N2 Substitution - people.uwec.edu

©2005 David E. Lewis

SN2 Substitution

X

R

R

R Nu

R

R

R

X: I, Br, Cl; etc. Nu: OH, OR; SH, SR; CN; NH2,NHR, NR2; PR3; SeR; etc.

Rate Law: k[RX][Nu] Stereochemistry: Inversion of configuration at reacting carbon. Effects of alkyl group on rate: allyl, benzyl>1°R>2°R>>3°R Effects of leaving group: I>Br>Cl>>F) Favored by strong nucleophiles and low temperatures. Favored by aprotic dipolar solvents (DMF, DMSO, HMPA, etc.) SN1 Nucleophilic Substitution

X

R

R

R Nu

R

R

R

X: I, Br, Cl; etc. Nu: OH, OR; SH, SR; CN; NH2,NHR, NR2; PR3; SeR; etc.

Rate Law: k[RX] Stereochemistry: Partial or total racemization of configuration at reacting carbon. Effects of alkyl group on rate: allyl, benzyl>3°R>2°R>>1°R>>Me Effects of leaving group: I>Br>Cl>>F) Favored by weak nucleophiles and low temperatures. Favored by protic dipolar solvents (H2O mixtures with organic solvents; HCO2H, CH3CO2H, etc.) E2 elimination

!

R

RR

RR

RR

R

H Xbase

Reagents: OH–/CH3CH2OH/Δ; RO–/ROH/Δ; NH2–; etc.

Rate Law: k[RX][B] Stereochemistry: anti. Regiochemistry: Zaitsev unless base is very hindered or anti elimination is not possible; Hofmann for X=F. Effects of alkyl group on rate: 3°R>2°R>1°R Effects of leaving group: I>Br>Cl>>F) Favored by strong bases and high temperatures.

E1 Elimination

!

R

RR

RR

RR

R

H Xbase

Reagents: ROH/Δ; AgNO3/ROH; etc. Rate Law: k[RX] Regiochemistry: Zaitsev, regardless of starting alkyl halide stereochemistry Effects of alkyl group on rate: 3°R>2°R>1°R Effects of leaving group: I>Br>Cl>>F) Favored by weak bases and high temperatures. Rearrangements possible.


Wagner-Meerwein Rearrangements

R!R

R

R

R!

R

R

R

Rearrangement of hydrogen or alkyl to adjacent carbon. Occurs at a reasonably rapid rate only when cation produced is more stable than starting cation; common in SN1 reactions.

Preparation of Alkyl Halides. (a) From alcohols:

R OH R X

X: Cl, Br, I. Reagents: HCl, HBr, HI; PCl3, PCl5, PBr3; P/I2; P/Br2; SOCl2; (C6H5)3P/CCl4, (C6H5)3P/Br2; etc. Mechanism: SN2 (1° R-OH with HX; 1° or 2° ROH with phosphorus-based reagents) SN1 (2°, 3°, allyl, benzyl alcohols with HX; 3°, allyl, benzyl alcohols with phosphorus-based reagents). Stereochemistry: inversion (SN2 mechanism); racemization (SN1 mechanism). (b) From alkyl halides:

YR X R Y

X: Cl, Br, I. Y: usually I–

Reagents: NaI/acetone; etc. Mechanism: usually SN2. Stereochemistry: inversion. (c) From alkenes:

R H

R RR

R X

R RR

Reagents: Cl2/hν, Br2/hν; SO2Cl2/hν; NBS/CCl4/Δ; NCS/CCl4/Δ; etc. (d) From alkanes:

R H R X

Reagents: Cl2/hν, Br2/hν; SO2Cl2/hν; etc.

Quenching of Organometallic Reagents

H X R H+ +R M M X

Reagents: H2O, D2O, H3O+, ROH; NH3, R2NH, NH4+, R3NH+; H2S, RSH; etc.

Any compound with an O–H or N–H bond will react with an organometallic reagent based on lithium, magnesium or zinc to give the hydrocarbon.

Direct Synthesis of Organometallic Reagents R X

MR M

M = Li, Mg, Zn, Al, etc.; X = Cl, Br, I

Reagents: Li/Et2O, Li/THF; Mg/Et2O; Zn/Et2O/Δ; etc. Stereochemistry: Chiral alkyl halides give partially or totally racemic organometallic reagents. Method works only for very electropositive metals.


Transmetallation (a) Metal-Halogen Exchange

R X R M+ +R! M R! X

Reagents: BuLi/THF/-78°C; t–BuLi/THF/-100°C; etc. Any halide may be used, including aryl and vinyl halides; bromides are most common. The organometallic reagent may not be methyllithium, and is almost always a butyllithium-type reagent. (b) Metal-Metal exchange

M X R M+ +R M! M! X M: Li; Mg; etc. M': Cu; Cd; Hg; etc.

Reagents: R′–M: RLi, RMgX; R2Zn, R3Al; etc. M–X: CuCl, CuBr, CuI, CuCN; CdCl2, CdBr2; SiCl4, R3SiCl; SnCl4, R3SnCl; MnCl2, ZnCl2, HgCl2, etc. M is always less electropositive than M′

Organocuprate Coupling

R X R R!

R: Not 3° alkyl; reaction is slow with 2° alkyl. Reagents: R2CuLi; R2Cu(CN)Li2; etc. Stereochemistry: inversion of configuration with alkyl halides; retention of configuration with vinyl halides.

Reductive Elimination

R

RR

RR

RR

R

Y X

X: Cl, Br, I; etc. Y: X; OR; etc.

Reagents: Na/C6H6; Li/Et2O; Mg/ROH; Zn/H2O, Zn/RCO2H; etc. Stereochemistry: anti elimination wherever possible, but E1cb elimination permits syn elimination.

Electrophilic Addition of Proton Acids

R R

RR

R

H X

R

RR

HX

Reagents: HCl; HBr; HI; HF; H2SO4; H+/ROH; etc. Stereochemistry: varies; often anti. Regiochemistry: Markovnikov (unless free-radical mechanism).

Addition of Halogens and Halogen-like Molecules

R R

RR

R

Y X

R

RR

X–Y

Reagents: Br2/CCl4; Cl2/CCl4; Br2/H2O; Br2/CH3OH; IN3; BrCl; ICl; Br2/LiCl; etc. Stereochemistry: predominantly anti. Regiochemistry: usually Markovnikov.


Acid-Catalyzed Hydration

R R

RR

R

H OH

R

RR

Reagents: H2SO4/H2O; HNO3/H2O; etc. Stereochemistry: varies; usually mixed syn and anti. Regiochemistry: Markovnikov; rearrangements possible.

Oxymercuration-Demercuration:

R R

RR

R

H OH

R

RR1) Hg(OCOR!)2/THF/H2O

2) NaBH4/NaOH/H2O

R': CH3, CF3, etc.

Stereochemistry: Step 1 is anti; step 2 is stereorandom. (OH group ends up on more hindered face). Regiochemistry: Markovnikov; usually no rearrangements.

Hydroboration-Oxidation:

R R

RR

R

H X

R

RR

2) [O]

1) HBR!2/THF

Reagents: R' = H; alkyl (Sia2BH, ThBH2, 9-BBN); etc. [O] = H2O2/OH–/H2O; (CH3)3N+O–; (X=OH); or I2/KOH (X=I); Br2/NaOCH3 (X=Br); or H2NOSO3H (X=NH2); etc. Stereochemistry: X=OH, NH2, syn (suprafacial); X=Br, I, mainly anti (antarafacial) Regiochemistry: anti-Markovnikov.

Base-Promoted Elimination from Alkyl Halides and Sulfonates

H R

XR

R R

R R

RRbase/!

X: Cl, Br, I, OSO2R, NR3

+, etc. Reagents: KOH/EtOH/Δ; KOCMe3/Me3COH; NaNH2/NH3; LiNR2/THF; etc. Mechanism: E2 (strong bases) or E1 (weak bases). Stereochemistry: anti (E2 mechanism). Regiochemistry: Zaitsev (E1 mechanism; E2 mechanism if also anti)

Reductive Elimination

H R

XY

R R

R R

RR

X, Y: Cl, Br, I, OSO2R, NR3

+, etc. Reagents: Li/NH3; Mg/Et2O; Zn/EtOH/Δ; Zn/CH3CO2H/Δ; or BuLi/Et2O; etc. Mechanism: E1cb or E2. Stereochemistry: anti (E2 mechanism); mainly anti (E1cb mechanism).


Dehydration

H R

OHR

R R

R R

RRH /!

