Appendix 1: Summary of Part 1 reactions used for synthesis

This appendix lists most, but not all, reactions covered in this textbook (part 1 only).  The focus is on reactions that are most useful in synthesis.

Appendix 1.1. Nucleophilic substitutions with alkyl halides

Overview

Most nucleophilic substitutions used in synthesis go via an SN2 mechanism.

A generic example of an SN2 reaction

  • SN2 reactions work best with R–X as an alkyl halide or sulfonate. Epoxides also work well for more complex targets.
  • Best with 1o alkyl, OK with 2o, fails with 3o and aryl
  • Works well with I, Br, OK with Cl, fails with F.
  • It requires a strong nucleophile, which usually means one bearing a negative charge such as ¯OH .
  • Works well in polar aprotic solvents such as DMSO.

A. Formation of alkyl halides

See section 9.3.  Most SN2 reactions utilize alkyl halides, so you need to know how to make them!  The most common route is from the corresponding alcohol, using PX3.  I recommend using alkyl bromides in synthesis, and these are made using PBr3.

  • Use PX3 (X = Cl, Br, I) to convert primary and secondary ROH to RX
  • SOCl2 also good for ROH to RCl
  • Mechanism involves activation of OH by PX3 to make it a good leaving group, then SN2 attack by X¯.

Reaction of a generic alcohol with PX3 to produce an alkyl halide

For example, (2R)-butan-2-ol reacts with PBr3 produces (2S)-2-bromobutane with inversion; note that all three bromines can be delivered.

For preparation of tertiary alkyl chlorides and bromides from the corresponding alcohols, HCl or HBr is the most effective reagent.

B. Formation of alcohols

This is synthetically the reverse of the PBr3 reaction.  Here, the nucleophile is hydroxide ion (¯OH).  As always with anions, it  has to have a cation with it, usually sodium or potassium.

RBr reacts with OH- to give ROH

For example:

BuBr reacts with KOH to give BuOH

C. Formation of amines

See section 9.4.

  • NH3, R’NH2 and R’2NH are strong enough to react with R–X, to produce products containing a new R–N bond.
  • An excess of the NH3 or amine reactant is needed to suppress the reaction of the product with a second mole of R–X.

RBr reacts with large XS of NH3 to make RNH2

There are also indirect methods for preparing amines, which avoid the need for a large excess of amine.  One of the most popular uses azide (N3–) as nucleophile, followed by reduction to the amine.

RBr reacts with NaN3 to produce RN3, which is then reduced to RNH2 using LiAlH4

D. Williamson ether synthesis

See section 9.5. This is the most important way to make an ether group.  The nucleophile is an alkoxide (the conjugate base of an alcohol).  Often this has to be made from the alcohol using NaH.
Reaction of an alkoxide with an alkyl halide to form an ether
In the synthesis of ethers containing a tertiary alkyl group, the tertiary group should be in the alkoxide to ensure a good SN2 reaction – see example below.
Two alternatives for Williamson ether synthesis of a tert-butyl ether - good and bad.

E. Enolate alkylation

See section 9.7.

  • The enolate nucleophile is usually the conjugate base of a ketone or ester.
  • As with the Williamson ether synthesis, the nucleophile has to be made from the ketone or ester with a strong base, usually LDA.  (NaH sometimes works, but LDA is usually better.).  At -78 oC, LDA forms the less substituted enolate.
  • This reaction makes a new C–C bond – often important in synthesis.  The reaction works well with primary alkyl bromides or iodides, and moderately with secondary, and fails completely with tertiary alkyl bromides or iodides.

Generic formation of an enolate using LDA, followed by alkylation using RX

F. Alkyne/Acetylide alkylation

See section 9.8.

  • The nucleophile is the conjugate base of an alkyne, called an acetylide.
  • Similar to D and E above, the nucleophile has to be made from the alkyne and a strong base, usually NaH or BuLi, though LDA also works.
  • As with E above, this makes a new C–C bond.
  • Reaction only works well with 1o R–X, since the acetylide is a strong base too.

