CHM2210 Reactions

Hydrohalogenation reaction

Markovnikov
Not stereospecific
Reactant: Alkene, cycloalkene
Reagent: HX
Mechanism: double bond of alkene acts as a nucleophile, attacks H of HX making a carbocation on the more substituted side. X anion acts as a nucleophile and attacks carbocation, forming bond on more substituted side.
End goal: Add X to more substituted side of double bond, and H to less. Racemic if chiral center formed.

Acid-Catalyzed Hydration reaction

Markovnikov

Not stereospecific

Reactant: alkene

Reagents: H₂O / H₂SO₄

Mechanism: double bond of alkene/cycloalkene acts as nucleophile and attacks H from H₃O⁺, adding it to less substituted side and forming carbocation. H₂O as a Nuc: attacks the carbocation. Another H₂O removes H, resulting in an OH.
End goal: Add OH to more substituted side of double bond. Racemic if chiral center formed.

Addition of X₂ (X=Br or Cl) alkene reaction

Anti-addition

Reactant: alkene

Reagents: X₂ / CCl₄ or CH₂Cl₂
Mechanism: double bond acts as Nuc: and attacks one of the X in X₂. X also acts as Nuc: and attacks double bond, forming a bridged (triangle) intermediate. X^- attacks bridge on more substituted side on the opposite face of bridge.
End Goal: Add X₂ across double bond in opposite faces (anti). Racemic if chiral center formed.

Halohydrin Formation reaction

Markovnikov with OH
Anti Addition

Reactants: Alkene

Reagents: X₂ / H₂O

Mechanism: double bond acts as Nuc: and attacks one of the X in X₂. X also acts as Nuc: and attacks double bond, forming a bridged (triangle) intermediate. H₂O attacks more substituted side of bridge on opposite face, and another H₂O removes H to form OH.
End Goal: Add X and OH across double bond, with OH on more substituted side and anti to X. Racemic if chiral center formed.

Oxymercuration-Reduction reaction

Markovnikov

Not stereospecific

Reactant: alkene

Reagents: 1. Hg(OAc)₂, THF or H₂O or CH₃OH / 2. NaBH₄ , H₂O

Mechanism: double bond acts as Nuc: and attacks Hg⁺OAc, which also acts as Nuc: and attacks double bond, forming bridged (triangle) intermediate. H₂O attacks bridge on opposite face on more substituted side, another H₂O grabs H and forms OH. NaBH₄ replaces HgOAc with H.

End Goal: Add OH to more substituted side of double bond. Racemic if chiral center formed.

Hydroboration-Oxidation

Anti-Markovnikov

Syn Addition

Reactant: alkene

Reagents: 1. BH₃ ,THF / 2. H₂O₂ , NaOH

Mechanism: Step 1 - Double bond bond acts as Nuc: and attacks BH₃ while one H in BH₃ goes to more substituted side (concerted, syn-addition). Repeats 2 more times to form BR₃. Step 2 - OH grabs H from H₂O₂ , forming ^-O-O-H which attacks Boron in BR₃. C bonded to B attacks O in BR₃OOH and OH leaves, forming R-O-BR₂. OH attacks B, which leaves and forms RO^-, which is then protonated by water.

End Goal: Add OH to less substituted side of double bond and H to more, syn addition.

Dihydroxylation

Syn-addition

Reactant: alkene

Reagents: KMnO₄ / NaOH (cold) or OsO₄ / H₂O₂ , H₂O

End Goal: Add OH to both sides of double bond in the same face.

Ozonolysis

Oxidative cleavage of Alkenes

Reactant: alkenes

Reagents: 1. O₃ / 2. (CH₃)₂S or Zn / H₂O

End Goal: Split C=C into aldehydes and ketones.

Catalytic Reduction (Hydrogenation)

Syn-addition

Reactant: Alkene

Reagents: H₂ / Pd, Ni, or Pt

End Goal: reduction of double bond by adding H₂ across the same face.

