Substitution Reactions
By James Ashenhurst
Introduction to Nucleophilic Substitution Reactions
Last updated: March 22nd, 2019
Following up on the 4 most important patters of reactions in Org 1, and introduction to acid-base reactions, here’s the second major pattern. It’s called nucleophilic substitution. I won’t go into nucleophiles and electrophiles in this post. The point is actually not to understand what’s going on here!
Don’t understand the reactions below. Just focus on being able to see one thing: what bonds are formed and what bonds are broken.
Just that one thing. Later on we’ll go into more detail about why things happen. But not today.
Here are three examples of nucleophilic substitution reactions.
What’s the pattern? In each case, we’re breaking a bond at carbon, and forming a new bond at carbon. (and yes, salts form too… but this is organic chemistry, so we’re carbo-centric.)
This is an extremely common pattern for reactions and you will see it over and over again in Org 1 and Org 2.
Now let’s set the stage for later discussion. Here’s some interesting results that experiments tell us. We don’t get this information by thinking about what happens and predicting – we have to interrogate nature in order to get her to give up her secrets.
Interesting observation #1: when we measure the reaction rate. In some substitution reactions the rate is proportional to the concentration of two different species (e.g. the alcohol and HBr). In other cases, it only depends on the concentration of one species (i.e. the alcohol). Interesting!
Interesting observation #2: In certain cases (like the reaction below) the reaction rate depends on the type of alkyl halide. Primary alkyl halides are slow, but tertiary alkyl halides are fast.
Interesting observation #3: In other cases, the reaction rate depends on the type of alkyl halide, but it is the primary alkyl halide that is fast. And the tertiary alkyl halide does not even give substitution products… you’ll notice the double bond there. This is actually an elimination reaction.
Interesting observation #4: Finally, there is a property that *some* molecules have of rotating plane polarized light. It’s been known since the late 19th century. In some substitution reactions, molecules that are “optically active” retain their optical activity in the reaction… but in others, this “optical activity” disappears.
What’s going on? How can we come up with a hypothesis for why and how these reactions work?
Next Post In The Series on Key Reactions: Introduction To Addition Reactions
OR
Get Started Learning About Substitution Reactions, in the Series: Walkthrough Of Substitution Reactions
Related Posts:
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 Is Tetrahedral?
- Hybrid Orbitals
- A Hybridization Shortcut
- 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
- Putting Acidity In Perspective
- 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
- Conformations
- Newman Projections
- Putting the Newman into ACTION
- Introduction to Cycloalkanes (1)
- Cis And Trans Cycloalkanes
- Cycloalkanes - How To Calculate Ring Strain
- Cycloalkanes - Ring Strain In Cyclopropane And Cyclobutane
- Ring Strain in Cyclopentane and Cyclohexane
- An Aerial Tour Of The Cyclohexane Chair
- How To Draw A Cyclohexane Chair
- The Cyclohexane Chair Flip
- The Cyclohexane Chair Flip - Energy Diagram
- Substituted Cyclohexanes - Equatorial vs Axial
- Substituted Cyclohexanes: "A Values"
- The Ups and Downs of Cyclohexanes
- Which Cyclohexane Chair Is Of Lower Energy?
- Fused Rings
- Bridged Bicyclic Rings (And How To Name Them)
- 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 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
- Isomers From Free Radical Reactions
- Selectivity In Free Radical Reactions
- Selectivity in Free Radical Reactions: Bromine vs. Chlorine
- 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
- Determining R/S (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)
- 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
- 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
09 Elimination Reactions
- Walkthrough of Elimination Reactions (1)
- Elimination Reactions (2): Zaitsev's 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
10 Rearrangements
11 SN1/SN2/E1/E2 Decision
12 Alkene Reactions
- Alkene Nomenclature: Cis and Trans and E and Z
- Addition Reactions: Elimination's Opposite
- Selective vs. Specific
- Addition Reactions: Regioselectivity
- Addition Reactions: Stereochemistry
- Markovnikov's Rule (1)
- Markovnikov's Rule (2) - Why It Works
- Curved Arrows and Addition Reactions
- Addition Pattern #1: The "Carbocation Pathway"
- Rearrangements in Alkene Addition Reactions
- Bromination of Alkenes - How Does It Work?
