many other transformations) on the degradation of amides to primary amines.
- A Mild and Efficient Modified Hofmann Rearrangement
Xicai Huang, Mehran Seid, and Jeffrey W. Keillor
The Journal of Organic Chemistry 1997, 62 (21), 7495-7496
This is a modified Hofmann Rearrangement carried out in methanol – in this case, the intermediate carbamic acid can react with the methanol solvent to produce methyl carbamates in good yield.
- METHYL CARBAMATE FORMATION VIA MODIFIED HOFMANN REARRANGEMENT REACTIONS: METHYL N-(p-METHOXYPHENYL)CARBAMATE
Jeffrey W. Keillor and Xicai Huang
Org. Synth. 2002, 78, 234
A reliable and independently tested procedure for the modified Hofmann Rearrangement in Ref #2.
- The Hofmann Reaction
Wallis, Everett L.; Lane, John F.
Org. React. 1946, 3, 267-306
An old but comprehensive (for its time) review on the Hofmann reaction (the amide to amine reaction, not to be confused with his other reactions).
- Notes – A Re-examination of the Limitations of the Hofmann Reaction
Ernest Magnien and Richard Baltzly
The Journal of Organic Chemistry 1958, 23 (12), 2029-2032
This is an interesting paper where the authors have attempted to extend the scope of the Hofmann rearrangement beyond what was described in the original paper by carefully adjusting the reaction conditions.
- 20. Hydrazide und Azide organischer Säuren
Curtius, T. I. Abhandlung.
Journal Für Praktische Chemie, 50(1), 275–294. (1894).
- Ueber Stickstoffwasserstoffsäure (Azoimid) N3H.
Berichte Der Deutschen Chemischen Gesellschaft, 23(2), 3023–3033.(1890).
First papers by Theodore Curtius describing the reactivity of acyl hyrazides and acyl azides.
- The Curtius Reaction
Smith, P. A. S.
Org. React. 1946, 3, 336
An old but comprehensive review of the Curtius reaction, which includes the history of the discovery of this rearrangement, substrate scope, limitations, comparison to other similar reactions, and experimental procedures.
- UNDECYL ISOCYANATE
F. H. Allen and Alan Bell
Org. Synth. 1944, 24, 94
An old but reproducible and tested procedure for synthesizing isocyanates through the Curtius Rearrangement.
- An Expedient Protecting-Group-Free Total Synthesis of (±)-Dievodiamine
William P. Unsworth, Christiana Kitsiou, and Richard J. K. Taylor
Organic Letters 2013 15 (13), 3302-3305
The first step in this total synthesis uses a Curtius rearrangement to effect an intramolecular cyclization of the indole-substituted carboxylic acid.
- Synthetic methods and reactions. 121. Zinc iodide catalyzed preparation of aroyl azides from aroyl chlorides and trimethylsilyl azide
K. Surya Prakash, Pradeep S. Iyer, Massoud Arvanaghi, and George A. Olah
The Journal of Organic Chemistry 1983 48 (19), 3358-3359
A convenient procedure for preparing aromatic aryl azides from Nobel Laureate Prof. George A. Olah. These can then be used for Curtius rearrangements.
00 General Chemistry Review
01 Bonding, Structure, and Resonance
- How Do We Know Methane (CH4) Is Tetrahedral?
- Hybrid Orbitals and Hybridization
- 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
- How To Find The Best Resonance Structure By Applying Electronegativity
- Evaluating Resonance Structures With Negative Charges
- Evaluating Resonance Structures With Positive Charge
- Exploring Resonance: Pi-Donation
- Exploring Resonance: Pi-acceptors
- In Summary: Evaluating Resonance Structures
- Drawing Resonance Structures: 3 Common Mistakes To Avoid
- How to apply electronegativity and resonance to understand reactivity
- Bond Hybridization Practice
- Structure and Bonding Practice Quizzes
- Resonance Structures Practice
02 Acid Base Reactions
- Introduction to Acid-Base Reactions
- Acid Base Reactions In Organic Chemistry
- The Stronger The Acid, The Weaker The Conjugate Base
- Walkthrough of Acid-Base Reactions (3) - Acidity Trends
- Five Key Factors That Influence Acidity
- Acid-Base Reactions: Introducing Ka and 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
- How Protonation and Deprotonation Affect Reactivity
- Acid Base Practice Problems
03 Alkanes and 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
- Wedge And Dash Convention For Tetrahedral Carbon
- Common Mistakes in Organic Chemistry: Pentavalent Carbon
- Table of Functional Group Priorities for Nomenclature
- Summary Sheet - Alkane Nomenclature
- Organic Chemistry IUPAC Nomenclature Demystified With A Simple Puzzle Piece Approach
- Boiling Point Quizzes
- Organic Chemistry Nomenclature Quizzes
04 Conformations and Cycloalkanes
- Staggered vs Eclipsed Conformations of Ethane
- Conformational Isomers of Propane
- Newman Projection of Butane (and Gauche Conformation)
- 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)
- Newman Projection Practice
- Cycloalkanes Practice Problems
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?