Reagents: H2SO4/Δ; H3PO4/Δ; etc. Mechanism: E1 (except 1° alcohols, which are E2) – rearrangements common where possible. Regiochemistry: Zaitsev, regardless of stereochemistry of starting alcohol

Wittig and Wadsworth-Emmons Reactions

O

R

R

R!

R

R

R!

Reagents: R3P=CR′2/THF (Wittig); [(RO)2P(=O)–CR′2]–Na+/THF (Wadsworth-Emmons). Stereochemistry: Z alkene predominates in Wittig reaction E alkene predominates in Wadsworth-Emmons reaction.

Reduction to give alkenes (a) Birch reduction

Li/NH3/Me

3COH

M: Li, Na, K, etc.; ROH: EtOH, Me3COH, etc.

Reagents: Li/NH3/Me3COH/THF; etc. (b) Alkyne reduction

R R

HH

R H

RH

and/or[H]

R R

Reagents: H2/Pd-CaCO3/Pb/quinoline (Lindlar's catalyst); or Na/NH3; etc. Stereochemistry: syn (hydrogenation); anti (Birch reduction).

Epoxidation

RR

R R

R R

RR O[O]

Reagents: m-CPBA/CH2Cl2; or (CH3)3COOH/VO(acac)2; (CH3)3COOH/Mo(CO)6; or Br2/H2O, then K2CO3; etc.

Sharpless Asymmetric Epoxidation

RR

R OH

R R

R O OH[O]

Reagents: (CH3)3COOH/Ti(OR)4/diethyl tartrate. Stereochemistry: D-(-)-dialkyl tartrate delivers oxygen to top face of double bond as drawn; L-(+)-dialkyl tartrate delivers

oxygen to bottom face of double bond as drawn.


Hydroxylation

R R

RR

HO OH[O]

R

R

R

R

Reagents: KMnO4/KOH/H2O; OsO4/(CH3)3COOH; OsO4/NaClO3/H2O; or HCO3H, then KOH/H2O; Br2/H2O, then KOH/H2O. Stereochemistry: syn (KMnO4 or OsO4-based reagents); anti (peracid or HOBr-based reagents).

Allylic Halgenation

[O]

R

R

R

R

R

H R

R

R

R

R

X

Reagents: Br2/hν, Cl/hν; etc. or NBS/CCl4/Δ; NCS/CCl4/Δ; etc.

Allylic Oxidation

[O]

R

R

R

R

R

H R

R

R

R

R

OCOR

Reagents: Me3CO-OCOR/Cu+/Δ.

Ozonolysis of alkenes

R!

R!R

R R!

R!

OO

R

R

+

Reagents: 1) O3/CH2Cl2/-78°C; 2) Zn/H2O; 1) O3/CH2Cl2/-78°C; 2) Me2S; etc. or 1) O3/CH2Cl2/-78°C; 2) CH3CO3H; etc.

Lemieux-Johnson Oxidation and Related Reactions

R!

R!R

R R!

R!

OO

R

R

+

Reagents: OsO4/NaIO4/CCl4/H2O; or (RuO4 or RuO2)/NaIO4/CCl4/H2O.

Catalytic Hydrogenation of alkenes

R

RR

R R

H H

R

RRH2/catalyst

catalyst: Ni; PtO2; Pd-C; Os; Ru; etc; (Pd-C is most common); [(C6H5)3P]3RhCl; etc. Stereochemistry: syn (suprafacial).


Diels-Alder Reaction ([4+2] cycloaddition)

R

Ra

Rb

R

Rd

Rc+

R1

R2

R3

R4

RbRa

R2

R1

R4

R3

Rd Rc

R

R

and/or

RbRa

R1

R2

R3

R4

Rd Rc

R

R

Reagents: 1,3-dienes with electron-donating groups (e.g. R, RO, R2N, etc.); alkenes with electron-withdrawing groups (e.g. C=O, C≡N, NO2, SO2, etc.). Stereochemistry: suprafacial with respect to both participants; endo orientation preferred if conjugating substituents on dienophile. Regiochemistry: unsymmetrical dienophiles react with unsymmetrical dienes to give mainly 1,4- or 3,4-disubstituted cyclohexenes.

Acetal and Ketal Formation

O

R

R

R

ROR!

OR!

Reagents: (CH2OH)2/TsOH/C6H6/Δ, Me2C(CH2OH)2/TsOH/C6H6/Δ; etc. (direct formation), or Me2C(OMe)2/TsOH/R′OH/hexane/Δ; etc. (transketalization) Reversal: H2SO4/H2O/THF; H2SO4/H2O/acetone; etc.

Thioketal and Thioacetal Formation

R

RSR!

SR!O

R

R

Reagents: HS(CH2)2SH/BF3/CH2Cl2, HS(CH2)3SH/ZnCl2/CH2Cl2, HS(CH2)2SH/SnCl4/CH2Cl2. Reversal: HgCl2/CdCO3/H2O; NBS/MeCN/H2O; MeI/acetone/H2O/Δ.

Cyanohydrin formation

O

R

R

R

ROR!

CN

R′: H, SiMe3.

Reagents: HCN; KCN/NaHSO3; etc. (R′ = H) or Me3SiCN/CH2Cl2; Me3SiCl/Zn(CN)2/KCN/MeCN; etc. (R′ = Me3Si) Reversal: KOH/H2O/Δ.

Imine Formation

O

R

R

NR!

R

R

R′: H, alkyl, aryl

Reagents: NH3/H2O; R–NH2/MeOH/Δ; Ar–NH2/MeCO2H/MeOH/Δ. Reversal: H2SO4/H2O/acetone.

Condensation with Hydrazine Derivatives

O

R

R

NR

R

N

R!

R!!

R′, R′′: H, alkyl, aryl, Ts, CONH2 (semicarbazide). Reagents: H2NNH.-/MeOH/Δ; C6H5NHNH3

+Cl–/MeCO2–Na+/MeOH/Δ; Me2NNH2/MeOH/Δ; TsNHNH2/MeOH/Δ.

Reversal: often not trivial; MeCOCO2H/Δ.


Oxime Formation

N–OH

R

R

O

R

R

Reagents: HONH3

+Cl–/MeCO2–Na+/MeOH/Δ.

Enamine Formation

O

R2CH

R

NR!2

R2C

R

R′: alky or aryl.

Reagents: R′2NH/TsOH/C6H6/Δ; etc. Reversal: MeCO2H/H2O/Δ; H2SO4/H2O/THF; (CO2H)2/H2O.

Enol Ether Formation

O

R2CH

R

OR!

R2C

R

Reagents: R′OH/Me2C(OMe)2/Δ, especially if R′OH is secondary; MeOH/TsOH/Δ; Me2C(OMe)2/TsOH/Δ; etc. Reversal: (CO2H)2/H2O; H2SO4/H2O/THF.

Addition of Organometallic Nucleophiles

O

R

R

OH

R

R

R!

R′: alkyl, aryl, R–C≡C–; (no O–H, N–H bonds, no C=O N=O bonds)

Reagents: 1) R′–Li/THF or Et2O, 2) H3O+ or NH4+/H2O;

1) R′–Mg–X/Et2O or THF, 2) H3O+; 1) R′–C≡C:–Na+/THF or Et2O or NH3, 2) H3O+. Solvents: Anhydrous Et2O or THF must be used for the additions of RMgX and RLi; liquid NH3 may be used as solvent for the additions of RC≡CM.

Wittig Reaction

O

R

R

R

R R!

R! Reagents: R′2CH=P(C6H5)3/BuLi/THF/-78°C. Stereochemistry: Unconjugated ylides (R′ is simple alkyl) give the Z alkene as the major product. Conjugated ylides tend to give more E alkene.

Wadsworth-Emmons Reaction

O

R

R

R

R E

E: CO2R′, COR′, CN, etc.

Reagents: (MeO)2P(=O)CH2-CO2Me/NaOCMe2Et/EtCMe2OH; (MeO)2P(=O)CH2-CN/NaH/Me2SO. Stereochemistry: The major product is usually the E alkene.

Formation of Ketones from Nitriles

R C N

O

R!R Reagents: 1) R′-MgX/Et2O, 2) HCl/H2O; 1) R′-Li/THF, 2) (CO2H)2/H2O.


Reduction of Nitriles (a) To Amines

R C N R CH2NH

2 Reagents: LiAlH4/Et2O; H2/Pt/EtOH/HCl; etc.

(b) To Aldehydes

R C N

O

HR Reagents: 1) DIBAL-H/0°C, 2) H3O+.

