Best Way To Form Amines
- “Initial Tails” and “Final Heads”
- 3 Ways To Make OH A Better Leaving Group
- A Simple Formula For 7 Important Aldehyde/Ketone Reactions
- 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
- 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
- Conjugate Addition
- Curved Arrow Refresher
- Curved Arrows
- 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
- Epoxides – Basic and Acidic
- Evaluating Resonance Forms
- Figuring Out The Fischer
- Find That Which Is Hidden
- Formal Charge
- Frost Circles
- Gabriel Synthesis
- 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 Shortcut
- 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
- 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
- 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
- Strong Acid Strong Base
- Strong And Weak Oxidants
- Strong and Weak Reductants
- Stronger Donor Wins
- 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
- The 4 Actors In Every Acid-Base Reaction
- 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
So what’s the most useful way to make amines?
Hint: It doesn’t involve the SN2. That can lead to problems such as “over”-alkylation, which gives us (fairly useless) ammonium salts.
The Gabriel synthesis is OK, but it only makes primary amines.
The most useful way to make amines by far, is called “Reductive amination”.
This is just a fancy way of saying that we do two things.
- starting with an amine, and an aldehyde (or ketone), form an imine
- reduce the imine to the amine with a reducing agent.
What makes this such a useful process is that imines are widely accessible from all different types of aldehydes and ketones.
Another neat part about this reaction is that we don’t actually need to isolate the imine in order to reduce it. We can do the whole process in one reaction flask. This means that as soon as the imine is formed, it is attacked by the reducing agent, generating the amine.
In order to do this, the reducing agent has to be stable to the mildly acidic conditions that we use to form imines. Thankfully, there are a number of reducing agents that are effective for this. The most common ones are:
- Sodium cyanoborohydride: NaBH3CN Similar to sodium borohydride, but with an electron withdrawing cyanide group.
- Sodium tri-acetoxy-borohydride: Na H-B(OAc)3 . For our purposes, essentially the same as the ones above. A source of hydride, and a reducing agent.
- Sodium borohydride: NaBH4 Also effective for reducing imines.
Bottom line: all kinds of amines can be formed this way. The image below gives some examples.
This next part is a little more advanced. You can skip it if you want.
Under the slightly acidic condtions we use to form imines (remember – their formation goes through the P A P E D mechanism) the imine will be protonated to give its conjugate acid, called an “iminium”. Iminiums are better electrophiles than imines (“the conjugate acid is always a better electrophile”) and the rate of reduction will be increased under these conditions.
You might remember that primary amines added to aldehydes/ketones give imines, but secondary amines give enamines. That’s because the last step in formation of enamines involved deprotonation – and since there were no hydrogens on the nitrogen, we had to deprotonate the alpha carbon to get there.
Well, here we don’t need to deprotonate for the last step. We’re reacting the reducing agent with the iminium! So the process still works for primary and secondary amines.
Tertiary amines, however, are a total bust. They still can’t be used here, since we can’t form imines/iminiums from them.
Tomorrow: a mish-mash of amine reactions
Thanks for reading! James