Formation of an acetylide using NaH, followed by SN2 reaction with an alkyl halide

G. Reduction of R–X with LiAlH4

  • LiAlH4 is a strong reducing agent, which in effect delivers hydride ion, H¯.  (Hydride ion itself is too small to react well in a direct SN2).
  • Reaction only works well with 1o R–X.

RX reacts with LiAlH4 to produce RH

Appendix 1.2. Nucleophilic substitutions with Epoxides

H. Reaction of epoxides with strong nucleophiles

  • Epoxides are strained 3-membered ring ethers that open very easily with strong nucleophiles, giving alcohols with the former nucleophile attached to the neighboring (less substituted) carbon.
  • The mechanism is SN2, with the leaving being the O¯ rather than a halide.
  • Any of the above strong nucleophiles (NH3, R’NH2, R’2NH, ¯OH, ¯OR’,  enolates, acetylides, LiAlH4, will attack epoxides at the less substituted carbon.  For example:
Reaction of an epoxide with methoxide ion showing attack at the less substituted position

I. Reaction of epoxides with weak nucleophiles

  • Epoxides do not open with weak nucleophiles, unless the epoxide is activated first with an acid such as H2SO4.
  • The product is an alcohol on the less substituted carbon, with the former nucleophile attached to the neighboring (more substituted) carbon.
  • Even at a tertiary center, the mechanism is SN2, with the leaving group being the OH rather than a halide.
  • Any weak nucleophiles (H2O, ROH, Cl¯) will attack epoxides at the more substituted carbon, since this is the more electrophilic carbon.  For example:

Appendix 1.3. Elimination reactions

Overview

  • There are two main mechanisms – E2 and E1.
  • E2 reactions make alkenes from alkyl halides and strong base
  • E1 reactions are usually used to make alkenes from an alcohol and catalytic acid (H2SO4 or H3PO4).
  • E2 is usually better for synthesis, to avoid rearrangements, but alcohol dehydration often works OK.
  • Both types of reaction usually obey Zaitsev’s rule – the most substituted/conjugated alkene is the major product.
  • All elimination reactions are favored by heat.

J. Formation of alkenes from alkyl halides (E2)

See section 9.9.

  • A strong base is needed, such as KOH, NaOCH3, or KOtBu.
  • Zaitsev’s Rule is followed, unless a sterically hindered base such as KOtBu is used.
  • Works well with all types of alkyl halide

Primary, secondary and tertiary alkyl halides react with strong bases to produce alkenes

K. Formation of alkenes from alcohols via dehydration (E1)

See section 9.9.

  • Uses an acid (H2SO4 or H3PO4) to protonate the OH and make it a good leaving group.
  • Obeys Zaitsev’s Rule.
  • Works best with 3o and 2o but 1o will often work too.

secondary and tertiary alcohols are heated with H2SO4 to produce Zaitsev alkenes

 

Appendix 1.4. Electrophilic additions to alkenes

Overview

Four main types of additions of electrophiles to alkenes
(a) Simple addition (seen with addition of H–X and H3O+)
(b) Additions that go via cyclic intermediates (addition of carbenes, halogens X2, oxymercuration, epoxidation (MCPBA)
(c) Net anti–Markovnikov additions
(d) Radical–type mechanisms (such as addition of H2, radical addition of HBr)

Markovnikov’s Rule

When adding an electrophile to an alkene, it puts the electrophilic group (often an H) onto the less substituted carbon; the nucleophilic part (e.g., halogen or oxygen) goes onto the more substituted carbon.  For example:

L. Addition of HCl or HBr to alkenes

See section 10.4.

Addition obeys Markovnikov’s Rule, and forms an alkyl halide with the halogen on the more substituted carbon.

HCl adds to but-1-ene to form 2-chlorobutane

M. Addition of H2O using H3O+

See section 10.4.