Addition of X₂ (X=Cl, Br) alkyne reaction

Anti-addition

Reactant: Alkyne

Reagents: X₂ / Ch₂Cl₂

Mechanism: pi bond acts as Nuc, attacks one of the X from X₂, which also acts as Nuc: and attacks double bond, forming a bridged (triangle) intermediate. 1 equivalence of X₂ yields dihaloalkene, 2 eq yields tetrahaloalkane.

End Goal: add X₂ across triple bond to form alkene (1 eq.) or alkane (2 eq.)

Addition of HX (X=Cl, Br, I) Alkyne reaction

Markovnikov

1st addition Anti, 2nd not stereospecific

Reactant: Alkyne

Reagents: HX

Mechanism: pi bond acts as a Nuc, attacks H of HX making a carbocation on the more substituted side. X anion acts as a Nuc and attacks carbocation, forming bond. If excess of HX, reaction continues with alkene, forming alkane with 2X on more substituted side.

End Goal: Add HX across triple bond to from alkene (1 eq) or alkane (excess).

Acid Catalyzed Hydration of Alkynes

Markovnikov

Generates ketones from 1-alkynes

Reagents: HgSO₄ / H₂SO₄, H₂O

Mechanism: pi bond acts as Nuc, attacks Hg²⁺ , which forms bridge intermediate with resonance. H₂O as Nuc attacks more substituted side of bridge, another H₂O removes H to form OH. pi bond attacks H from H₃O⁺ , Hg⁺ leaves and resulting enol tautomerizes with acid to form ketone.

End Goal: Add carbonyl group to more substituted side of alkyne.

Hydroboration-Oxidation of Alkynes

Anti-Markovnikov

Reagents: 1. HB(sia)₂, THF / 2. H₂O₂, NaOH

Mechanism: Initial product yields enol, which undergoes tautomerism with base to yield aldehyde (terminal alcohol) or ketone (internal alcohol). Step 2 mechanism: OH^- grabs H from enol, pi bond grabs H from H₂O to from aldehyde/ketone.

End Goal: Add carbonyl group to less substituted side of alkyne.

Complete Catalytic Reduction of Alkynes

Syn-Additions (2x)

Reagents: H₂ / Pd or Pt or Ni

End Goal: Add H₂ across triple bond twice to yield alkane.

Alkyne Reduction to Cis-Alkene

Syn Addition
Reagents: H₂ / Lindlar’s Catalyst

End Goal: add H₂ across triple bond to form cis alkene

Dissolving Metal Reduction

Reagents: Na (metal) / NH₃

Free-radical mechanism

End Goal: add H₂ across triple bond to form trans alkene

Radical Bromination

Reagents: Br₂ / hv (light) or heat

Mechanism: Initiation with light forms Br radical. 1 Br radical grabs H from most substituted/stable C, forming C radical. C radical grabs Br radical from Br₂ to form bond with Br. Leftover radical terminates.

End Goal: Add Br to most stable carbon radical (often most substituted, or benzylic position).

Radical Chlorination

Reagents: Cl₂ / hv (light)

No strong preference for tertiary position

End Goal: Add Cl to carbon, mixture of all possible products formed

Allylic Bromination

Formed via most stable allylic radical

Major product has most stable (usually most substituted) double bond, intermediate can resonate so consider resonance form.

Reagents: NBS or trace Br₂ / hv or heat

Mechanism: light forms Br radical, which grabs allylic H to form HBr and allylic radical (which can resonate). allylic radical grabs Br from Br₂, forming bond.
End Goal: Add Br to allylic position to form most stable double bond. Different from normal bromination Br₂/hv would get rid of double bond.

Radical Addition of HBr to alkenes

Anti-Markovnikov

Not stereospecific

Reagents: HBr / peroxides, heat

End Goal: Add Br to less substituted side of double bond and H to more. All stereoisomers can form is chiral center forms.

