Home / Reagent Friday: Lithium Di-isopropyl Amide (LDA)
Organic Reagents
Reagent Friday: Lithium Di-isopropyl Amide (LDA)
Last updated: October 16th, 2020 |
Lithium Diisopropyl Amide (LDA), A Strong, Sterically Hindered Base
In a blatant plug for the Reagent Guide, each Friday I profile a different reagent that is commonly encountered in Org 1/ Org 2. Version 1.2 just got released last week, with a host of corrections and a new page index.
If NaNH2 is a piranha, then today’s reagent – lithium diisopropylamide (LDA) is like a hammerhead shark. It’s also got a powerful bite, but that distinctive proboscis can get in the way. So LDA can’t reach into tight spaces the same way that NaNH2 can.
Formation Of Less Hindered (“Kinetic”) Enolates With LDA
In other words: LDA is a strong, bulky base. The most common use of LDA is in the formation of enolates. In the example below, notice how both carbons flanking the C=O have C-H bonds? LDA will remove the proton selectively from the carbon substituted with the fewest number of carbons:
Also note the temperature (–78 °C). There’s nothing special about –78° relative to –72° or –60° for this to work – it’s just that cold temperatures improve the selectivity, and –78°C happens to be the temperature of a very cheaply prepared cold bath (dry ice and acetone). A common solvent for this is tetrahydrofuran (THF).
Alkylation, Halogenation, And Aldol Reaction Of Enolates Obtained With Lithium Diisopropylamide
Why is LDA useful? Well, enolates are extremely useful nucleophiles, able to participate in SN2 reactions with alkyl halides as well as the aldol reaction (among many other things). If we used NaNH2 to form an enolate like this, we’d likely get a mixture of two enolates, which would lead to a mixture of products. The selectivity of LDA in forming the less substituted enolate makes it extremely useful.
Formation of Less-Substituted Alkenes (“Non-Zaitsev” or “Hoffmann” Products) In Elimination Reactions
Although less common, LDA can also be used for the formation of “Hoffman” products in elimination reactions. The usual base for this is potassium t-butoxide, but LDA can do it too:
Formation Of Less Substituted Enolates With LDA: Mechanism
How it works:
This diagram below shows the reaction between LDA and the ketone. Note the bonds that are forming (N-H, C-C) and the bonds that are breaking (C–H, C–O). The enolate that is formed has a resonance isomer where the negative charge is on the carbon. This is, in some respects, the more “important” resonance form, as it is the carbon that tends to be a better nucleophile than oxygen in reactions of enolates.
P.S. You can read about the chemistry of LDA and more than 80 other reagents in undergraduate organic chemistry in the “Organic Chemistry Reagent Guide”, available here as a downloadable PDF.
(Advanced) References and Further Reading
- THE α-ALKYLATION OF ENOLATES FROM THE LITHIUM-AMMONIA REDUCTION OF α,β-UNSATURATED KETONES
Gilbert Stork, Perry Rosen, and Norman L. Goldman
Journal of the American Chemical Society 1961, 83 (13), 2965-2966
DOI: 10.1021/ja01474a051
This paper has one of the first descriptions of kinetic enolate formation in the literature – “The success of the trapping of the enolate ion IV depends on the alkylation reaction being faster than equilibration of the initially produced enolate IV to the more stable II via proton transfer with some initially formed neutral alkylated ketone.” - Tetrahedron report number 25: Ketone enolates: regiospecific preparation and synthetic uses
Jean d’Angelo
Tetrahedron 1976, 32 (24), 2979-2990
DOI: 10.1016/0040-4020(76)80156-1
This review covers various methods for enolate formation, and has data on the composition of various ketone-enolate mixtures formed under kinetic and thermodynamic conditions.Prof. H. O. House (MIT, then Georgia Tech) published a series of papers on carbanion and enolate chemistry, studying kinetic and thermodynamic enolate formation in detail. A selection of these papers is below: - The Chemistry of Carbanions. V. The Enolates Derived from Unsymmetrical Ketones
Herbert O. House and Vera Kramar
The Journal of Organic Chemistry 1963, 28 (12), 3362-3379
DOI: 10.1021/jo01047a022 - The Chemistry of Carbanions. IX. The Potassium and Lithium Enolates Derived from Cyclic Ketones
Herbert O. House and Barry M. Trost
The Journal of Organic Chemistry 1965 30 (5), 1341-1348
DOI: 10.1021/jo01016a001 - Chemistry of carbanions. XV. Stereochemistry of alkylation of 4-tert-butylcyclohexanone
Herbert O. House, Ben A. Tefertiller, and Hugh D. Olmstead
The Journal of Organic Chemistry 1968, 33 (3), 935-942
DOI: 10.1021/jo01267a002 - Thermodynamic and Kinetic Controlled Enolates: A Project for a Problem-Oriented Laboratory Course
Augustine Silveira Jr., Michael A. Knopp, and Jhong Kim
Journal of Chemical Education 1998, 75 (1), 78
DOI: 1021/ed075p78
A paper from J. Chem. Ed. that covers how to demonstrate the concepts of kinetic and thermodynamic enolates in an undergraduate laboratory session.