  • H2O itself isn’t electrophilic enough to add, but strong acids can add
  • The reaction is usually done in two steps, with H2SO4 followed by an H2O quench

1-Methylcyclohexene reacts with water and acid to form 1-methylcyclohexanol

N. Addition of carbenes: Making cyclopropanes

See section 10.7.

  • Carbenes are made from diazo compounds such as diazomethane, by loss of N2 using light.
  • Reaction produces a new three-membered ring
CH2N2 decomposes in light to form the carbene :CH2
Reaction of :CH2 with cis-but-2-ene to form cis-1,2-dimethylcyclopropane

O. Addition of Cl2 or Br2

See section 10.7.

  • Initial syn-addition forms a chloronium or bromonium ion with a three-membered ring.
  • The halide ion present immediately does SN2 back-side attack to gives the product an anti-dihalide
Mechanism for addition of bromine to an alkene, showing the bromonium ion intermediate

P. Epoxidation

See section 10.7.

  • Use MCPBA with the alkene
  • Product is the syn-epoxide (oxirane) which contains a three-membered ring ether.
  • Mechanism involves only a single step.
Cyclohexene reacts with MCPBA to produce epoxycyclohexane

Q. Oxymercuration-demercuration

  • This reaction gives the same alcohol product as with hydration, but the addition is exclusively anti.
  • Obeys Markovnikov’s Rule – OH goes on the more substituted carbon.
  • Mechanism involves a three-membered ring mercurinium ion intermediate.
Hydration of 1,2-dimethylcyclohexene using Hg(OAc)2 to give the anti alcohol

R. Anti-Markovnikov addition of water

Use hydroboration-oxidation to form an alcohol on the less substituted carbon
Hydroboration of isobutylene, followed by oxidation with alkaline hydrogen peroxide, to give an anti-Markovnikov alcohol

S. Anti-Markovnikov addition of HBr

Compare with reaction L.  See section 10.8. In the presence of an organic peroxide (ROOR) and heat, a radical addition mechanism takes over and the Br ends up on the less substituted carbon.
HBr/ROOR/heat causes anti-Markovnikov addition of HBr to propene to give 1-bromopropane

Appendix 1.5. Electrophilic additions to alkynes

Alkynes do many of the same reactions as alkenes.  However, we will just focus on three main ones.

T. Addition of HCl, HBr or HI

Compare with reaction L above.  See section 10.5.

  • The reaction follows Markovnikov’s Rule.
  • It can be done with either one or two moles of HX per mole of alkyne, to give different products.
  • When one mole HX is added to an internal alkyne, the product is mainly anti (with Z double bond).
  • If two HX are added, the X atoms both end up on the same (more substituted) carbon.

Addition of 1 HBr and 2 HBr to but-t-yne

U. Addition of water to alkynes

Compare with reaction M above.  See section 10.5.

  • Markovnikov’s Rule applies.
  • As with alkenes, an acid catalyst is needed.  Internal alkynes can add water under similar conditions to alkenes – H2SO4/H2O.
  • Terminal alkynes require a mercury(II) catalyst, usually HgSO4.  Unlike oxymercuration, NaBH4 is not needed for forming the product.
  • Although an enol is initially formed, this rearranges easily to give a ketone as the isolated product.
But-2-yne adds H2O in presence of H2SO4; but-1-yne also does this but also needs HgSO4 catalyst

V. Anti-Markovnikov addition of H2O to alkynes

See section 10.8., and compare with reaction U above.
  • With alkenes, hydroboration-oxidation using BH3.THF produces net anti-Markovnikov hydration; with alkynes, a sterically hindered derivative of BH3 is used, such as dicyclohexylborane (Cy2BH) or disiamylborane (Sia2BH).
  • Internal alkynes produce ketones, similar to those formed using H2O/H2SO4, but terminal alkynes produce aldehydes.
  • As with H2O/H2SO4/HgSO4, the initial product is an enol, which then rearranges to the aldehyde or ketone.

Hydroboration-oxidation of but-1-yne to produce butanal