S_N2

Good Nuc

primary alkyl halide best, secondary if Nuc is weak base.

Polar aprotic solvent (THF, DMSO, DMF)

Stereospecific: inversion of configuration at alpha C

Mechanism: Concerted bimolecular backside attack. Nuc attacks alpha C on opposite face of leaving group, which leaves at the same time.

End Goal: Replace leaving group with Nuc, inversion of stereochem

E2

Strong base, bulky if Secondary alkyl halide to avoid competition with S_N2

3 RX > 2 RX >> 1 RX (usually gives S_N2)

Reagents: Base / protic solvent

Regioselectivity affected by bulkiness: Zaitsev (base grabs more substituted H) major usually, Zaitsev and Hofmann (grabs less substituted H) if bulky base.

Stereospecific: beta H must be anti peri-planar

End Goal: form double bond by eliminating leaving group and beta H.

S_N1 and E1

Compete with each other, mix of both products usually

Carbocation intermediate

Reagents: Weak base or Nuc / Polar protic solvent (can also be the Nuc)

Rate: 3 RX / 2 RX no 1 RX

Not stereospecific

Mechanism: Leaving group leaves, forming carbocation (unimolecular). Rearrangements can occur. Nuc attacks carbocation / Base grabs beta H to form double bond.

End Goal: replace leaving group with Nuc (S_N1), form double bond (E1)

Alcohol with Active Metals (Li, Na, K)

Alcohol reacts as acid

NaH, LDA, Na/K/Li react as base

Polar Protic solvent (THF)

Reagents: NaH, LDA, or Na/K/Li / THF

End Goal: Deprotonate OH

Alcohols with HX (X=Cl, Br, I)

Primary/methyl: S_N2

Secondary: Mix of S_N2 and S_N1

Tertiary: S_N1

Reagents: HX

End Goal: replace alcohol with X

Alcohol with PBr₃

Primary and Secondary alcohols ONLY

Reagents: PBr₃

Mechanism: S_N2. OH attacks P and a Br leaves, forming H-⁺O-PBr₂ (good LG). Br^- does backside attack on C and HO-PBr₂ leaves.

End Goal: make prim/sec alcohol into good leaving group and replace with Br to form alkyl bromide, inverted config.

Alcohol with Thionyl Chloride (SOCl₂)

Primary and Secondary alcohols ONLY

Reagents: SOCl₂ / pyridine

Mechanism: S_N2. OH attacks S, forming H-O⁺-SCl₂O. Cl leaves after O resonates, and pyridine picks up H in OH. Cl^- attacks C and O leaving group to form SO₂ and Cl^-.

End Goal: Make alcohol into good leaving group and replace with Cl to form alkyl chloride, inverted config.

Formation of Sulfonates from alcohol

Reagents: TsCl (Tosyl Chloride) / pyridine

End Goal: replace OH group in alcohol with OTs (great leaving group), config. stays the same.

Pinacol Rearrangement

Reactant: Glycols = Vicinal diol = 1,2-diols

Reagent: H₂SO₄ / heat

Mechanism: one OH acts as base, grabs H from H₂SO₄ to form good leaving group. ⁺OH₂ leaves, H on C with other OH rearranges to form carbocation on C-OH. OH resonates, H₂O grabs H to form ketone.

End Goal: form ketone from glycol (ketone on less substituted side if asymmetric).

Acid Catalyzed Dehydration of Alcohol

Reagent: H₂SO₄ / heat

Primary alcohol with Beta branching: E2

All other alcohols: E1

Lower Temp for more substituted alcohols

Reversible with water

Mechanism: OH grabs H from acid and leaves forming carbocation (which can rearrange/shift). H₂O grabs beta H to form pi bond.

End Goal: Remove OH and form pi bond.

Oxidation with Chromic Acid

Strong oxidizing agent

Primary alcohols —> carboxylic acid

Secondary alcohols —> ketones

Tertiary —→ Don’t react.

