RACC 1

Normally the bond to the aromatic ring is broken to give a synthon with a _________ charge on the aromatic ring as they react with __________ in ____________substitutions

negative, electrophiles, electrophilic

OH & OR groups are difficult to add to a benzene ring, so don’t disconnect them but use _______ as a starting material

phenol

To improve regioselectivity, introduce a temporary _______ group e.g.

convert an NH₂ group into a larger NHCOCH₃ group

blocking

Grignards are formed by Mg insertion into an aryl halide.

They are strong nucleophiles & react with a range of electrophiles to form C–C bonds.

Wittig reaction is the general method for making ______ bonds.

C=C

Stabilised ylides are prepared by deprotonation of a phosphonium salt, that has an EWG, Ph₃P⁺CH₂EWG w/ weak base. The EWG stabilises the carboanion formed

They:

• are unreactive to ________

• react with aldehydes to give mainly ___ - alkenes, why?

ketones, E

E is more thermodynamically stable

Stabilised ylides are prepared by deprotonation of a phosphonium salt, that has an EDG, Ph₃P⁺CH₂EDG w/ strong base. The EDG further destabilises the carboanion formed

They:

• react with ketones & aldehydes to give mainly ___ - alkenes

Z

A deprotonated phosphonate ester (________ charge) is more reactive to a ____ bond than a phosphonium ylide (neutral).

Reactions of stabilised (EWG) phosphonate ester anions w/ aldehydes/ketones

gives mainly ____ - alkenes.

negative, C=O, E

Alkynyl anions are formed by deprotonation of _____________ w/ base

They’re strong nucleophiles & react with a range of electrophiles to form C–C bonds.

C≡C bond can be reduced to form ________ stereoselectively using:

• _____________ to form a Z–alkene

• ________ to form an E–alkene

Terminal alkynes, alkenes

• H₂/Lindlar catalyst

• Na/NH₃

Heck reaction:

Palladium(0)-Catalyst can be used to form a disubstituted alkene from a terminal alkene, base &:

• aryl halide (___)

or

• vinyl halide (____) – the C bonded to X must be ___ hybridised

Reaction is highly selective:

• R group is introduced at the _______________ end of the C=C bond

• More stable _________ is formed.

• ArX

• C=CX, sp²

least hindered, E-alkene

___-Unsaturated carbonyl compounds are RASM’s that are prepared via aldol condensation reactions of aldehydes, ketones & esters

Conjugation of the C=O bond with the C=C bond means that α,β-unsaturated carbonyls are susceptible to attack by ___________ at both the 2- & 4-positions

1,4-addition, is called Michael addition

Addition of carbon nucleophiles results in _____ bond formation

α,β , nucleophiles, C–C

1,2-Addition (C=O addition):

Grignard reagents (____) attack directly at the ___ bond

Under ________ control because the stronger C=O bond is broken & the weaker _____ is retained

Grignard reagent is a _________ & the C on C=O is a _____________ because

• C on C=O is a _____________ because it is directly attached to O which has a high δ⁺ density

• Grignard reagent is a _______________ because the R in RMgX has a high δ^– density as it’s adjacent to an electropositive Mg

Hard reacts preferably w/ hard so Grignard reagent prefers 1,2 (C=O) addition

RMgX, C=O, kinetic, C=C

• hard electrophile

• hard nucleophile

1,4-Addition (Michael addition):

Organocopper reagents (RCu) & cuprates (R₂CuLi) attack the ___ bond

Under ___________ control because the stronger ___ bond is retained & the weaker C=C bond is broken (more stable product is formed)

• C at position 4 is a ______________ because it has low d+ density

• A cuprate is a ______________ because the R groups in R₂CuLi have low d– density because they’re adjacent to a weakly electropositive Cu

Soft reacts preferably w/ soft so organocopper reagents/cuprates prefer 1,4 (Micheal) addition

C=C, thermodynamic, C=O

• soft electrophile

• soft nucleophile

Organometallics containing copper can be prepared from ________ compounds:

organolithium

RC(=O)R → RC(-OH)R (ketone to secondary alcohol)

1. LiAlH₄

2. H⁺

RC(=O)OH → RC(-OH)H (carboxylic acid to primary alcohol)

1. LiAlH₄

2. H⁺

RC(=NH)R → RC(-NH2) (imine to amine)

1. NaBH₄

2. H⁺

Ph-NO₂ → Ph-NH₂ (benzene w/ nitro to benzene w/ amine

Sn, HCl

R-C☰C-R → Z- RHC=CHR (alkyne to Z-alkene)

H₂, Lindlar catalyst

RHC=CHR → RH₂C-CH₂R (alkene to alkyl)

H₂, Pd/C

RC(-OH)R → RC(=O)R (secondary alcohol to ketone)

CrO₃, H⁺ reflux

RC(-OH)R → RC(=O)R (primary alcohol to ketone)

CrO₃, H⁺ distillation (or milder oxidant e.g. PCC)

RHC-OH → RCO₂H (primary alcohol to carboxylic acid)

CrO₃, H⁺ reflux

Ph-CH₃ → Ph-COOH

KMnO₄ (potassium permanganate)

RH₂C=CH₃ → peroxide

RCO₃H (peracid)

RH₂C=CH₃ → RH(HO-)C-C(-OH)H₂ (alkene to diol)

aq. OsO₄

R⁺

• R-I

• R-Br

• R-OSO₂Me (R-OMs)

• R-OTs

HO-C⁺

Ketone/aldehyde

HO-C-C⁺

Epoxide

O=C⁺-R

Carboxylic acid derivatives

e.g. X=

• Cl

• OCOR

• OR

• NR₂

• CO₂

R(O=)C-CH₂-C⁺

α,β-unsaturated carbonyl

RHC(-OH)R → RHC(-X)R (alcohol to halogen)

• PBr₃ (when X = Br)

or

• PCl₃ (when X = Cl)

RC(=O)OH → RC(=O)Cl (carboxylic acid to acyl chloride)

SOCl₂

RC(=O)Cl → RC(=O)NHMe (acyl chloride to secondary amide)

MeNH₂, base

RC(=O)OH → RC(=O)OMe (carboxylic acid to ester)

MeOH, H⁺

epoxide → R(HO)C-C(OH)H₂ (epoxide to diol)

• H₂O, HO^–

or

• H₂O, H⁺

RH(Br)C-CH₃ → RHC=CH₂ (halogenoalkane to alkene)

Base (e.g. ^tBuO^–)

RHC=CH₂ → RH(X)C-CH₃ (alkene to halogenoalkane)

HBr (when X = Br)

Ph-NH₂ → Ph-OH (aniline to phenol)

1. NaNO₂, HCl

2. H₂O, heat

R^-

Organometallics

• ^δ–R–MgX

• ^δ–R–Li

• ^δ–R₂CuLi

Ar^-

• ArH

• ^δ–Ar–MgX

• ^δ–Ar–Li

• ^δ–Ar₂CuLi

RC(=O)C^-H₂ (ketone)

RC(=O)CH₃ + base for α-deprotonation

ROC(=O)C^-H₂ (ester)

ROC(=O)CH₃ + base for α-deprotonation