Hydrolysis of Nitriles (a) To carboxylic acids

R C N

O

OHR Reagents: 1) KOH/EtOH/H2O/Δ, 2) H3O+; HCl/H2O/Δ.

(b) To amides

R C N

O

NH2

R

Reagents: KOH/H2O/H2O2.

Oxidation of Alcohols

H

OHR

R

O

R

R

Reagents: K2Cr2O7/H2SO4/H2O; CrO3/H2SO4/H2O or CrO3/py (Sarett); CrO3•2py/CH2Cl2 (Collins) or pyHCrO3Cl/CH2Cl2 (PCC); (pyH)2Cr2O7/CH2Cl2 (PDC) or Me2SO/(COCl)2/CH2Cl2/Et3N/-60°C (Swern) or TPAP/NMMO/CH2Cl2 or KMnO4 Note: tertiary alcohols are resistant to oxidation

Oxidative Cleavage of Alkenes

O

R

R

R

R R

R Reagents: 1) O3/CH2Cl2/-78°C; 2) Me2S or OsO4/NaIO4/THF/H2O (Lemieux-Johnson)

Preparation of Nitriles from Aldoximes

H

CH=NOHR

RH

CNR

R Reagents: P2O5; POCl3; (CH3CO)2O; (COCl)2; RN=C=NR; R-N=C=O


Enolate Anion Formation

R

R R

O

H

R

R R

O

Reagents: LDA/THF/-78°C; LICA/THF/-78°C; LiTMP/THF/-78°C;NaHDS/THF/-78°C; LHDS/THF/-78°C; KHDS/THF/-78°C (kinetic enolate formation) or KOCMe3/Me3COH; KOCMe3/Me2SO (thermodynamic enolate formation) Thermodynamic enolate has most substituted double bond; kinetic enolate has less substituted double bond.

Epimerization and Exchange

H

O

R

R2

R1

(D or) H

O

R

R2

R1base

Reagents: Epimerization: K2CO3/CH3OH; KOH/H2O/THF or 1) LDA (or LICA, etc.)/THF/-78°C; 2) H3O+ H-D Exchange: KOD/D2O; KOC(CH3)3/(CH3)3COD or 1) LDA (or LICA, etc.)/THF/-78°C; 2) D2O

Silyl Ether Formation

1) base

2) R!3SiClH

O

R

R

R

R

OSiR!3

R

R

Base: LDA (or LICA, etc.)/THF/-78°C. R′3SiCl: Me3SiCl (TMS-Cl); Me3CSiMe2Cl (TBDMS-Cl)

Alkylation

H

O

R

R

R

R

O

R

R!

R

Reagents: 1) LDA (or LICA, etc.)/THF/-78°C; 2) R′–X or 1) LDA (or LICA, etc.)/THF/-78°C; 2) R3SiCl; 3) R′–X/TiCl4

Selenylation, Sulfenylation, Halogenation

H

O

R

R

R

R

O

R

X

R

X = SeR, SR, I, Br, Cl.

Reagents: 1) LDA (or LICA, etc.)/THF/-78°C; 2) (C6H5Se)2 [X=SeR] or 1) LDA (or LICA, etc.)/THF/-78°C; 2) C6H5SCl [X=SR] or X2/CH3CO2H [X=halogen]

Aldol Addition

RH

O

R R

R R!

O

R R

OH

R!

Reagents: 1) LDA (or LICA, etc.)/THF/-78°C; 2) R′2C=O


Reduction of Aldehydes and Ketones

O

R

R

H

OHR

R

Reagents: LiAlH4/Et2O (or THF); NaBH4/CH3OH; LiR3BH/THF; etc. or R2CH-CR2-MgX; R2CH-CR2-BR2; etc. or (R2CH-O)3Al/R2CHOH (Meerwein-Ponndorf-Verley reduction; Tishchenko reaction); or H2C=O/KOH (Cannizzarro) or DIBAL-H/hexane; etc.

Reduction of Conjugated Carbonyl Compounds (a) To Allylic Alcohols

R O

R R

R

R OH

R R

R

Reagents: LiAlH4/Et2O/low temp./short time; DIBAL-H/hexane; NaBH4/CeCl3/CH3OH; etc. (b) To Saturated Ketones

R O

R R

R

R O

R R

R

Reagents: H2/Pd-C; etc. or Li/NH3 (no proton source); etc. (c) To Saturated Alcohols

R O

R R

R

R OH

R R

R

Reagents: Li/NH3/ROH; etc. or NaBH4/CH3OH; LiAlH4/Et2O/room temp./longer time

Deoxygenation

H

HR

R

O

R

R

Reagents: H2NNH2/KOH/HOCH2CH2OH/Δ (Wolff-Kishner); or 1) TsNHNH2/CH3OH/Δ, 2) NaBH3CN/CH3OH/Δ; or Zn(Hg)/HCl/H2O/Δ (Clemmensen). or 1) HSCH2CH2SH/BF3, 2) H2/Ra-Ni; 1) HSCH2CH2SH/BF3, 2) Na/NH3; (reductive desulfurization);

Oxidation of Aldehydes

R CHO R CO2H

Reagents: K2Cr2O7/H2SO4/H2O; CrO3/H2SO4/H2O; CrO3/H2SO4/acetone (Jones reagent) or KMnO4 or Ag2O/NH3/H2O (Tollens' reagent)

Baeyer-Villiger Oxidation

O

RR

O

ORR

Reagents: RCO3H/CH2Cl2; m-CPBA/CH2Cl2; etc.


Formation of Alkoxide Anions.

R

R

OHR

R

R

OR

Reagents: active metal (Li, Na, K, etc.) or hydride anion bases (LiH, NaH, KH, etc.) or metal alkyls (RMgX, RLi, etc.) or amide anion bases (NaNH2, LiNR2, etc.)

Formation of Amide Anions.

RN

R

RN

RH

Reagents: active metals (Na, K, etc. – usually requires catalysis) or metal alkyls (RLi, RMgX, etc.)

Formation of Esters.

pyR

R

OHR

R

R

OCOR!RR!COCl

Formation of Amides.

R

N

R

H

R

N

R

COR!R!COCl

Formation of Sulfonate Esters.

pyR

R

OHR

R

R

OSO2R!RR!SO2Cl

R′: CH3 (Ms), C6H5, CH3-C6H4 (Ts), O2N-C6H4 (Ns), BrC6H4 (Bs), CF3 (Tf) Analogous reactions using thionyl chloride (SOCl2) give alkyl chlorosulfites; analogous reactions with phosphorus trihalides give trialkyl phosphites. Both these compounds readily react further to give alkyl halides.

Williamson Ether Synthesis:

R

R

OR!R

R

R

OR

R

R

OHR

R′: alkyl, R3Si, etc.

Reagents: NaH/R′–X; R′–X/EtN(i-Pr)2; etc. This reaction may be applied intramolecularly to make cyclic ethers including epoxides.

Formation of Halides.

R

R

OHR

R

R

XR

X: Cl, Br, I

Reagents: HCl, HBr, HI (SN1); HCl/ZnCl2. or PCl3, PCl5, SOCl2, PBr3, P/I2. or (C6H5)3P/CCl4/Δ; (C6H5)3P/Br2/DMF.


Cleavage of Ethers.

RO

R!R X Y R!+

Reagents: HI, HCl/ZnCl2. or BBr3/CHCl3, BCl3/CH2Cl2, etc. or (CH3)3SiI, (CH3)3SiCl/NaI

Ring Opening of Epoxides. (a) Basic conditions

1) Nu

2) H3O

O

R!

R R Nu

HO

R!

Reagents: 1) RLi, 2) H3O+; 1) RMgX/CuCl, 2) H3O+; 1) R2CuLi, 2) H3O+; or 1) LiOCR=CR2, 2) H3O+; or 1) LiAlH4, 2) H3O+; or HO–/H2O, RO–/ROH, RS–/ROH, etc.; or NH3, RNH2, R2NH. (b) Acidic conditions

H–Nu/HO

R!

R

R OH

Nu

R!

Reagents: H2O/H2SO4, ROH/H2SO4, RSH/H2SO4, HCl/H2O, HBr/H2O, HI/H2O, etc.

Base Cleavage of Epoxides.

R

HO

R!

R

O

R!

R R

base

Reagents: LDA/THF/-78°C, LiTMP/THF/-78°C, LICA/THF/-78°C, etc.