Reagents - H₂CrO₄ OR CrO₃ / H₂SO₄ OR K₂Cr₂O₇ / H₂SO₄

End Goal - Add carbonyl group to C attached to OH, turn into ketone or Carboxylic acid.

Oxidation with PCC

Weaker oxidizing agent, stops at aldehyde rather than oxidizing aldehyde to carboxylic acid.

NO WATER

Primary alcohols —> aldehydes

Secondary alcohols —> ketones

Tertiary —→ Don’t react.

Reagents - PCC / CH₂Cl₂

End Goal: Add carbonyl to C attached to OH, turn into ketone or aldehyde.

Oxidative Cleavage of Glycols with Periodic Acid

Reagent: HIO₄ (Periodic Acid)

Glycols oxidized to aldehydes (secondary ROH) and ketones (tertiary ROH) with periodic acid.

Must be able to form 5-membered ring intermediate

End Goal: Turn C’s attached to OH’s into carbonyl groups (aldehyde or ketone), breaking 5 membered ring

Williamson Ether Synthesis

Step 1 - Strong base (NaH, Na/Li/K, LDA) deprotonates alcohol.

Step 2 - S_N2. Alkoxide (Nuc) attacks alkyl halide (primary is best, secondary competes with E2, tertiary only does E2). Halide leaves, forming ether. Original stereochem stays!

Reagents: 1. NaH (or other strong base) / 2. XR, THF

End Goal: Prepare ether from alkoxide and primary alkyl halide

Addition of Alcohol to Alkene

Reagent: CH₃OH / HCl (cat.)

Alkene must be able to form carbocation

Alcohol must be small to be good nucleophile

Mechanism: pi bond acts as Nuc, attacks H in CH₃OH₂⁺ to make carbocation on more substituted side. CH₃OH attacks carbocation, another CH₃OH grabs extra H to form ether.

End Goal: Add alcohol to alkene on more substituted side of double bond to make ether.

Acid Catalyzed Cleavage of Ethers by HX (X=Cl, Br, I)

Reagent - excess of HBr OR HCl OR HI

Mechanism: depending on alkyl group, vinyl and aryl ethers are not cleaved.

End Goal: Cleave ether and replace O with X on both sides.

Preparation of Epoxides by Alkene Oxidation

Syn Addition

Original stereochem maintained (cis alkene —→ cis epoxide)

Non-polar solvent (CHCl₃, CH₂Cl₂)

Reagents: mCPBA (or any RCO₃H) / CHCl₃

End Goal: Create epoxide from alkene

Epoxides from Halohydrins

Reagents: Strong Base (NaH, NaOH) / Polar Protic solvent (THF, H₂O)

Mechanism: Intramolecular S_N2. Strong base deprotonates alcohol on halohydrin (alkane with OH and X anti peri-planar to each other). O^- does intramolecular attack on C bonded to X and X leaves. Forms epoxide. Nuc and LG must be on opposite faces.

End Goal: form epoxide from halohydrin (which is formed by addition of HOX to alkene)

Acid-Catalyzed Ring Opening of Epoxides

Anti-Addition

Inversion of config. of ring C attacked

Reagents: Acid Catalyst (HCl, H₂SO₄) / Weak Nuc

Mechanism: O in epoxide grabs H from acid. Nuc attacks more substituted ring carbon fro, opposite face of epoxide. Weak Nuc reacts as base to remove extra H.

End Goal: Open epoxide with Nuc on more substituted side and OH on the other.

Nucleophilic Ring Opening of Epoxides

Anti-Addition

Inversion of config. of ring C attacked

Reagents: 1. Strong Nuc / 2. Workup (written in single step of solvent of Nuc can be used for Workup)

Mechanism: Strong Nuc attacks less substituted side of epoxide on the opposite face (anti). Workup step protonates O^- that was the epoxide.

End Goal: Open epoxide with Nuc on less substituted side and OH on the other.