- What makes a good leaving group?
- 3 Factors That Stabilize Carbocations
- Equilibrium and Energy Relationships
- 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
- Free Radicals Practice Quizzes
07 Stereochemistry and Chirality
- Types of Isomers: Constitutional Isomers, Stereoisomers, Enantiomers, and Diastereomers
- How To Draw The Enantiomer Of A Chiral Molecule
- How To Draw A Bond Rotation
- Introduction to Assigning (R) and (S): The Cahn-Ingold-Prelog Rules
- Assigning Cahn-Ingold-Prelog (CIP) Priorities (2) - The Method of Dots
- 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
- On Cats, Part 4: Enantiocats
- On Cats, Part 6: Stereocenters
- Stereochemistry Practice Problems and Quizzes
08 Substitution Reactions
- Introduction to Nucleophilic Substitution Reactions
- Walkthrough of Substitution Reactions (1) - Introduction
- Two Types of Nucleophilic Substitution Reactions
- The SN2 Mechanism
- 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
- Common Blind Spot: Intramolecular Reactions
- The Conjugate Base is Always a Stronger Nucleophile
- Substitution Practice - SN1
- Substitution Practice - SN2
09 Elimination Reactions
- Elimination Reactions (1): Introduction And The Key Pattern
- Elimination Reactions (2): The Zaitsev Rule
- Elimination Reactions Are Favored By Heat
- Two Elimination Reaction Patterns
- The E1 Reaction
- The E2 Mechanism
- E1 vs E2: Comparing the E1 and E2 Reactions
- Antiperiplanar Relationships: The E2 Reaction and Cyclohexane Rings
- Bulky Bases in Elimination Reactions
- Comparing the E1 vs SN1 Reactions
- Elimination (E1) Reactions With Rearrangements
- E1cB - Elimination (Unimolecular) Conjugate Base
- Elimination (E1) Practice Problems And Solutions
- Elimination (E2) Practice Problems and Solutions
11 SN1/SN2/E1/E2 Decision
- Identifying Where Substitution and Elimination Reactions Happen
- Deciding SN1/SN2/E1/E2 (1) - The Substrate
- Deciding SN1/SN2/E1/E2 (2) - The Nucleophile/Base
- SN1 vs E1 and SN2 vs E2 : The Temperature
- Deciding SN1/SN2/E1/E2 - The Solvent
- Wrapup: The Quick N' Dirty Guide To SN1/SN2/E1/E2
- Alkyl Halide Reaction Map And Summary
- SN1 SN2 E1 E2 Practice Problems
12 Alkene Reactions
- E and Z Notation For Alkenes (+ Cis/Trans)
- Alkene Stability
- Addition Reactions: Elimination's Opposite
- Selective vs. Specific
- Regioselectivity In Alkene Addition Reactions
- Stereoselectivity In Alkene Addition Reactions: Syn vs Anti Addition
- Hydrohalogenation of Alkenes and Markovnikov's Rule
- Hydration of Alkenes With Aqueous Acid
- Rearrangements in Alkene Addition Reactions
- Addition Pattern #1: The "Carbocation Pathway"
- Halogenation of Alkenes and Halohydrin Formation
- Oxymercuration Demercuration of Alkenes
- Alkene Addition Pattern #2: The "Three-Membered Ring" Pathway
- Hydroboration Oxidation of Alkenes
- m-CPBA (meta-chloroperoxybenzoic acid)
- OsO4 (Osmium Tetroxide) for Dihydroxylation of Alkenes
- Palladium on Carbon (Pd/C) for Catalytic Hydrogenation
- Cyclopropanation of Alkenes
- Alkene Addition Pattern #3: The "Concerted" Pathway
- 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
- Alkene Reactions Practice Problems
13 Alkyne Reactions
- Acetylides from Alkynes, And Substitution Reactions of Acetylides
- Partial Reduction of Alkynes With Lindlar's Catalyst or Na/NH3 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
- Alkyne Reactions Practice Problems With Answers
14 Alcohols, Epoxides and Ethers
- Alcohols - Nomenclature and Properties
- Alcohols Can Act As Acids Or Bases (And Why It Matters)
- Alcohols - Acidity and Basicity
- The Williamson Ether Synthesis
- 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 The Mechanisms of Alcohol Oxidations
- 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)
- Alcohol Reaction Practice Problems
- Epoxide Reaction Quizzes
- Oxidation and Reduction Practice Quizzes
- What's An Organometallic?
