Reaction

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Announcements
1) Important Due Dates: Experiment #6: Diels-Alder Nov. 1/2

Diene NMR on website Product NMR on server (note: Exp. # follows HawkID) Experiment #7: Wittig 2) 3) Next Week: Experiment #8: Grignard Repeat Wittig lecture Nov. 5 Nov. 8/9

Experiment #8: Grignard Reaction
- Grignard reaction: carbonyl compound and Grignard reagent - useful reaction in organic synthesis: forms C-C bond

R

X

R

MgX

Grignard reagent

R = 1o, 2o, or 3o alkyl, aryl, vinylic X = Cl, Br, or I
O C
OH C

1. RMgX, ether 2. H3O+

+
R

HOMgX

Mechanism
O C R

O C

R

H3O+

OH C R

carbonyl compound

alkoxide intermediate

alcohol

- Grignard reagent acts as a nucleophilic carbon anion, or carbanion; the addition of the Grignard is analogous to the addition of a hydride

Formaldehyde Reaction
MgBr O

+
H

1. Mix
H

CH2OH

C

2. H3O+

cyclohexylmagnesium bromide

formaldehyde

cyclohexylmethanol (65%)

Aldehyde Reaction
CH3 H3C C H O CH2 CH
MgBr

+

1. ether solvent r 2. H3 O+

CH3 H3C C H

OH CH2 C H

3-methylbutanal

phenylmagnesium bromide

3-methyl-1-phenyl-1butanol (73%)

Ketone Reaction
O OH CH2CH3

1. CH3CH2MgBr, ether 2. H3O+

cyclohexanone

1-ethylcyclohexanol (89%)

Ester Reaction
O CH3CH2CH2CH2 C OCH2CH3
1. 2(CH3MgBr), ether 2. H3O+

OH CH3CH2CH2CH2 C CH3 CH3

ethylpentanoate

2-methyl-2-hexanol (85%)

+ CH3CH2OH

Limitations of Grignard Reagents
- Grignard reagent cannot be prepared from an organohalide if there are other reactive functional groups in the same molecule - this limits the structures of the products

Br

molecule

FG

- Grignard cannot be made where FG =

= -OH, -NH, -SH, -COOH
O CH ,
C N, O CR , O CNR2 SO2R

protonate Grignard

Thus, water is a problem!

=

adds to Grignard

NO2 ,

Our Grignard Reaction
O O C OCH2CH3
HO OH

O

O

O C OCH2CH3

PhMgBr Et2O

1 (IR)

2 [IR, NMR (provided on web)]

O

O

OH C Ph Ph

H3O+

O

OH C Ph Ph

O

Ph C PH

3 [IR, NMR (provided on web)]

4

5 [IR, NMR (determined)]

Protecting group (add step 1 to 2, remove step 3 to 4): - allows a molecule with several active centers to undergo reaction selectively at one center while leaving the other center intact

Procedures and Precautions
Part A (Day 1): Protection of Ketone (Formation of Ketal)
1) react ethyl acetoacetate with ethylene glycol to produce ketal

Note: will use Dean-Stark trap - azeotrope: liquid mixture with constant boiling point (e.g. hexane-water)

2) transfer to separatory funnel and isolate/dry organic layer 3) isolate product (rotary evaporator): IR, NMR (on web), TLC (later), mp

Procedures and Precautions
Parts B & C (Day 2): Preparation of Phenyl Magnesium Bromide/Grignard Reaction 1) weigh out magnesium turnings and grind to expose metal 2) add magnesium to a dry, three-necked flask with condenser 3) flame dry the apparatus (start at the bottom and work your way up)* Note: must use drying Drierite (drying tubes) 4) allow to cool, start water running, and add bromobenzene, add ether (drop) Note: onset of reaction is appearance of bubbles on metal 5) reflux for 20 min., cool in ice bath, and immediately add ketal 6) stir for 30 min. and add ice to quench the reaction 7) work-up reaction using extraction and re-crystallization 8) characterize: IR, NMR (on web), TLC (later), mp

Apparatus for Grignard Reaction

Procedures and Precautions
Parts D & E (Day 3): Ketal Hydrolysis and Column Chromatography 1) reflux tertiary alcohol in acetone and HCl solution 2) work-up reaction by way of an extraction (note: separatory funnel) 3) characterize: IR, NMR, TLC (later), mp 4) purify final product by way of column chromatography i) assemble the column (TA will provide lots of instruction) ii) elute the column using hexane:ether solution (16 × 150 mm test tubes) iii) evaluate the fractions using TLC iv) visualize plates using UV (line) and...
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