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
- 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"
- 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
- Learning New Reactions: How Do The Electrons Move?
- 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
- 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
- Learning Organic Chemistry Reactions: A Checklist (PDF)
- 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
- Stereochemistry Practice Problems and Quizzes
08 Substitution Reactions
- Nucleophilic Substitution Reactions - 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
- 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
10 Rearrangements
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 Key Factors For Determining 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
- Alkene Addition Reactions: "Regioselectivity" and "Stereoselectivity" (Syn/Anti)
- Stereoselective and Stereospecific Reactions
- Hydrohalogenation of Alkenes and Markovnikov's Rule
- Hydration of Alkenes With Aqueous Acid
- Rearrangements in Alkene Addition Reactions
- Halogenation of Alkenes and Halohydrin Formation
- Oxymercuration Demercuration of Alkenes
- Hydroboration Oxidation of Alkenes
- m-CPBA (meta-chloroperoxybenzoic acid)
- OsO4 (Osmium Tetroxide) for Dihydroxylation of Alkenes
- Palladium on Carbon (Pd/C) for Catalytic Hydrogenation of Alkenes
- Cyclopropanation of Alkenes
- 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
- Partial Reduction of Alkynes With Na/NH3 To Obtain Trans Alkenes
- Alkyne Hydroboration With "R2BH"
- Hydration and Oxymercuration of Alkynes
- Hydrohalogenation of Alkynes
- 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
15 Organometallics
- 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
16 Spectroscopy
- 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
18 Aromaticity
- 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
- Transesterification
- 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
- Decarboxylation
- 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
23 Amines
- 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
24 Carbohydrates
- 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
- A Gallery of Some Interesting Molecules From Nature
- 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
- On Cats, Part 4: Enantiocats
- On Cats, Part 6: Stereocenters
- Organic Chemistry Is Shit
- The Organic Chemistry Behind "The Pill"
- Maybe they should call them, "Formal Wins" ?
- Why Do Organic Chemists Use Kilocalories?
- The Principle of Least Effort
- Organic Chemistry GIFS - Resonance Forms
- Reproducibility In Organic Chemistry
- What Holds The Nucleus Together?
- How Reactions Are Like Music
- Organic Chemistry and the New MCAT
26 Organic Chemistry Tips and Tricks
- Common Mistakes: Formal Charges Can Mislead
- Partial Charges Give Clues About Electron Flow
- Draw The Ugly Version First
- Organic Chemistry Study Tips: Learn the Trends
- The 8 Types of Arrows In Organic Chemistry, Explained
- Top 10 Skills To Master Before An Organic Chemistry 2 Final
- Common Mistakes with Carbonyls: Carboxylic Acids... Are Acids!