Organometallic Synthesis of Alcohols:

R!-M

R

R

O

R

R

OHR!

M: Mg (Grignard reagent); Li; Zn (with aldehydes); etc.

Aldol Addition:

R1

O

R2

R1

O

R2

OH

R31) base

2) R3CHO

Base: LDA (or LICA or LHMDS or NaHMDS, etc.)/THF/-78°C

Preparation of Alcohols by Reduction:

[H]

R

R

O

R

R

OH

[H]: LiAlH4/Et2O; NaBH4/EtOH; DIBAL-H/hexane; etc.


Hydration of Alkenes:

R

R R

R R

R R

OH

R

H

Reagents: 1) BH3•THF; 2) H2O2/NaOH/H2O; other hydroborations; anti-Markovnikov; syn. or H2SO4/H2O (H3O+); Markovnikov; stereorandom. or 1) Hg(OAc)2/THF/H2O, 2) NaBH4/NaOH/H2O; Markovnikov; first step anti, second step stereorandom.

Hydroxylation of Alkenes:

R

R R

R R

R R

OH

R

HO

Reagents: 1) HCO3H; 2) OH– (anti addition) or OsO4/Me3C–OOH/Me3C-OH; KMnO4/KOH/H2O (syn addition);

Solvomercuration-Demercuration:

R

R R

R R

R R

OR!

R

H

Reagents: 1) Hg(OCOCF3)2/THF/R′OH; 2) NaBH4/NaOH/H2O Regiochemistry: Markovnikov

Sharpless Asymmetric Epoxidation of Allylic Alcohols:

OHOHO

(+)-DET/CH2Cl2/-20°CO

OH

Ti(O-i-Pr)4/Me3C–OOHTi(O-i-Pr)4/Me3C–OOH

(-)-DET/CH2Cl2/-20°C Proceeds with high levels of stereoselectivity to give enantiomer shown.

Preparation of Amines by Reduction:

R C N[H]

R CH2NH2

[H]R NO2 R NH2

[H]R N3 R NH2

Reagents: LiAlH4/Et2O; etc. (nitriles); or Sn/HCl/H2O/Δ; other metals may be Fe, Zn, Mg, etc.; or Na/EtOH; Li/NH3/ROH; or other variant of Birch reduction; or H2/Pd-C/EtOH

Reductive Amination:

[H]

R

R

O

R

R

NHR!R! NH2+

Reagents: RNH2/H2/Pd-C/EtOH; other catalysts may also be used; or RNH2/NaBH3CN/MeOH; or HCO2H/NH3 (Leuckart Reaction); HCO2H/RNH2 (Wallach Reaction); or H2CO/HCO2H (Eschweiler-Clarke Reaction) The intermediate imine may or may not be isolated. Ammonia or primary or secondary amines may be used for this reaction.


Gabriel Synthesis:

1) C6H4(CO)2N–M

+

2) N2H4

R NH2R X

Restricted to those alkyl halides and sulfonates that will participate in SN2 reactions. Hydrazinolysis is preferred for obtaining the primary amine from the product.

Dehydration of Alcohols:

R

R R

RR

R R

OH

R

H

Reagents: H2SO4/Δ, H3PO4/Δ (E1 preferred; strongly Zaitsev) or POCl3/py; SOCl2/py (probable E2 through chlorophosphate or chlorosulfite esters)

Oxidation of Alcohols: (a) To aldehydes and ketones

[O]

R

R

O

R

R

OH

Reagents: Cr (VI) – PCC/CH2Cl2, PDC/CH2Cl2, CrO3•2py/CH2Cl2, etc. or Me2SO – (COCl)2/Me2SO/CH2Cl2/Et3N/-60°C (Swern), etc. or TPAP/NMMO/CH2Cl2/r.t. or Mn (IV) – MnO2/C6H6/Δ (allylic and benzylic alcohols only) (b) To carboxylic acids

[O]R CO2HR CH2OH

Reagents: Cr (VI) – K2Cr2O7/H2SO4/H2O, etc. Mn (VII) – KMnO4/H2O.

Oxidative Cleavage of 1,2-Diols:

R!R

R!R

HO OH[O]

O

R

R

O

R!

R!

+

Reagents: HIO4; Pb(OAc)4/CH3CO2H; CrO3; etc. Cyclic esters may be intermediates in the cleavage of 1,2-diols by these oxidants; in cyclic systems cis-diols react faster than their corresponding trans isomers.

Hydrogenolysis:

[H] R

RR

R

H

RR

R

R

X

R

R

X: OH, OR, OCOR, NH2, NHR, NR2, NR3

+, NHCOR, NRCOR, SH, SR, halogen, etc. Reagents: H2/Pd-C; Li/NH3/ROH; Na/EtOH; etc.

Deamination.

NO

R

R

NH2R

R

R

R

R

R

N2R

Reagents: HNO2, NaNO2/HCl/H2O; NOCl; RONO. Reaction involves intermediate diazonium ion which rapidly decomposes by loss of nitrogen to "hot" carbocation; products may be substitution or elimination products by SN1 or E1 pathways.


Nucleophilic Acyl Substitution in Acid Derivatives (a) Hydrolysis

RCOX → RCO2H (X: Cl, OCOR′, OR′, NR′2) Reagents: H2O (X = Cl, OCOR′); H3O+/Δ; HO–/Δ. Hydrolysis by OH— is rendered irreversible by removal of the carboxylic acid from the final equilibrium as the carboxylate anion. Hydrolysis of amides by H3O+ is rendered irreversible by removal of the amine from the final equilibrium as the ammonium salt. (b) Alcoholysis (transesterification)

RCOX → RCO2R′ (X: Cl, OCOR′, OR′, NR′2) Reagents: R′OH (X = Cl, OCOR′); R′OH/H+ (X = OH, OR; reversible); R′O–/R′OH (X = OR; reversible) (c) Ammonolysis

RCOX → RCONR′2 (X: Cl, OCOR′, OR′, NR′2) Reagents: R′2NH

Conversion of Carboxylic Acids to Derivatives (a) Conversion to Esters – Esterification

RCO2H → RCO2R′ Reagents: R′OH/H+/Δ

(b) Conversion to Acid Chlorides RCO2H → RCOCl

Reagents: PCl3, PCl5; SOCl2/Δ; (COCl)2/Δ

(c) Conversion to Anhydrides RCO2H → RCO-O-COR′

Reagents: R′COCl/Et3N; or 1) base (NaH, RMgX, RLi); 2) R′COCl.

(d) Formation of Cyclic Anhydrides

O (CH2)n

O

O

HO2C

HO2C

(CH2)n

n = 0, or 1

Reagents: Δ; RCOCl; etc.

(e) Conversion to Amides – Ammonolysis RCO2H → RCONR′2

Reagents: 1) PCl3, 2) R′2NH.

(f) Formation of Cyclic Imides

N (CH2)n

O

O

RHO2C

HO2C

(CH2)n

n = 0, or 1

Reagents: RNH2/Δ.


Reactions with Organometallic Nucleophiles

COXRR

O

R!

R

OH

R!R!

Reagents: (a) To give ketone: X = O–; R′Μ = R′Li X = Cl, OCOR; R′M = R′2Cd, R′2CuLi, R′2Zn X = NR′2; R′M = R′MgX (b) To give tertiary alcohol: X = Cl, OCOR, OR; R′M = R′Li, R′MgX, (R′2Zn [excess])

Reductions of Acyl Compounds

COXR ROH

X = Cl, OCOR, OR, OH, O–

Reagents: LiAlH4, Red-Al®; BH3•THF (X=OH); DIBAL-H (X=Cl, OCOR, OR).

CONR2

RR

NR2

X = Cl, OCOR, OR, OH, O–

Reagents: LiAlH4, Red-Al®.

Alkylations and Aldol-type Additions of Enolates (a) Alkylation

COXR

R COX

R!

X = OR′, NR′2

Reagents: 1) LDA/THF/-78°C; 2) R′-X

(b) Aldol addition reactions

COXR COX

R

OH

R!

X = OR′, NR′2

Reagents: 1) LDA/THF/-78°C; 2) R′-CHO

(c) The Reformatskii reaction

COX

R

OH

R!

COXR

Br

X = OR′, NR′2

Reagents: 1) Zn/Et2O; 2) R′-CHO .


Tiffeneau-Demyanov Rearrangement:

RR

H2N OH

RR R R

OR

RNO

Reagents: HONO, NOCl/py, etc. Rearrangement strictly analogous to pinacol rearrangement.

