Mechanisms 2 Flashcards
Hammond’s Postulate
The transition state looks more like the structure it’s closest in energy to.
SN2 Reaction
When Does SN2 Happen:
- Leaving Group Substitution: Methyl > Primary > Secondary (never tertiary)
- Nucleophile: Strong/ Impatient base or nucleophile
- Negative sign on X, O, N, or C
- Small molecule (less steric hindrance) = Zaitseff product
- Lower down on periodic table is better
- Halides = SN2 or SN1
- Polar Aprotic solvent (promotes SN2 and E2)
Regiochemistry: The product’s absolute configuration is the opposite of the reagent’s
Rate Expression: k*[nucleophile]*[electrophile]
SN1 Reaction
When Does SN1 Happen:
- Leaving Group Substitution: Tertiary > Secondary (stable carbocations)
- Benzyllic & Allylic Carbocations (you can resonance your way into SN1, but steric hindrance keeps SN1 in SN1)
- Nucleophile: Poor/patient base/nucleophile
- Neutral nucleophile or negative sign on an X, O, N, or C that can resonate well
- Small molecule
- Lower down on periodic table is better (nucleophiles)
- Halides = SN2 or SN1
- Polar Protic Solvent (promotes SN1 and E1)
Stereochemistry: Zaitsev (small nucleophile) or Hofmann (large nucleophile)
Reigochemistry: Produces enantiomers/racemic mixture
Rate Expression: k*[electrophile]
E1 Reaction
When Does E1 (beta elimination) Happen:
- Leaving Group: Tertiary and Secondary (stable carbocations)
- Base: Poor/patient base
- Neutral base or negative sign on an O, N, or C with resonance (not X)
- Higher up on periodic table is better (base)
- Heat promotes elimination reactions
Stereochemistry: Always Zaitsev Product, Trans/E Product
Reaction Rate: k*[electrophile]
E2 Reaction
When Will E2 Happen:
- Leaving Group: Tertiary and Secondary > Primary (not Methyl)
- Base: Good/impatient base:
- Negative sign on an O, N, or C (not X)
- Small base = competition with SN2 & E2 and Zaitseff product
- Bulky base = E2 and Hoffman product
- Higher up on periodic table is better (base)
- Heat promotes elimination reactions
- Polar Aprotic Solvent (promotes SN2 and E2)
Beta Hydrogen has to be Anti to Leaving Group
Regiochemistry: Zatisev w/small base, Hofmann w/large base
Reaction Rate: k*[electrophile]*[nucleophile]
Reagents: Br2 & light or NBS
Free Radical Halogenation:
- Functionalizes alkanes (typically first step in synthesis)
- Only occurs on sp3 hybridized carbons
Regiochemistry: Markovnikov Addition or More Stable Radical (benzylic > allylic > tertiary > secondary with resonance)
How to Determine if Good Leaving Group
Characteristics:
- Lower pKa
- Easier bonds to break
- Stronger acids
Promote:
- SN2
How to Determine if Good Nucleophile
Characteristics:
- Larger pKa
- Releases more energy when bond forms
- Weak bases
- Left and Down on Periodic Table (atoms get softer)
Favors:
- SN2
Very Good Leaving Groups
Want EWG:
- RSO3- (most often R = CF3, tol, or CH3)
- I-
Good Leaving Groups
- R2O (water, alcohol, or ether)
- Br-
- Cl-
Poor Leaving Groups
- F-
All Strong Bases:
- RO-
- R2N-
- R3C-
Very Good Nucleophiles
- RS-
- NC-
- I-
- PR3
- **R3C-
- **R2N-
- **RC≡C-
- **RO-
** = Strong bases that will favor elimination with heat
Good Nucleophiles
- Br-
- R2S
- NR3
- Cl-
- RCO2-
- N3-
Poor Nucleophiles
All Strong Acids:
- F-
- HCO3-
- R2O (water, alcohol, or ether)
Reagents: HX (acid) + Alcohol
Halogenation of an Alcohol using HX (X= Cl, Br, or I)
- Two step mechanism:
- Create a good leaving group before SN2
Reagents: SOCl2
Halogenation of an Alcohol
- Replaces bad OH leaving group with good Cl leaving group
Reagents: PBr3
Halogenation of an Alcohol:
- Replaces bad OH leaving group with good Br leaving group
Synthetic Uses of SN2 Reactions
Replace leaving groups with:
- Any nucleophile
- OH
- OR
- R
Small Nucleophiles
Definition:
- Single atom
- Methyl or primary not next to a branch point
Large Nucleophiles
Definition:
- Tertiary
- Secondary
- Primary next to a branch point (attached directly to a 2° or 3° atom)
Common Polar Protic Solvents
- Water
- Methanol
- Ethanol
- Acetic acid
- DMF
Favors SN1 (hydrogen bonding stabilizes carbocation in solution)
Common Polar Aprotic Solvents
- Acetone
- DMSO
- THF
- Chloroform
- Dichloromethane
- Diethyl ether
Favors SN2 (don’t want hydrogen bonding)
Common Nonpolar Solvents
- Benzene
- Cyclohexane
- Liquid carbon dioxide
- Hexane
- Carbon tetrachloride
Conjugation
Definition:
- Neighboring p orbitals that are parallet to one another creating a bond-like attraction
- Favorable
- Lowers potential energy of molecule
- Shortens bonds between double bonds because of shared electron density