- Formation of Grignard and Organolithium Reagents
- Organometallics Are Strong Bases
- Reactions of Grignard Reagents
- Protecting Groups In Grignard Reactions
- Synthesis Problems Involving Grignard Reagents
- Grignard Reactions And Synthesis (2)
- Organocuprates (Gilman Reagents): How They're Made
- Gilman Reagents (Organocuprates): What They're Used For
- The Heck, Suzuki, and Olefin Metathesis Reactions (And Why They Don't Belong In Most Introductory Organic Chemistry Courses)
- Reaction Map: Reactions of Organometallics
- Grignard Practice Problems
- 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
- 1H NMR: How Many Signals?
- Homotopic, Enantiotopic, Diastereotopic
- Diastereotopic Protons in 1H NMR Spectroscopy: Examples
- C13 NMR - How Many Signals
- 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
- 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 Products
- 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
- The Intramolecular Diels Alder Reaction
- Regiochemistry In The Diels-Alder Reaction
- The Cope and Claisen Rearrangements
- Electrocyclic Reactions
- Electrocyclic Ring Opening And Closure (2) - Six (or Eight) Pi Electrons
- Diels Alder Practice Problems
- Molecular Orbital Theory Practice
- Introduction To Aromaticity
- Rules For Aromaticity
- Huckel's Rule: What Does 4n+2 Mean?
- Aromatic, Non-Aromatic, or Antiaromatic? Some Practice Problems
- Antiaromatic Compounds and Antiaromaticity
- The Pi Molecular Orbitals of Benzene
- The Pi Molecular Orbitals of Cyclobutadiene
- Frost Circles
- Aromaticity Practice Quizzes
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
- Birch Reduction
- Synthesis (7): Reaction Map of Benzene and Related Aromatic Compounds
- Aromatic Reactions and Synthesis Practice
- Electrophilic Aromatic Substitution Practice Problems
20 Aldehydes and Ketones
- What's The Alpha Carbon In Carbonyl Compounds?
- Nucleophilic Addition To Carbonyls
- Aldehydes and Ketones: 14 Reactions With The Same Mechanism
- Sodium Borohydride (NaBH4) Reduction of Aldehydes and Ketones
- Grignard Reagents For Addition To Aldehydes and Ketones
- Wittig Reaction
- Hydrates, Hemiacetals, and Acetals
- Imines - Properties, Formation, Reactions, and Mechanisms
- All About Enamines
- Breaking Down Carbonyl Reaction Mechanisms: Reactions of Anionic Nucleophiles (Part 2)
- Aldehydes Ketones Reaction Practice
21 Carboxylic Acid Derivatives
- Nucleophilic Acyl Substitution (With Negatively Charged Nucleophiles)
- Addition-Elimination Mechanisms With Neutral Nucleophiles (Including Acid Catalysis)
- Basic Hydrolysis of Esters - Saponification
- Proton Transfer
- Fischer Esterification - Carboxylic Acid to Ester Under Acidic Conditions
- Lithium Aluminum Hydride (LiAlH4) For Reduction of Carboxylic Acid Derivatives
- LiAlH[Ot-Bu]3 For The Reduction of Acid Halides To Aldehydes
- Di-isobutyl Aluminum Hydride (DIBAL) For The Partial Reduction of Esters and Nitriles
- Amide Hydrolysis
- Thionyl Chloride (SOCl2)
- Diazomethane (CH2N2)
- Carbonyl Chemistry: Learn Six Mechanisms For the Price Of One
- Making Music With Mechanisms (PADPED)
- Carboxylic Acid Derivatives Practice Questions
22 Enols and Enolates
- Keto-Enol Tautomerism
- Enolates - Formation, Stability, and Simple Reactions
- Kinetic Versus Thermodynamic Enolates
- Aldol Addition and Condensation Reactions
- Reactions of Enols - Acid-Catalyzed Aldol, Halogenation, and Mannich Reactions
- Claisen Condensation and Dieckmann Condensation
- The Malonic Ester and Acetoacetic Ester Synthesis
- The Michael Addition Reaction and Conjugate Addition
- The Robinson Annulation
- Haloform Reaction
- The Hell–Volhard–Zelinsky Reaction
- Enols and Enolates Practice Quizzes
- 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
- Amine Practice Questions
- D and L Notation For Sugars
- Pyranoses and Furanoses: Ring-Chain Tautomerism In Sugars
- What is Mutarotation?
- Reducing 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
- Isoelectric Points of Amino Acids (and How To Calculate Them)
- Carbohydrates Practice
- Amino Acid Quizzes
25 Fun and Miscellaneous
- Organic Chemistry GIFS - Resonance Forms
- 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" ?
- Intramolecular Reactions of Alcohols and Ethers
- 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)
- Reproducibility In Organic Chemistry
- 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
- How Reactions Are Like Music