Synthesis and Reactions of β-Ketoacid Derivatives (a) The Claisen condensation

CO2RR

CO2RR

R

O

Reagents: RO–/ROH/Δ. Reaction is reversible. Tertiary amide or nitrile may be substituted for ester (nirtiles give β-ketonitriles)

(b) The Dieckmann condensation

CO2R

OCO

2R

CO2R OR

Restricted to formation of 5- and 6-membered rings

Synthesis of Carboxylic Acids by Oxidation (a) Oxidation of primary alcohols

RCH2OH → RCO2H Reagents: K2Cr2O7/H2SO4/H2O/Δ; KMnO4/H2O/Δ.

(b) Oxidation of α-ketols

R

O OH

R!

R![O]

R CO2H O

R!

R!

+

Reagents: HIO4 (other product is an aldehyde); KMnO4/H2O/Δ (both products are acids)

(c) Ozonolysis of alkenes with oxidative isolation of products

1) O3 HO2C R!

R

H H

R!2) [O]

R CO2H +

Oxidizing agent for ozonide: H2O2; RCO3H (e.g. m-CPBA).

(d) Oxidation of aldehydes RCHO → RCO2H

Reagents: K2Cr2O7/H2SO4/H2O; KMnO4/H2O or Ag2O/NH3/H2O (Tollens Reagent)

(e) Oxidative rearrangements of ketone derivatives

O

R R!

O

XRR!

Reagents: X = O: [O] = RCO2OH (Baeyer-Villiger reaction) X = NH: [O] = 1) NH2OH, 2) H+ (Beckmann rearrangement) X = NH: [O] = HN3 (Schmidt rearrangement)


Diazomethane esterification

R-CO2H + CH2N2 → R-CO2CH3 Reagent: CH2N2/Et2O.

Synthesis of Carboxylic Acids from Alkyl Halides (a) Carbonation of Grignard Reagents

R–M + X=C=O → R–CO–XH M: Li; MgCl, MgBr, MgI. X: O; NR′. (b) Cyanation

R–X + CN → RCN → RCO2H SN2 displacement of halide is followed by acid or base hydrolysis of nitrile

Hofmann, Lossen and Curtius Rearrangements

N

R

COO

C

NR

X

(a) Hofmann rearrangement: X = Br Reactant: primary amide Reagents: Br2/KOH/H2O; Br2/RO–/ROH; etc.

(b) Lossen rearrangement: X = OH2+, OCOR, OSO2R Reactant: hydroxamic acid Reagents: H2SO4, TsOH, etc.; TsCl/py; RCOCl/Δ, etc.

(c) Curtius rearrangement: X = N2+ Reactant: acyl azide Reagents: Δ or hν.

Haloform Reaction

baseor

O

CH3

R

X2

O

OR

R

O

O

R

Reagents: Cl2/KOH/H2O, Br2/KOH/H2O, I2/KOH/H2O [give carboxylate anion] or Cl2/NaOR/ROH, Br2/NaOR/ROH, I2/NaOR/ROH [give ester]

Favorskii Rearrangement

O

R!

R

XR

O

R!!O

R

R!R

R!!O

X = halogen or other good leaving group

Reagents: KOH, KOR′′, etc.

Michael Addition

E

R

R

NuE

R

R

H–Nu

E = RC=O, ROC=O, C≡N, NO2, etc. (an electron-withdrawing group)

Reagents: CN–, RS–, RO–, etc. or R2CuLi/THF, R2Cu(CN)Li2/THF, RCu•BF3, etc. or enolate anions, enamines, etc. or R2S(O)=CR2 (gives cyclopropanes); ROO– (gives epoxides).


Robinson Annelation

R1 O

R2

R5

O

R4

R3 R3

R2

R1O

R3

R3

R4

R5

+base

base: RO–/ROH/Δ; NaH; etc. enamines may be used instead of the enolate anion.

Decarboxylation of β-Ketoacids and β-Diacids

G

O

CO2H

R!R!

"G

O

R!

R!G

OH

R!

R!

Acetoacetic Ester Synthesis of Ketones

O

CO2R

1) base

2) R!X

O

CO2R

R!

1) hydrolysis

2) "

O

R!

base: RO–/ROH/Δ; NaH; etc. R'—X: RCH2X, CH3X (reaction is SN2 mechanism) hydrolysis: HCl/H2O/Δ; H2SO4/H2O/Δ; etc.; or K2CO3/EtOH; KOH/H2O/Δ

Malonic Ester Synthesis of Carboxylic Acids

RO2C CO2R1) base

2) R!X

RO2C CO2R

R!

1) hydrolysis

2) " R!

CO2H

base: RO–/ROH/Δ; NaH; etc. R'—X: RCH2X, CH3X (reaction is SN2 mechanism) hydrolysis: HCl/H2O/Δ; H2SO4/H2O/Δ; etc.; or K2CO3/EtOH; KOH/H2O/Δ

Nitration

NO2

Reagents: HNO3/H2SO4; HNO3/(CH3CO)2O (for activated systems).

Sulfonation

SO3H

Reagents: H2SO4, SO3/H2SO4; pyridine•SO3.

Halogenation

X

X = Cl, Br

Reagents: Cl2/AlCl3; Br2/Fe, Br2/FeBr3; Br2/pyridine.


Friedel-Crafts Alkylation

R

Reagents: RCl/AlCl3; ROH/PPA/Δ; R2C=CR2/H+. Electrophile is a Lewis acid-Lewis base complex if the alkyl group is methyl or primary, and the carbocation if the alkyl group is secondary, tertiary, allyl or benzyl. The reaction does not occur if the aromatic ring is strongly deactivated (e.g. nitrobenzene). Polyalkylation may be a problem.

Friedel-Crafts Acylation

COR

Reagents: RCOCl/AlCl3; (RCO)2O/AlCl3. Electrophile is an acylium ion. The reaction does not occur if the aromatic ring is strongly deactivated (e.g. nitrobenzene).

Side-Chain Oxidation to Benzoic Acids

[O]Ar CO2HAr R

Reagents: KMnO4/Δ; K2Cr2O7/H3O+/Δ; etc.

Side-Chain Oxidation.

Ar R

H

Ar R

X[O]

X = Cl, Br, OCOR Reagents: X=halogen: Br2/hν; NBS/CCl4/Δ; etc. X=OCOR: Me3CO–OCOPh/Cu(II); etc.

Hydrogenolysis

Ar R

H

Ar R

X [H]

X: OH, OR, OCOR, NR2, NRCOR′, Cl, Br, I, OTs, etc.

Reagents: H2/Pd-C; Ca (or Na or Li or K)/NH3/ROH

Nucleophilic Aromatic Substitution by Addition-Elimination

X

Nu

E

E

E

Nu

E

E

EX

E

E

E

E = NO2, CN, COR, CO2H, CO2R, etc. X = F, Cl, Br, I, OSO2R, etc.

Substitution by this mechanism requires an electron-withdrawing group o- or p- to the leaving group. 2- and 4-Halopyridines react by this mechanism.


Nucleophilic Aromatic Substitution by the Benzyne Mechanism

BBX

X = F, Cl, Br, I, OSO2R, etc. B = NH2

–, RNH–, R2N–, RLi, etc. Substitution by this mechanism required a powerful base as the initiating reagent. It is the mechanism followed when there are no activating electron-withdrawing groups on the ring.

Kolbe Carbonation

KOH/H2O

OH

CO2H

O

CO2

OCO

2

Diazonium Ion Substitution

Ar N2 Ar X

Reagents: X≠H: I–, RS–, H2O/Δ, CuCl/Δ, CuBr/Δ, CuCN/Δ, etc. X=H: H3PO2; C2H5OH/Δ, etc. Copper-catalyzed reaction is known as the Sandmeyer reaction.

Catalytic Hydrogenation of Alkynes

H2

H2

R!

H

H H

H

R

H

R R!

H

R R!

Catalysts: Pt, Pd-C, Ni, etc. give alkane product. Pd-BaSO4/PbSO4/quinoline (Lindlar catalyst) gives Z alkene. Other variants of Lindlar catalyst use CaCO3 as support; catalyst is always poisoned with lead or quinoline.

Birch Reduction of Alkynes

M/NH3/ROH

H

R H

R!

R R!

M: Li, Na, K, Ca, etc.

Stereochemistry: E alkene predominates (usually the only product).

Cycloadditions of alkynes

R!

R

R

R!

R

R

R!

R!

+

At least one electron-withdrawing group required on dienophile.


Addition of Electrophiles to Alkynes

E–NuE–NuR!

