Orgo Exam 2

Five ways to generate Organometallics

Oxidative insertion of Mg into Alkyl Halides

Oxidative insertion of Li into Alkyl Halides

Deprotonation of Alkynes

Halogen-metal exchange
Transmetalation

Oxidative Insertion of Mg into Alkyl Halides

Results in?

Mg goes from oxidation level 0 —> 2
inserted between the alkane and halogen

Results in a GRIGNARD REAGENT

Stability of Mg in this state drives the reaction

Grignard reagent

R-MgBr

Oxidative insertion of Li into Alkyl Halides

Li oxidizes from 0 —> 1

Reaction requires TWO Li

1. Forms the organolithium

2. Forms a lithium salt

Stability of Lithium in this state drives the rxn

Deprotonation of Alkynes

One organometallic deprotonates an alkyne to generate another, more complex, organometallic

Substitution of metal for H

Alkynes are acidic enough to be deprotonated by organometallics/N-Bases

Halogen-Metal Exchange

Organolithiums can remove Halogens from alkyl/aryl halides

Nucleophillic attack of organometallic on halogen

Forms a carboanion intermediate

Direction of reaction depends on the stability of the carboanion, according to the pK_a of its conjugate acid

Metal swaps places with the halogen

Carboanion stability

Phenyl > Vinyl > alkyl

n-butyl > t-butyl

R-MgBr + R-X

No real reaction occurs due to Transmetalation

Grignard + haloalkanes will be in equilibrium, with the R groups swapping between MgBr and Br

Organometallic addition to CO2. Reduction of oxidation level

Carboxyllic Acid

Organometallic addition to formaldehyde forms

primary alcoholsother

organometallic addition to other aldehydes (not formaldehyde)

Secondary alcohols

Organometallic addition to ketones

tertiary alcohols

Acid Chloride/Acyl Chloride + Alcohol

Ester

Acid Anhydrides + Alcohol

Ester

Amines + Acyl Chlorides

Amides

Acid Chlorides + Carboxyllic Acids

Acid Anhydrides

Amides only react with…

Why?

Powerful nucleophiles (-OH, LiAlH4, Organometallics)

Nitrogen lone pair electrons delocalize far more readily than others into C=O as it’s not that electronegative. The bond therefore has more C=N character, spending more time with a high energy pi* orbital
High energy pi*’s are less energetically favorable for attack by a Nu

Turner Syndrome

Aneuploidy

XO, monosomic for X

2n - 1 = 45

Triple X Syndrome

Aneuploidy

XXX - Trisomic for X

2n + 1 = 47 chromosomes

Klinefelter Syndrome

Aneuploidy

XXY - Disomic for X chromosomes

2n + 1 = 47

XYY

Aneuploidy, Disomic for Y chromosome

2n + 1 = 47

Patau Syndrome

Somatic Aneuploidy

Trisomic for 13
2n + 1 = 47

Edwards Syndrome

Trisomic for chromosome 18

2n + 1 = 47

Trisomy 8

2n + 1 = 47

Down Syndrome

Trisomy 21

Often the result of non-disjunction during gamete formation in mother

4% due to inheritance of 14-21 robertsonian translocation (familial)

Hydrolysis of a protonated nitrile

Nitrile is protonated to catalyze the nucleophilic attack
Strong enough electrophile for attack by water (HYDROLYSIS)

Amide —> Forms a carboxylic acid + ammonia

Carboxyllic Acids + SOCl₂ or PCl₅

Acid ChloridesTGe

Tertiary alcohols with 2 identical R’ groups can be formed by esters and Grignard Reagents

2x R’MgBr + RCOOR —> HOR’₂R

R is from the original ester

LiAlH₄ + Ester

AlcoholT

Transmetallating the Grignard/Li-R with Cu allows for the formation of a ketone from an ester (acyl chloride — ester)

Organocoppers react well with Acyl Chlorides but not reactive enough for a ketone

Addition of organometallics to Weinreb Amides

Leads to non-collapsible tetrahedral that is chelated by the metal

Acid workup allows for the formation of the KETONE

DMF helps adding ______ to organometallic nucleophiles

Aldehydes (CHO)

Aldehydes react with alcohols to form

Hemiacetals

Aldehydes/Ketones + alcohols in the presence of acids

Acetal

Acetals can be hydrolyzed only in ___ but are stable to ___

Acid; base

Amine + Aldehyde/Ketone

ImineDe

dehydration of hemiaminal yields…

ImineI

Imines only stabilized by…

Stable if bound to ___ groups

Aromatic ring

Electronegative groups

Imine Formation

Amine + Carbonyl —> Hemiaminal intermediate —> Imminium ion —> Imine

Acetal Formation (REQUIRES …)

Carbonyl + H+ —> Protonated Carbonyl + Alcohol —> Hemiacetal Intermediate —> Oxinium ion —> AcetalA

Aldehydes/Ketones + SECONDARY Amines

Aldehydes/Ketones + PRIMARY Amines

Requires ______ and ______

Enamines

Imines

Acid Catalysis and removal of waterI

Iminium vs. Oxonium

Oxonium acts as an electrophile then forms Acetal, while Iminium gets deprotonated to form an Imine

First choice in amine synthesis (secondary)

Reductive Amination: Reduction of imines/iminium ions

Reductive amination using ____ as a reducing agent

Ketone —> Imine —> Amine

[BH3(CN)]Na

Amides + LiAlH4 —>

Imminium

DCC, DIPC, EDC/NHS, BoP

Coupling Reagent. Activates COOH for attack by Nu

SOCl2, PCl5, oxalyl chloride

Activation of a carboxyllic acid via conversion to an acyl chloride

New C-C bond indicates

Organometallic reaction

NaBH4 only reacts with
whereas LiAlH4 can react with

Aldehydes and Ketones, no COOH derivatives

LiAl with everything, all the way