Hyperconjugation
Definition:
- Empty p orbital aligning not perfectly parallel with a sigma bond
- Weaker than proper conjugation
- Shares electron density and stablizes carbocations (why tertiary is best)
Lowers the pKa of most carbocations to zero (easy to pull off hydrogens beta to the carbocation carbon)
- Tertiary carbocation is such a strong acid it will react with even a very weak base (why second step in elimination occurs)
Zaitsev’s Rule
The most substituted alkene is most stable/lowest PE
- Elimination = substituted alkene dominates product mixture
Reagents: Acid, Heat + Alcohol
Common E1: heating an alcohol in acid:
- Eliminates HOH
- Produces Zaitsev Product
Small Base
Definition:
- Single Atom
- Methyl or Primary not next to a branch point
Directs to Zaitsev Product
- Small enough to reach any ß-H with minimal steric hindrance
Large Base
Definition:
- Tertiary
- Secondary
- Primary next to a branch point (attached directly to a 2° or 3° atom)
Directs to Hofmann Product
- Too big and too much steric hindrance to reach crowded hydrogens
How to Favor E2 over SN2
When a small base/nucleophile is being used:
- Normal conditions will produce both products
- Heat will favor elimination (likes strong base)
- Removing heat/cold will favor SN2 (likes good nucleophile)
- Polar aprotic solvents will favor both
Large base will favor E2 because of steric hindrance
Nucleophile Only (SN1 or SN2)
Think SUBSTITUTION!
Halides:
- Cl-
- Br-
- I-
Sulfur Nucleophiles:
- HS-
- RS-
- H2S
- RSH
Base Only (E2)
Think ELIMINATION!
- H-
- t-BuO-
- Steric hindrance makes this better base than nucleophile, favoring E2 over SN2
Strong Nucleophile / Strong Base (SN2 or E2)
Think 1 STEP MECHANISM!
- HO-
- MeO-
- EtO-
- t-BuO-
- Too much steric hindrance to act as a nucleophile, typically strong base
Weak Nucleophile / Weak Base (SN1 or E1)
Think 2 STEP MECHANISM!
- H2O
- MeOH
- EtOH
E2 is only possible on a substituted cyclohexane ring ONLY when the LG is in an “______” position and the beta hydrogens are “______” to the LG. This will create the “_______” product.
Axial, anti, E
Relative Rates of Radical Halogenation
F2 >> Cl2 > Br2 >> I2
- F is so fast it’s explosive
- Cl selective for secondary < tertiary = allylic = benzylic
- Br selective for secondary << tertiary << allylic << benzylic
- I is too slow to be practical
- Typically used as an inhibitor to terminate a radical halogenation
H-type Preference for Radial Halogenation
Benzyllic > Allylic > Tertiary > Secondary > Primary > Methyl
- Benzyllic = a H on a benzyllic C / a C next to a benzene ring
- Allylic = A H on an allylic C / a C next to a pi bond
Reagents: Cl2, hv
Radical Chlorination of an Alkane
- Two Products: Markovnikov and Anti-Markovnikov Replacement of alpha-H with Chlorine
Reagents: Br2, hv or NBS, hv
Radical Bromination of Alkane:
- Markovnikov Replacement of Alpha-H with Bromine
- Doesn’t interact with double bonds, only replace H’s
Radical Stability and PE
Highest to Lowest PE:
- H
- CH3
- Primary
- Secondary
- Tertiary
- Allylic
- Benzylic
- X
Radicals can be resonance stabilized, but not rearranged
- No methyl or hydride shifts, only resonance structures
Three Parts of a Radical Chain Reaction
- Initiation = net generation of radicals
- Create a problem
- Propagation = one radical consumed, one radical produced
- Push the problem onto something else
- Termination = net consumption of radicals
- Add terminator/inhibitor to solve the problem
- Typically I because it reacts so slowly or radicals with high conjugation structures/high resonance to make them stable
Reagents: Br2, cold/dark
Bromonium Ring on Alkene:
- Mark Addition
- Interacts with double bonds to add 2 Br or Br + OR
- Trans Products
Reagents: HBr, ROOR
Antimarkovnikov Radical Halogenation of Alkene:
- Anti-Mark addition
- Interacts with double bond in radical chain reaction
Reagents: HBr, cold/dark
Markovnikov Addition of Br to Alkene:
- Mark Addition
- Interacts with double bond to add 1 Br
Synthesis: When starting with an alkane, always “__________”
Start with radical halogenation
Reagents: 2 Li°, diethyl ether
Lithium Reagent to make Base:
- Only react with alkyl halides to make base
- Acidic hydrogens (hydrogens next to a functional group) will neutralize the carbanion before other reactions can occur
- Reacts as base when in solution with a hydrogen donator (HOH, HOR)
- Doesn’t react well with alkyl halides once made into grignard/lithium reagent - likes carbonyls
Think of these as salts with a carbanion!