Nu

E Nu

E

R

R

E R!

Nu

R R!

E = H, Cl, Br, I, etc. Nu = OR, OCOR, Cl, Br, I, etc.

Reagents: HCl, HBr, HI; (RCO)2O/RCO2H/H2SO4; ROH/H2SO4; etc. Regiochemistry: anti-Markovnikov. Stereochemistry: often (but not always) anti.

Hydration of alkynes

H3O

R

H R!

OH

R R!Hg2

+

R

H R!

O

H

usually requires catalysis by mercuric ion Regiochemistry: Markovnikov; terminal alkynes give methyl ketones; internal alkynes usually give a mixture unless one intermediate carbocation is more stable.

Hydroboration-Oxidation of alkynes

R R!

R

H R!

O

H1) R2BH•THF

2) [O]

Reagents: 1) BH3•THF, 2) H2O2/KOH/H2O; 1) Sia2BH/THF, 2) NMMO; etc. Regiochemistry: anti-Markovnikov. Stereochemistry: syn addition; vinylborane usually adds a second equivalent of borane.

Formation of Alkynide Anions

baseR H R M

M=Li, Na, K, Mg, Cu, Ag, etc.

Reagents: RLi, RMgX, etc. or LDA/THF, NaNH2, NaH/DMSO, etc. or Mn+/NH3/H2O (M=Cu, Ag, etc), etc.

Alkynide Substitutions

R M R EE–Nu

M=Li, Na, K, Mg, Cu

E–Nu = R–X, R2C=O, epoxides, X2, etc. Mechanism: SN2 when E–Nu is alkyl halide or epoxide. [Cu+ aids substitutions of alkyl halides]. Regiochemistry: 1,2-addition with conjugated carbonyl compounds; attack is at less substituted carbon of epoxide ring.

Formation of Alkynes by E2 Elimination

X

X H

H

R R!

X

H X

H

R R!or R R!base

Reagents: NaNH2, LDA, etc. (favor terminal alkyne) or KOCMe3, etc. (favor internal alkyne)


Formation of Alkynes from Alkylidene Dihalides

X

XR

H

R H

X=Br, Cl, I

Reagents: 1) RLi/THF/-78°C, 2) H2O; etc. Propargyl Rearrangements

R

X

R R!Nu

R!

NuR

R

X=Cl, Br, I, OSO2R, OCOR, OR, NR3

+, etc. Nu=R, OR, OCOR, etc.

Reagents: R2CuLi/THF, RMgX/CuCl, etc. or LiAlH4, etc. or RCO2H/AgClO4/CH2Cl2 (X=OCOR).

Reaction synopsis Homolysis (a) Peroxides

RO OR 2 RO•! or h"

Reagents: Me3COOCMe3, PhCO2–O2CPh, etc. (b) Aliphatic Azo compounds

2 R•! or h"

R N N R + N2

Popular for initiating radical reactions with azo-bis-isobutyronitrile (AIBN). (c) Nitrite Esters

•NORO•! or h"

RO N=O + (d) Barton Esters

N

SO

O R

! or h"

N

S•

+ CO2 + R•

(e) Organomercury Hydrides

R Hg XNaBH4

R•

X = Cl, Br, OCOR, etc.

Reagents: NaBH4/NaOH/H2O; etc.


Atom Abstraction (a) Hydrogen

R•R H

Reagents: ROOR/Δ or hν; etc. Relatively non-specific unless the C–H bond is activated (e.g. benzylic or allylic) or the reaction is intramolecular. Intramolecular hydrogen atom abstraction occurs through a six-membered cyclic transition state. (b) By Stannyl Radicals

R•R X

X = Cl, Br, I, SR, OC(=S)–SR SeR, etc.

Reagents: Bu3SnH/AIBN/Δ or hν; etc. Fragmentation (a) Alkoxy Radicals

R

O

R

+R•

R

O

R

R•

Reagents: Me3CO–OCMe3, etc. (b) Carboxy Radicals

+R• CO O

O

XO

R

O

O

R

•

X = Br, OCOR, OR, etc.

Reagents: RCO2OR′; RCO2Ag/Br2; (RCO2)2; etc. Addition of Radicals to Alkenes

R

R R

R

R!•

R

R

R!

R

R

•

Regiochemistry: Markovnikov. Single Electron Transfer (s.e.t.)

R X •–R X R• + X

X

R

R

• X

R

R

Reagents: Li (Na, K, Ca, etc.)/NH3; Li (Na, K, Mg, Ca, etc.)/PhH; etc. Reaction synopsis


Radical Additions (a) Intramolecular Radical Cyclization

(CH2)n

•CH2•CH2

(CH2)n

n = 1, 2, 3, 4 Closure to 3- to 6-membered rings gives smaller of two possible rings. (b) Intermolecular Additions

R

RXY

R

R

Y

X

Reactants: CCl4/ROOR, BrCCl3/ROOR; HBr/ROOR; etc. First step always gives more stable radical: Markovnikov addition for most reagents; results in anti-Markovnikov addition for HBr (Br adds first). Radical Combination (a) Pinacol Reaction

O

R

R

R

R

HO

R

R

OH

Reagents: Mg(Hg)/PhH; or Ti/THF; K/TiCl4/THF; TiCl3/Zn(Cu)/THF; etc.


(b) Acyloin Condensation

O

RO

R

R

O O

R R

O OH

R

Reagents: Na/xylene/Δ; or 1) Na/xylene/Me3SiCl/Δ, 2) H3O+. (c) Phenol Coupling

OH

OH

O O

OH

HO

OH

OH

OH

OH

OH

or or or or

Reagents: FeCl3; KOH/K3Fe(CN)6; etc. or VOCl3. Barton Reaction

ONOHR

R!

OH

NOR

R!

OH

NOHR

R!

OHHR

R!

Reagents: 1) NOCl/pyridine; 2) hν. Hydrogen abstraction step of reaction occurs through a six-membered cyclic transition state. Hofmann-Löffler-Freytag Reaction

NHR!

X

R

N

R

R!

X

N

R

R!base

Reagents: NBS/hν.; I2/Pb(OCOMe)4/hν; Br2/H2SO4/hν; etc. Hydrogen abstraction step of reaction occurs through a six-membered cyclic transition state. N-Haloamide Isomerization

NH2

O

RNH

2

O

R XO

R O

base

Reagents: Pb(OCOMe)4/I2/Δ or hν. Substitution


R H R X X=Cl, Br, OCOR, etc.

Reagents: SO2Cl2/ROOR/Δ, Br2/Δ or hν; Cl2/Δ or hν; etc.; (alkanes; unactivated positions) or NBS/CCl4/AIBN/Δ; Me3CO–OCOPh/CuCl/Δ; etc.; (allylic position of alkenes) Reaction synopsis Ketone Photolysis

h!R"

OHROH

R R"

Hydrogen abstraction step of reaction occurs through a six-membered cyclic transition state. Homolysis of Azo Compounds

R!R R

R R• •

R!

R

R R

R

NN

R!

R

R R

R

h" or #

Hydrogenolysis of Cyclopropanes

R

R

[H] Me

Me

R

R

Regents: H2/PtO2/CH3CO2H; H2/Pd-C/CH3CO2H; etc. Least substituted bond ususlly reacts.

Electrophilic Cleavage of Cyclopropanes (a) Proton Acids

HX

H X

R

R

R

R

Reagents: HCl, HBr, HI; H2SO4/H2O/Δ (X=OH); etc. Most substituted ring bond breaks; hydrogen atom of acid ends up bonded to less substituted end of ring bond. (b) Halogens and Similar Molecules

XY

X Y

R

R

R

R

Reagents: Cl2/CCl, Br2/CCl; ICl, BrCl; HO–Br, HO–Cl, etc. Most substituted ring bond breaks; more electronegative atom of reagent ends up bonded to more substituted end of ring bond.

Wurtz Coupling

R X R RM

Reagents: usually Na or K in a hydrocarbon solvent (e.g. Na/C6H6).


Addition of Carbocations (a) To Simple Alkenes

R!

R

R

R

H

RR

R

R

R

R

RR!

Reagents: ROH/H+; R2C=CR2/H+; RCl/AlCl3, RCl/TiCl3; etc. Regiochemistry: Markovnikov addition. Most widely used in intramolecular sense to form carbocyclic rings. (b) To Enol Trimethylsilyl Ethers

Lewis acidR R

RMe3SiO

R R

RO

R!R'–X

Reagents: RCl/TiCl4/CH2Cl2; RCl/SnCl4/CH2Cl2; etc.

