What Makes A Good Nucleophile?

• “Initial Tails” and “Final Heads”
• 3 Ways To Make OH A Better Leaving Group
• A Simple Formula For 7 Important Aldehyde/Ketone Reactions
• Acetoacetic
• Acids (Again!)
• Activating and Deactivating
• Actors In Every Acid Base Reaction
• Addition – Elimination
• Addition Pattern 1 – Carbocations
• Addition pattern 2 – 3 membered rings
• Addition Reactions
• Aldehydes And Ketones – Addition
• Alkene Pattern #3 – The “Concerted” Pathway
• Alkyl Rearrangements
• Alkynes – 3 Patterns
• Alkynes: Deprotonation and SN2
• Amines
• Aromaticity: Lone Pairs
• Avoid These Resonance Mistakes
• Best Way To Form Amines
• Bulky Bases
• Carbocation Stability
• Carbocation Stability Revisited
• Carboxylic Acids are Acids
• Chair Flips
• Cis and Trans
• Conformations
• Conjugate Addition
• Curved Arrow Refresher
• Curved Arrows
• Decarboxylation
• Determining Aromaticity
• Diels Alder Reaction – 1
• Dipoles: Polar vs. Covalent Bonding
• E2 Reactions
• Electronegativity Is Greed For Electrons
• Electrophilic Aromatic Substitution – Directing Groups
• Elimination Reactions
• Enantiocats and Diastereocats
• Enolates
• Epoxides – Basic and Acidic
• Evaluating Resonance Forms
• Figuring Out The Fischer
• Find That Which Is Hidden
• Formal Charge
• Frost Circles
• Gabriel Synthesis
• Grignards
• Hofmann Elimination
• How Acidity and Basicity Are Related
• How Are These Molecules Related?
• How Stereochemistry matters
• How To Stabilize Negative Charge
• How To Tell Enantiomers From Diastereomers
• Hybridization
• Hybridization Shortcut
• Hydroboration
• Imines and Enamines
• Importance of Stereochemistry
• Intermolecular Forces
• Intro to Resonance
• Ketones on Acid
• Kinetic Thermodynamic
• Making Alcohols Into Good Leaving Groups
• Markovnikov’s rule
• Mechanisms Like Chords
• Mish Mashamine
• More On The E2
• Newman Projections
• Nucleophiles & Electrophiles
• Nucleophilic Aromatic Substitution
• Nucleophilic Aromatic Substitution 2
• Order of Operations!
• Oxidation And Reduction
• Oxidative Cleavage
• Paped
• Pi Donation
• Pointers on Free Radical Reactions
• Protecting Groups
• Protecting Groups
• Proton Transfer
• Putting it together (1)
• Putting it together (2)
• Putting it together (3)
• Putting the Newman into ACTION
• Reaction Maps
• Rearrangements
• Recognizing Endo and Exo
• Redraw / Modify
• Robinson Annulation
• Robinson Annulation Mech
• Sigma and Pi Bonding
• SN1 vs SN2
• sn1/sn2 – Putting It Together
• sn1/sn2/e1/e2 – Exceptions
• sn1/sn2/e1/e2 – Nucleophile
• sn1/sn2/e1/e2 – Solvent
• sn1/sn2/e1/e2 – Substrate
• sn1/sn2/e1/e2 – Temperature
• Stereochemistry
• Strong Acid Strong Base
• Strong And Weak Oxidants
• Strong and Weak Reductants
• Stronger Donor Wins
• Substitution
• Sugars (2)
• Synthesis (1) – “What’s Different?”
• Synthesis (2) – What Reactions?
• Synthesis (3) – Figuring Out The Order
• Synthesis Part 1
• Synthesis Study Buddy
• Synthesis: Walkthrough of A Sample Problem
• Synthesis: Working Backwards
• t-butyl
• Tautomerism
• The 4 Actors In Every Acid-Base Reaction
  • Conjugation
• The Claisen Condensation
• The E1 Reaction
• The Inflection Point
• The Meso Trap
• The Michael Reaction
• The Nucleophile Adds Twice (to the ester)
• The One-Sentence Summary Of Chemistry
• The Second Most Important Carbonyl Mechanism
• The Single Swap Rule
• The SN1 Reaction
• The SN2 Reaction
• The Wittig Reaction
• Three Exam Tips
• Tips On Building Molecular Orbitals
• Top 10 Skills
• Try The Acid-Base Reaction First
• Two Key Reactions of Enolates
• What makes a good leaving group?
• What Makes A Good Nucleophile?
• What to expect in Org 2
• Work Backwards
• Zaitsev’s Rule

As I said yesterday, in a substitution reaction, the nucleophile is the species that gives up a lone pair of electrons to the electrophile.

Let’s talk about the factors that affect nucleophilicity.
First, nucleophilicity and basicity are very similar. One difference is that nucleophile strength is measured by how fast it reacts, whereas acid-base strength is measured by equilibrium (pKa).  Also, substitution reactions are much more subject to steric hindrance than acid-base reactions. It’s OK to think of nucleophilicity as correlating with basicity, with two exceptions (cases 3 and 4, below).

For now, let’s just think of nucleophiles as lone pairs on atoms.(Note 1). Imagine comparing two compounds, and asking “which of these is most nucleophilic?”.

So what would make one atom more likely to give up its lone pair of electrons than another? There are at least four factors.

1. Charge.“The conjugate base is always a better nucleophile”. HO- is a better nucleophile than H2O. NH2(-) is a better nucleophile than NH3. HS(-) is a better nucleophile than H2S. The greater the negative charge, the more likely an atom will give up its pair of electrons to form a bond.
2. Electronegativity. Nucleophilicity increases as you go to the left along the periodic table.

H3C(-) > H2N(-) > HO(-) > F(-)

This makes sense when you think about it, electronegativity – “greed for electrons” – is the opposite of nucleophilicity – “giving away electrons”.

3. Hydrogen bonding solvents (polar protic solvents) 

This causes the most confusion, because it is solvent-dependent. In polar protic solvents (e.g. water and alcohols, any solvent with OH) nucleophilicity increases as you go down the periodic table (F- < Cl- < Br- < I – ). In polar aprotic solvents (e.g. DMSO, acetone) the order is reversed, and the most basic nucleophiles are also the most nucleophilic. (F- > Cl – > Br – > I – ).

Why is this? Because hydrogen bonding has a dramatic effect on nucleophilicity. In hydrogen bonding solvents (polar protic solvents) the most basic nucleophiles (e.g. F-) are surrounded by an entourage of solvent molecules. It might help for you to think that this makes them far more “sterically hindered” than they would normally be, and they are less reactive.

By contrast, the least basic nucleophiles  (e.g. I-) get involved with less hydrogen bonding, and are less hindered – therefore more nucleophilic.

4. Steric bulk

Remember the Pavlovian association between “t-butyl” and “steric hindrance”  I mentioned earlier? Here it comes again!

The bulkier the groups that are adjacent to a nucleophilic atom, the slower the reaction will be (and hence the poorer the nucleophile).

Phew! that’s a lot. Here’s a little table that should help to make sense of things.

Tomorrow: What makes a good leaving group?

Thanks for reading! James

P.S. Note 1   (Pi bonds – found in alkenes and alkynes – can act like nucleophiles too, but that’s a subject for later).