- Bromination of Alkenes: The Mechanism
- Alkene Addition Pattern #2: The "Three-Membered Ring" Pathway
- Hydroboration of Alkenes
- Hydroboration of Alkenes: The Mechanism
- Alkene Addition Pattern #3: The "Concerted" Pathway
- An Arrow-Pushing Dilemma In Concerted Reactions
- A Fourth Alkene Addition Pattern - Free Radical Addition
- Alkene Reactions: Ozonolysis
- Summary: Alkene Reaction Pathways
- Synthesis (4) - Reactions of Alkenes
13 Alkyne Reactions
- The 2 Most Important Reactions of Alkynes
- Partial Reduction of Alkynes To Obtain Cis or Trans Alkenes
- Hydroboration and Oxymercuration of Alkynes
- Alkyne Reaction Patterns - The Carbocation Pathway
- Alkyne Addition Reactions: The 3-Membered Ring Pathway
- Alkyne Addition Reactions - The "Concerted" Pathway
- Alkynes Via Elimination Reactions
- Alkynes Are A Blank Canvas
- Synthesis (5) - Reactions of Alkynes
14 Alcohols, Epoxides and Ethers
- Alcohols (1) - Nomenclature and Properties
- How To Make Alcohols More Reactive
- Alcohols (3) - Acidity and Basicity
- The Williamson Ether Synthesis
- Williamson Ether Synthesis: Planning
- Synthesis of Ethers (2) - Back To The Future
- Ether Synthesis Via Alcohols And Acid
- Cleavage Of Ethers With Acid
- Epoxides - The Outlier Of The Ether Family
- Opening Of Epoxide With Base
- Opening of Epoxides With Acid
- 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 and the SNi Mechanism
- Synthesis (6) - Reactions of Alcohols
15 Organometallics
- What's An Organometallic?
- Synthesis of Grignard and Organolithium Reagents
- Organometallics Are Strong Bases
- Reactions of Grignard Reagents
- Protecting Groups In Grignard Reactions
- Synthesis Using Grignard Reagents (1)
- Grignard Reactions And Synthesis (2)
- Gilman Reagents (Organocuprates): 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
16 Spectroscopy
- Degrees of Unsaturation (Index of Hydrogen Deficiency)
- How Bleach Works: Understanding Colors From Nature
- Introduction To UV-Vis Spectroscopy
- UV-Vis Spectroscopy: Absorbance of Carbonyls
- UV-Vis Spectroscopy: Some Practice Questions
- Bond Vibrations, IR Spectroscopy, and the "Ball and Spring" Model
- Infrared Spectroscopy: A Quick Primer On Interpreting Spectra
- IR Spectroscopy: Some Simple Practice Problems
- Homotopic, Enantiotopic, Diastereotopic
- Liquid Gold: Pheromones In Doe Urine
- Natural Product Isolation (1) - Extraction
- Natural Product Isolation (2) - Purification of Crude Mixtures 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
- Molecular Orbital Diagram For A Simple Pi Bond - Bonding And Antibonding
- 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
- Molecular Orbitals 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
18 Aromaticity
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
- 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 of Diazonium Salts: Sandmeyer and Related Reactions
- 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"
- Aromatic Synthesis (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
- The Simple Two-Step Pattern For Seven Key Reactions of Aldehydes and Ketones
- Wittig Reaction
- Imines and Enamines
- Acid Catalysis Of Carbonyl Addition Reactions: Too Much Of A Good Thing?
- On Acetals and Hemiacetals
- Carbonyl Chemistry: 10 Key Concepts (Part 1)
- Carbonyls: 10 key concepts (Part 2)
- 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
- The Magic Wand of Proton Transfer
- The Power of Acid Catalysis
22 Enols and Enolates
23 Amines
- Amides: Properties, Synthesis, and Nomenclature
- Basicity of Amines And pKaH
- 5 Factors That Affect Basicity 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
- Introduction to Peptide Synthesis
- The Strecker Synthesis of Amino Acids
24 Carbohydrates
- D and L Sugars
- What is Mutarotation?
- Reducing Sugars
- Pyranoses and Furanoses: Ring-Chain Tautomerism In Sugars
- The Big Damn Post Of Sugar Nomenclature
- 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" ?
- Introduction To Synthesis
- 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
(Psst. – The second equation under example #1 is incorrect, unless you intended to show that no reaction occurs.)
Thanks! Fixed
very nice!!
Please give little more explanation regarding example #3
This is a classic example of an E2 being favored over SN2, see this post (and those previous) – https://masterorganicchemistry.com/2013/01/18/wrapup-the-quick-n-dirty-guide-to-sn1sn2e1e2/
1) In example #3, should the products be 2-methyl propan-2-ol and NaBr instead of HBr (in the reaction that doesn’t take place, assuming it did).
2)In #4, why isn’t the second compound optically active? Isn’t C3 acting as a chiral centre for the compound?
a) Because the SN2 reaction does not operate on tertiary alkyl halides. b) C3 is a chiral centre, but the molecule loses optical activity (becomes racemic) due to the fact that it proceeds through an SN1 mechanism (containing a carbocation)
I think that, the final product in example 4 “3-methylhexan-3-ol” is an optically active. The central carbon still attached with 4 different substituent group.
There is a chiral centre, but it can still be optically inactive if it is present as a 1:1 mixture of enantiomers.