Prins Reaction

R R

RR

R R

RR

HO

OH

R!

R'–CH=O

Lewis acid or H

R': H, alkyl, aryl.

Reagents: H2C=O/H2SO4/H2O; RCHO/Et2AlCl; RCHO/BF3•Et2O; etc. Stereochemistry: usually anti. Electrophile adds to less hindered face of double bond. Regiochemistry: Markovnikov addition.

Mukaiyama Reaction (Maukaiyama variant of Prins reaction)

Lewis acidR R

RMe3SiO

R R

RO OH

R!

R'–CH=O

R': H, alkyl, aryl.

Reagents: RCHO/TiCl4/CH2Cl2, RCHO/SnCl4/CH2Cl2, etc.

Sulfoxide and Selenide Elimination

H R

Y–R'R

R R

R R

RR[O]

Y: S, Se. R': CH3, C6H5, etc. Reagents: H2O2; (CH3)3COOH; NaIO4; m-CPBA; etc. Reaction temperature: >-10°C (Y=Se); 60-150°C (Y=S). Stereochemistry: syn.

Alkene Isomerization

R

O

nR

O

n

RhCl3/EtOH


Carbene Cycloaddition

R1

R2

R3

R4

R1

R2

R3

R4

R

R

CR2

Reagents: CHCl3/(CH3)3CO–K+; R2CBr2/C4H9Li/Et2O; etc. (α-elimination); or CH2N2/Cu; CH2N2/[Rh(OCOCH3)2]2; etc. Stereochemistry: suprafacial with respect to alkene.

Simmons-Smith Reaction

R1

R2

R3

R4

R1

R2

R3

R4

R

R

CR2

Reagents: CH2I2/Zn(Cu)/Et2O; CH2I2/Et2Zn; etc. Stereochemistry: suprafacial with respect to alkene.

[2+2] Cycloaddition of Ketenes

R!

R!R!

R!

OR

R+

R!

R!

R!

R!

O

R R

Reagents: R2CHCOCl/Et3N/Et2O; R2CClCOCl/Zn/Et2O. Stereochemistry: suprafacial with respect to alkene. Regiochemistry: Markovnikov addition based on ketene carbonyl group

Sigmatropic Rearrangements

R n

m

R

m

n

m

n n

m

Rearrangement designated as [m.n] sigmatropic rearrangement, where m and n indicate loci of new σ bond formation based on locus of broken σ bond in starting material. Rearrangement is relatively facile when m+n=4x+2, and difficult when m+n=4n.

Cope Rearrangement

R!!

R R!

R!!!

"

R!!

R R!

R!!!

Stereochemistry: suprafacial with respect to both halves of the molecule. Reaction occurs through a chair-like transition state.


Addition of Sulfur Ylides

O

R

R

R

R R!O

R! Reagents: R′2CH-SR2

+/NaH/THF; R′2CH-SR2+/NaCH2SOMe/Me2SO.

Mannich Reaction

RH

O

R R

R NR!2

O

R R

Reagents: R′2NH/CH2O/CH3CO2H/Δ or 1) LDA (or LICA, etc.)/THF/-78°C; 2) [R′2N=CH2]+

Non-Basic Aldol Reactions and Alkylations

orR

H

O

R R

R R!

O

R R

OH

R!

RR!

O

R R

Reagents: 1) LDA (or LICA, etc.)/THF/-78°C; 2) R3SiCl; 3) (R′)2C=O/TiCl4 or 1) LDA (or LICA, etc.)/THF/-78°C; 2) R3SiCl; 3) R′–X/TiCl4 or 1) R2B–OTf/R3N; 2) R′2C=O or 1) R2NH/TsOH/C6H6/Δ; 2) R′–X

Dissolving Metal Reduction of Aldehydes and Ketones

O

R

R

H

OHR

R

Reagents: Na/EtOH; Na/NH3, Li/NH3; etc.

Pinacol Reaction

O

R

R

R

R R

R

OHHO

Reagents: Mg/Et2O; Ti/THF, TiCl3/K/THF; etc.

Beckmann Rearrangement

HON

R

R

O

N

R

R

H Reagents: H2SO4 , H3PO4; P2O5, POCl3; PCl5, SOCl2, (COCl)2; (MeCO)2O; R–N=C=N–R, R–N=C=O or NaN3/HCl (or HN3) [Schmidt]


Schmidt Reaction

O

R

R

O

N

R

R

H Reagents: NaN3/HCl (or HN3); Me3SiN3/ZnCl2; etc.

Formation of Sulfonamides.

R

N

R

H

R

N

R

SO2R!R!SO

2Cl

R′: CH3 (Ms), C6H5, CH3-C6H4 (Ts), O2N-C6H4 (Ns), BrC6H4 (Bs), CF3 (Tf)

Mitsunobu Reaction.

R

R

OHR

R

R

NuR1) DEAD/(C6H5)3P

2) H–Nu or Nu

Nu: OR, OCOR, RNH2, Cl, Br, I, RS, etc.

Pinacol Synthesis of 1,2-Diols:

[H]

R

R

O

R

R

HO

R

R

OH

[H]: Mg/Et2O; Ti/THF; etc.

The Darzens glycidic ester condensation

COXR

Br

COX

R

R!

OR!

X = OR′, NR′2

Reagents: KOBut/R′2CO

Hofmann Exhaustive Methylation:

1) MeI

2) base/!R

R R

RR

R R

NR2

R

H

Base: Ag2O/H2O (Effectively AgOH); KOH/EtOH/Δ; KOCMe3 Regiochemistry: Hofmann (mainly least substituted alkene). Stereochemistry: mainly anti. [Some syn elimination can occur in Hofmann eliminations.]

Pyrolytic Eliminations:

!

R

R R

RR

R R

X

R

H


Deoxygenation of Alcohols:

[H]

R

R

HR

R

R

OHR

Reagents: 1) PCC/CH2Cl2, 2) H2NNH2/KOH/HOCH2CH2OH/Δ; (if 1° or 2° ROH) or 1) TsCl/py, 2) KOCMe3/Δ, 3) H2/Pd-C; or 1) TsCl/py, 2) LiAlH4/Et2O/Δ (if 1° or 2° ROH); or 1) KOH/CS2, 2) Bu3SnH/AIBN/hν

Demyanov Rearrangement.

NH2 OH OHHNO2

+

A special case of deamination which involves the rearrangement of a primary cation to give an equilibrium mixture of products.

Pinacol Rearrangement:

RR

HO OH

RR R R

OR

R

Reagents: H2SO4; TsOH/C6H6; etc. Migratory aptitude of groups same as Baeyer-Villiger rearrangement; in geometrically fixed systems, group anti to leaving group migrates. Unsymmetrical diols lose OH group which would give most stable carbocation as intermediate.

(d) The Darzens glycidic ester condensation

COXR

Br

COX

R

R!

OR!

X = OR′, NR′2 Reagents: KOBut/R′2CO

(e) The Stobbe condensation

CO2R

CO2R

CO2R

R!

CO2H

R!

Reagents: KOBut/R′2CO. Note that product has the ester group conjugated with the double bond' the free carboxylic acid group is not conjugated with double bond.

(f) Evans asymmetric aldol addition

1) R2B–OTf/EtN(i-Pr)2

2) R!CHOO N

R

O O

O N

R

O O

R!

OH

Note that new chiral centers are formed so that substituents appear on opposite side of chain relative to ring substituent in conformation where carbonyl groups are drawn parallel


Oxidative Substitution at the α Carbon (a) Hell-Volhard-Zelinsky bromination

R CO2H

X

CO2HR

X = Cl, Br, I

Reagents: X2/P, X2/PX3, X2/POX3 (b) Selenylation and sulfenylation

R COX

Y

COXR

X = OR′, NR′2 Y = SR′, SeR′

Reagents: 1) LDA/THF/-78°C; 2) Y2

Mitsunobu esterification

R′OH + RCO2H → RCO2R′ Reagents: DEAD/(C6H5)3P

Ester cleavage by strong nucleophiles

R-CO2CH3 → R-CO2H

Reagents: RSNa/DMF/Δ, RSNa/HMPA/Δ; or LiI/DMF/Δ, etc.

Borodin-Hunsdiecker reaction

R CO2Ag R BrBr2

Kolbe electrolysis

R CO2 R Relectrolysis

Barton decarboxylation

OS

NO

CR

S

N

YXR +

X–Y/! or h"

X = H, Cl, Br, I, SR, SeR, etc. Y = SnR3,CCl3, CBr3, SR, SeR, etc.