Reagents: Mg°, diethyl ether
Grignard Reagent to make Base:
- Only react with alkyl halides
- Acidic hydrogens (hydrogens next to a functional group) will neutralize the carbanion before other reactions can occur
- Reacts as base when in solution with a hydrogen donator (HOH, HOR)
- Doesn’t react well with alkyl halides once made into grignard/lithium reagent - likes carbonyls
Think of these as salts with a carbanion!
Reagent: LiAlH4
Reacts as if Hydride Anion (H-):
- Strong H- delivery reagent
- Reacts with any carbonyl
- Reduces aldehydes/ketones to alcohols (followed by acid workup)
Reagent: NaBH4
Reacts as if Hydride Anion (H-):
- Milder H- delivery reagent
- Only reacts with aldehydes and ketones
- Reduces aldehydes/ketones to alcohols (followed by acid workup)
Reagents: Li°, CuI
Lithium Dialkyl Cuprate Reagents:
- Loose half of the original molecules to counterion permanently
- Softer and milder than lithium and Grignard reagents = work on alkyl halides once the reagent
- Don’t react with alkyl halides once the reagent
A bulky “_________” is better than a bulky “________”
nucleophile, electrophile
“__________” are better electrophiles than “__________”
Aldehydes, ketones
Reagents: Aldehyde, H2O, H3O+ (catalyst)
Hydrate Formation:
- Adds H2O to the aldehyde
- Protonates C=O
- Adds H2O and deprotonates to leave diol
Reagents: Aldhyde, HC≡N, -C≡N (catalyst)
Cyanohydrin Formation:
- Adds HCN to aldehyde
- Protonates existing C=O
- Adds C≡N to molecule
What base is too patient for nucleophilic addition-elimination?
Any base with Bromide (Br)!
Reagents: -Nuc, H-Nuc, Acid Halide
Nucleophilic Acyl Substitution:
- Nucelophile attaches to a carbonyl, then reforms the carbonyl by kicking out the LG in a SN1 reaction
- Can only occur on sp3 hybridized carbons
Reagents: SOCl2, carboxylic acid OR PBr3, carboxylic acid
Acid Halide Preparation from Carboxylic Acids:
- Makes acid halide by replacing the OH with Cl or Br
Reagents: R’-NH2 (methyl or primary amine), H+ (catalyst), aldehyde/ketone
Imine Formation:
- Replaces the C=O with C=N-R’
- Produces water
- Deprotonates N twice
Reagents: R’-NH-R’ (secondary amine), H+ (catalyst), aldehyde/ketone
Enamine Formation:
- Replaces C-C=O with C=C-NR’2
- Produces water
Reagents: 1 molar equivalent R’-OH, H+ (catalyst)
Hemiacetal Formation:
- Turns C=O into OH group
- Adds OR’ group to carbon
Reagents: 2nd molar equivalent R’-OH, H+ (catalyst)
Acetal Formation:
- Replaces OH group with OR’ group
- Produces water
Reagents: Ethylene glycol, H+ (catalyst), aldehyde/ketone
Protection of a Carbonyl Against Nucleophiles:
- Adds OCCO ring onto carbonyl to keep nucleophile from attacking it
- Undone with excess water and acid
- React more readily with aldehydes than ketones
Reagents:
- NaH (acid), alcohol
- R’-X (alkyl halide)
Williamson Ether Synthesis:
- Turns alcohol into conjugate base, then adds an R’ group to produce an ether