- Planning Organic Synthesis With "Reaction Maps"
- Alkene Addition Pattern #1: The "Carbocation Pathway"
- Alkene Addition Pattern #2: The "Three-Membered Ring" Pathway
- Alkene Addition Pattern #3: The "Concerted" Pathway
- Number Your Carbons!
- The 4 Major Classes of Reactions in Org 1
- How (and why) electrons flow
- Grossman's Rule
- Three Exam Tips
- A 3-Step Method For Thinking Through Synthesis Problems
- Putting It Together
- Putting Diels-Alder Products in Perspective
- The Ups and Downs of Cyclohexanes
- The Most Annoying Exceptions in Org 1 (Part 1)
- The Most Annoying Exceptions in Org 1 (Part 2)
- The Marriage May Be Bad, But the Divorce Still Costs Money
- 9 Nomenclature Conventions To Know
- Nucleophile attacks Electrophile
27 Case Studies of Successful O-Chem Students
- Success Stories: How Corina Got The The "Hard" Professor - And Got An A+ Anyway
- How Helena Aced Organic Chemistry
- From a "Drop" To B+ in Org 2 – How A Hard Working Student Turned It Around
- How Serge Aced Organic Chemistry
- Success Stories: How Zach Aced Organic Chemistry 1
- Success Stories: How Kari Went From C– to B+
- How Esther Bounced Back From a "C" To Get A's In Organic Chemistry 1 And 2
- How Tyrell Got The Highest Grade In Her Organic Chemistry Course
- This Is Why Students Use Flashcards
- Success Stories: How Stu Aced Organic Chemistry
- How John Pulled Up His Organic Chemistry Exam Grades
- Success Stories: How Nathan Aced Organic Chemistry (Without It Taking Over His Life)
- How Chris Aced Org 1 and Org 2
- Interview: How Jay Got an A+ In Organic Chemistry
- How to Do Well in Organic Chemistry: One Student's Advice
- "America's Top TA" Shares His Secrets For Teaching O-Chem
- "Organic Chemistry Is Like..." - A Few Metaphors
- How To Do Well In Organic Chemistry: Advice From A Tutor
- Guest post: "I went from being afraid of tests to actually looking forward to them".
What will the attaching position of LDA for 1-chloro-3,4-difluorobenzene?
LDA will not attach, but it may be strong enough to form an aryne. For example one could deprotonate C-H and elimination of the best leaving group (Cl) would give an aryne, which could then undergo attack by a nucleophile. When the nucleophile does attack, it will likely do so such that the negative charge is placed closer to the electron withdrawing fluoro groups.
See this artice on arynes – possibly helpful. https://www.masterorganicchemistry.com/2018/09/17/nucleophilic-aromatic-substitution-2-benzyne/
How does LDA react with a benzene ring?
Sometimes on benzene rings with a good leaving group it will deprotonate C-H adjacent to the carbon with a good leaving group, resulting in a new pi bond. These species are called “arynes”. https://www.masterorganicchemistry.com/2018/09/17/nucleophilic-aromatic-substitution-2-benzyne/
Why does it have amide in the end, even though amide linkage is not seen in LDA ?
Confusingly, the name for the amide linkage you speak of, and the name of the conjugate base of an amine are both “amide”. Some chemists pronounce the two differently but that doesn’t really translate to the written word. It’s helpful to use the term “metal amide” when referring to the conjugate base – this differentiates it from the (neutral) functional group.
Uhm, the reaction of NaNH2 is with a terminal alkyne. Can internal alkynes react with NaNH2?
The pKa of the CH3 adjacent to a triple bond is at least 40, so without significant heating, no.
How to decompose LDA?
Why do you want to decompose it? Just cool it in an ice bath and (slowly) add saturated NH4Cl as a mild acid.
What does LDA do if you have equal substitution at either side of the ketone? Is it possible to can count carbons to determine least substituted (if we had methyl vs, ethyl, not isopropyl, for example in #2). In this case will addition occur on the side of the methyl?
Not sure about methyl vs ethyl, but methyl vs. primary alkyl gives about 95:5 favoring the methyl, so long as it is kept at -78 and the enolate isn’t allowed to equilibrate.