Lead tetraacetate decarboxylation

RR

RR

RR

CO2HHO2C

R RPb(OCOCH3)4


Synthesis of Azetidinones (a) Addition of isocyanates to alkenes.

+

R!

R!

R!

R!N

O

X

N

R!

R!R!

R!

O X

Reagents: ClSO2–N=C=O Note: X must be strongly electron-withdrawing. (b) Addition of ketenes to imines.

+

R!

NR!

R!

O

R R

N

R!

R!

O

R

R

R!

Reagents: R2C=C(OLi)OR/THF/-20°C (lithium enolate decomposes to ketene). Lithium enolate is generated from ester and LDA at -78°C.

Claisen Rearrangement (and Ireland ester enolate Claisen rearrangement).

OR!!

R R!

R!!!

OR!!

R R!

R!!!

"

R′′′ = alkyl: Claisen rearrangement

R′′′ = MeSi3O: Ireland ester enolateClaisen rearrangement

Reagents: 1) LDA/THF/-78°C; 2) Me3SiCl; 3) Δ; gives E(O) enolate; 1) LDA/THF-HMPA/-78°C; 2) Me3SiCl; 3) Δ; gives Z(O) enolate Stereochemistry: suprafacial with respect to both halves of the rearranging molecule; chair-form cyclic transition state Occurs near room temperature when R′′′ is alkoxy, and around 200°C when R′′′ is alkyl.

Alkylation of Conjugated Carbonyl Compounds (a) Kinetic alkylation

O

R

R

R! R

O

R

R

R

2) R!–X

1) base

Base: LDA/THF/-78°C, LICA/THF/-78°C, etc. or NaH/DMSO/Δ, etc. (b) Thermodynamic alkylation

O

RR

R

R!

2) R!–X

1) base

O

RR

R

Base: KOC(CH3)3/(CH3)3COH, etc.


α-Hydroxymethylene Carbonyl Compounds

HCO2R/RO

–/! K

2CO

3/H2O/!

O

R

R

HO

H

O

R

R

O

R

R

Formylketones exist predominantly in the enol (hydroxymethyleneketone) form. The hydroxymethylene group is added under strongly basic anhydrous conditions, and removed under aqueous conditions.

Alkoxymethylene Blocking Group

O

R

R

HO

H

R!OH/H

O

R

R

R!O

H

H3O

O

R

R

HO

H

The blocking group is formed and hydrolyzed under acidic conditions; α-alkoxymethylenecarbonyl compounds lack an acidic hydrogen on the side of the alkoxymethylene substituent.

Thorpe and Thorpe-Ziegler Condensation

R

CN R

O R

CN

1) base

2) H3O

base: RO–/ROH/Δ; NaH; etc. May be used to form cyclic compounds with up to 8 members in the ring.

Formylation

CHO

Reagents: HCl/CO/AlCl3 (Gattermann-Koch); Zn(CN)2/HCl/AlCl3 (Gattermann);

Vilsmeier-Haack formylation

POCl3/DMF

CHO

Reagents: POCl3/DMF. Requires activated aromatic compound.

Ring Oxidation of Arenes

[O]R CO2HR Ar

Reagents: 1) O3; 2) RCO3H or H2O2; or RuO4/CCl4; RuO2/NaIO4/CCl4/H2O; etc.

Birch Reduction of Arenes

M/NH3

ROH

M/NH3


Reaction synopsis Paal-Knorr Synthesis

Reagents: X = O: ZnCl2, H2SO4, P2O5; X = S: P2S5; X = NH or NR: NH3, RNH2 Fischer Indole Synthesis

Reduction of Pyridines

NHN[H]

Reagents: LiAlH4 or M/NH3/ROH

Reimer-Tiemann Formylation

KOH/H2O

OH

CHCl2

• •

O

CCl2

OCCl

2

• • OH

CHO

Reagent: CHCl3/KOH/H2O.

Chichibabin Reaction

N

B

N

B

N

B

H

1) !

2) H3O

B = NH2

–, NHR–, RLi

Alkylation of Alkylpyridine Side-Chains

N

CHRR!

N

CH2R

B R!–X

N

CHR

B = RLi, NH2

–, LDA, etc.

Radical Coupling of Diazonium Ions: Gomberg-Bachmann-Hey Reaction

Ar N2

NaOH

Ar!-HAr Ar!


NN

H

R2

R2

N

R1

R2

H

H

!

Reagents: PPA/Δ; etc. Hantzsch Pyridine Synthesis

NR1

RO2C CO2R

R1

R2

1) R2CHO/NH3

2) [O]R1

RO2C

O

Skraup Quinoline Synthesis

R1

O

R2

H+/C6H5NO

2

N R1

R2

NH2

+

Bischler-Napieralski Isoquinoline Synthesis

NH

O

R

1) POCl3

2) [O]N

R

Decarboxylation of Heterocyclic Aromatic Carboxylic Acids

Ar CO2H HAr

!

Reagents: soda lime; Cu/quinoline. Hydroalumination

R R!

H

R H

AlR!!2

R!!2AlHLi[R!!3AlH]Li

R

H H

AlR!!3

Reagents: DIBAL-H; LiAlH4, etc Regiochemistry: anti-Markovnikov. Stereochemistry: neutral aluminum hydrides result in overall syn addition; anionic aluminum hydrides result in overall anti addition. Organocuprate addition

R R!

R!!

R R!

CuR!!

R!!2CuLi


Regiochemistry: anti-Markovnikov Stereochemistry: syn addition. Oligomerization

(CH)2nNi salts

H H

Carbonylation

NiBr2/CuI

R HCO/H

2O

RCO

2H

Cyclotrimerization

R

R

R

R

R

R CpCo(CO)2R

R

R

RR

R

May be applied to diynes to give bicyclic products. Cycloadditions (a) alkynes

R!

R

R

R!

R

R

R!

R!

+

(b) allenes

R!

R!

+

RR

RRR!

R

R!

R

R

R

At least one electron-withdrawing group required on dienophile; endo product usually predominates. Reaction synopsis Addition of Electrophiles (a) alkynes

E–NuE–NuR!

Nu

E Nu

E

R

R

E R!

Nu

R R!

E = H, Cl, Br, I, etc. Nu = OR, OCOR, Cl, Br, I, etc.

Reagents: HCl, HBr, HI; (RCO)2O/RCO2H/H2SO4; ROH/H2SO4; etc.


Regiochemistry: anti-Markovnikov. Stereochemistry: often (but not always) anti. (b) allenes

H

HR

R

R

R

Nu

E

R

R E

R

R EE–Nu

localized cation delocalized cation

H

H

R

E

RH

R Nu

E R

E–NuR

HH

R

vinyl cation

X = Cl, Br, I, OCOR, OR, OH, BR2, etc.

Reagents: HCl, HBr, HI; (RCO)2O/RCO2H/H2SO4; ROH/H2SO4; R2BH; etc. Regiochemistry: Proton adds to center carbon of 1,1-disubstituted allenes; proton adds to terminal carbon of 1,3-disubstituted or monosubstituted allenes. Cyclic iodonium ion opens to allylic cation; bromonium and chloronium ions do not. Rupe Rearrangement

HR!HO

R

R

O

R!

R

R

Reagents: HCO2H/Δ; H2SO4/CH3CO2H/Δ; etc. [Note absence of mercuric ion] Meyer-Schuster Rearrangement

HR!HO

R

RR!

R

R

O

Reagents: HCO2H/Δ; H2SO4/CH3CO2H/Δ; etc. [Note absence of mercuric ion] Reaction synopsis Glaser Coupling

R H[O]

R R

Reagents: Cu(II)/pyridine/O2; etc. Oxidative Cleavage (a) alkynes

+R R![O]

R CO2H HO2C R!


Reagents: KMnO4/Δ; or 1) O3/CH2Cl2, 2) CH3CO3H/CH3CO2H; etc. (b) allenes

R

R

R!

R![O]

R!

R!

O

R

R

O +

Reagents: KMnO4/Δ; or 1) O3/CH2Cl2, 2) Me2S; etc. Acetylene Zipper

R (CH2)nCH3 R(CH2)nCH2 H

Reagents: 1) KNH(CH2)3NH2 (KAPA)/Δ; 2) H3O+. Note: the chain must not be branched in order fr this reaction to give the terminal acetylene; when the chain is branched, a mixture of acetylenes results. Reaction synopsis

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