Why LDA, NaNH2 called as amide even without amide functionality in it. Thank You
Because chemists use the word “amide” to describe two completely different functional groups: the conjugate bases of amines (e.g. sodium amide) and also carboxylic acid derivatives with nitrogens adjacent to the carbonyl. That’s just the way it is.
Hello,
do you know in what cases we’d use n-BuLi over LDA?
Will there be a change in mechanism for the reaction at room temperature?
No, but there will be a change in selectivity. It won’t be as selective for the less substituted enolate at a higher temperature.
Though there is no amide group then why LDA is named as lithium Di isopropyl amide?
Confusingly, the term “amide” refers both to a deprotonated amine, and also a carbonyl derivative with a nitrogen substituent.
Hi James,
I love your site! I understand basically how LDA works, thanks so much for that. I do have a situation question to better understand. I get that if you are adding an alkyl halide to a carbonyl compound it will add to the least substituted carbon. However, if you are adding a dihalide alkene, where will the akyl compound attach? Is it still least substituted (due to bulky nature)? Is it always the end halide? IE: If we have 1,2 dibromo but-2-ene, will it attach at the 1 carbon because it always attaches at the end? Or the 1 carbon because it’s least substituted? Or the 2 carbon because things like to mess with double bonds? Or a mixture because both are likely to happen? Does it matter if the butene is cis or trans (since that makes the 2 carbon more or less accessible)? Thanks, just trying to understand better how this mechanism works.
Alkylation of enolates with alkyl halides is an SN2 reaction, and SN2 reactions will only occur at sp3-hybridized carbons. In the reaction you describe, only the 1-carbon is sp3-hybridized, and thus the enolate will perform substitution at C-1. The C-Br bond at C2 will be unaffected. Sorry for taking so long to get back to you.
Does NaNH2 also give Hoffmann product like LDA in dehydrohalogenation?
No, since NaNH2 is small, I would expect it to give the Zaitsev product.
how LDA reacts with heptanedinitrile or cn-ch2-ch2-ch2-ch2-ch2-cn
Deprotonates the carbon adjacent to CN
This might be slightly off topic. My textbook mentions that lithium enolates cannot participate in conjugate addition, only direct carbonyl addition because the lithium coordinates with the electrophile’s carbonyl oxygen and the reaction occurs through a cyclic chair-like transition state. Do you perhaps have any insight on that because I have a bunch of homework problems which does agree with this
does not*
TL;DR Your textbook is pretty much correct. “Cannot” is a pretty strong word, because there are always exceptions*, but on the whole it’s a good rule of thumb.
More detail: It depends on the nature of the carbonyl. Alpha,beta unsaturated aldehydes, for instance, will almost always undergo 1,2 addition. With alpha beta unsaturated ketones, and especially alpha beta unsaturated esters, there is a lot of wiggle room. [1,4 addition to an ester is particularly favoured vs 12 addition, since you’re going from a ketone enolate to a (less stable) ester enolate.] The steric hindrance around the carbonyl and the beta position will also be important, as will the choice of solvent. Since you’re likely dealing with an advanced textbook, I’ll use the more advanced terminology “hard” and “soft”.
A lithium enolate is a relatively “hard” nucleophile and is more likely to react at the “hard” carbonyl electrophilic site. Lithium ion coordination would help with this, as would solvents that facilitate aggregation (e.g. ethereal solvents like THF and Et2O).
It’s possible to favor 1,4 addition by using a base with a larger, less-coordinating counterion (such as potassium instead of lithium) and using a polar aprotic “co-solvent” such as HMPA which will break up aggregation. These reactions tend to go through open transition states rather than through the Zimmerman-Traxler six-membered transition state that you mentioned.
*Exceptions? Sure. Like if you formed a lithium enolate in a molecule which also contained an alpha beta unsaturated ketone, and 1,4-addition would form a 5 or 6 membered ring. Much faster than 1,2 addition in that case, due to ring closure rates.
Another example would be sterically hindered ketones.
Digging through my copy of March (5th ed) chapter 15 on addition to C-C multiple bonds doesn’t mention a specific prohibition of lithium enolates in 1,4 addition, but it’s not uncommon to see people use a Mukaiyama-Michael or a Sakurai reaction (using a Lewis acid in the presence of a silyl enol ether) to perform a 1,4 addition instead of the lithium enolate, likely for the reasons you mentioned.
Thanks for the great question.
1) What is the effect of preparing LDA at higher temperature like -20 C?
2) Is LDA formation instantaneous at -20 C?
LDA formation would essentially be instantaneous at –20 °C. In fact it’s not uncommon to make the LDA at sub-zero temperature and then cool it to -78 prior to using it for enolate formation.
Amazingly explained, thanks! One question tho, how come neither LDA nor LCHIA work with aldehydes?
They add to the aldehyde carbon instead of deprotonating the alpha carbon.
in LDA there is no CO NH bond, but why this is called amide in the name?
They are both called, “amide”. I know it’s confusing.
this may because of the the parent compound from which it has been prepared was an amide
NaNH2 calledd sodamide and LiNH2 called lithium amide
in LDA, two hydrogens replaced by isopropyl group and hence called lithium diisopropylamide
So, basically LDA helps in anti markovnikov reaction mechanisms and hofmann eliminations right ? If that’s the case, then in example 2 shouldn’t the CH3 be on the 3 degree carbon (that’s anti markovnikov)?
Under what conditions is LDA nucleophilic? I have a book (science of synthesis, Houben-Weyl) that says it happens in the absence of a weakly acidic proton donor. For example, it can reduce an alkenylphosphenate by 1,2 addition across the double bond with lithium. But it doesn’t go into further detail, and I’m not sure what in particular a weakly acidic proton donor has to do with this reaction. Do you know anything about LDA functioning as a nucleophile? Thanks!
Is LDA basic enough to abstract the proton from a tertiary alcohol? I’ve seen NaH used but being non-soluble, the reaction can only take place on the interface of the NaH and the tertiary alcohol.
I’ve also seen some recent work in which erbium triflate is used as a catalyst for ether formation from alcohols. Makes sense, but then the choice of methylating agent becomes more limited due to solubility issues.
Oh, absolutely. pKa of tertiary alcohol is about 18, pKa of diisopropylamine is about 36.
Question is why would you want to use LDA? NaH is fine, especially in an ethereal solvent like THF that can coordinate to the sodium.
why you given reagents name friday reagent.?????
Because it was a fun way to talk about reagents, that’s all.
Sir, beautifully explained. I just have one doubt though. What will happen if end carbons of the isopropyl groups are attached toa strong -I group like NO2? Then will the H+ be abstracted by the LDA from the tertiary carbon atom of the isopropyl group?
That reagent doesn’t make very much sense.
The above example of shark is mind blowing. Helped understand the reagent in one stroke.
Glad to hear it!
In example 4, the aldol reaction, wouldn’t be Li+ instead of LiBr?
There’s no bromide anywhere in the reactant side.
In resonance forms atoms do not move about. The picture you have of the Li cation being next to the methanide atom and then close to the oxide atom is actually a dynamic equilibrium. (The picture of a free enolate represents resonance.) This is an important distinction because, by Hard-Soft Acid-Base Theory the hard LI+ is more tightly bound to the hard O- leaving the methanide more available for attack while in KDA the the soft K+ binds preferentially to the soft methanide making the oxide more available for attack.
Dr. Ashenhurst, you say “The most common use of LDA is in the formation of enolates. In the example below, notice how both carbons flanking the C=O have C-H bonds? LDA will remove the proton selectively from the carbon substituted with the fewest number of hydrogens” however it shows that the pi bond is with the alpha carbon and the beta carbon with more hydrogens. so LDA will remove the proton from the beta carbon with the most hydrogens, ie hoffman product.
Oops – typo, fixed. Thanks for the spot.