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D. Grove, Chem. 222 Carbonyl Chemistry I Week of April 12, 2004

Chapter 15 of 8 Carbonyl Chemistry IH:\MyFiles\wpdocs\Org2.00\Lec Notes\acetal formation.doc

Mechanism of Acetal and Ketal Formation

R 1

C

O

H

O

H

H R 3

R 1

C

O

H

H

OHH

+R 1

C

O

H

H

OHR

3

hemiacetal

R 1 C

O

H

H

OHR 3

O HR 3

R 1 C

O

H

H

OR 3

activated carbonyl compound

OH R 3

H

R 1 C

O

H

H

OR 3

H

R 1

CH

OR 3

R 1

C

O

H

R 3

activated carbonyl compoundOHR 3

R 1 C

O

H

R 3

OHR 3

OHR 3

R 1 C

O

H

R 3

OR 3

acetal

O

H

H R 3

+

regenerated acid catalyst

water as a leaving group

A completely reversible reaction. Can take the productand add water and catalytic acid to regenerate thecarbonyl compound.

Recall, carbonyl group is Lewis basic at oxygen lone pair.

Alcohol, R 3OH, is a weak nucleophile but will attackactivated carbonyl compound.

Protonation of hemiacetal generates a good leavinggroup, i.e., water.

Water is ejected to give a second “activated” carbonylcompound and the alcohol attacks a second time.

Final deprotonation produces the acetal.

Note the resonance structures. These clearly show thatthe protonated/alkyated carbonyl compound is“activated,” with a full positive charge on the carbonylcarbon.

Note that the acid catalyst is regenerated at the end ofthe reaction.

To drive equilibrium to the right (i.e., products) oneremoves the water as it is formed. An example ofLeChatelier’s Principle.

An Intramolecular Example—very common .

O

OHOH

O

O+TsOH

PhH, heat





Imine FormationAmines

R O

HR N

H

H

alcohol 1o amine

R N

R

H

R N

R

R

2o amine 3o amine

Note the similarity between the alcohol and the 1 o amine; also note that there arethree types of amine. One would expect these to have similar reactivities withcarbonyl compounds, and indeed they do. Basicity: RNH 2 > ROH (remember this!).Question: of the 1 o, 2o, and 3 o amines, which would you predict to be most

basic/nucleophilic? Why?

General Reaction

R 1

C

O

R 2+ NH2R 3

R 1

C

N

R 2

R 3

amineimine

H3O+

pH = 4-5

The product obtained in this reaction is called an imine . Note the difference between

this and an acetal. Account for via mechanism. When R 3 is an aryl group, theimines is called a Schiff base (common in biology).

Mechanism

R 1

C

O

H

NHR 3

H

deprotonation at N,

reprotonation at O.

R 1 C

O

H

NHR 3

H

"killed" charge

R 1 C

O

H

N

H

R 3 H

O

H

H H

R 1 C

O

H

NHR 3

HH

R 1C

H

NHR 3

R 1C

H

NHR 3

hemiaminal

OHH

+O

HH

R 1C

H

NR 3

O

H

H H

+

water leaving

imine

imine

rate-limiting step

A completely reversible reaction. Can hydrolyzeimines to give carbonyl compound.

Water is a good leaving group as was the case withacetal formation.

Dehydration is the rate-limiting step.

Imine formation is slow at high pH and low pH. Therate of formation reaches a maximum at pH = 4-5.

Need acid to protonate hemiaminal to make goodleaving group, but if too acidic, the basic amine iscompletely protonated and initial attack cannot occur.

Protonated product is called an iminium salt .

Imine formation and protonated imines are veryimportant in biological chemistry.





Grignard Reagents

Magnesium (At. No. = 12)

1s 22s 22p 63s 2

Mg 2+ + 2e -

1s 22s 22p 6

filled valence shell

Mg 0

Magnesium is an alkaline earth metal . It readily forms salts, e.g., MgCl 2, MgBr 2,Mg(OH) 2, etc. The metal forms salts by readily giving up two electrons to achieve aninert gas electronic configuration.

Preparation of Grignard Reagents

2 Li 0 R CH 2 LiR CH 2 Br ether

+organolithium reagent

-20 oC+ LiCl

need 2 equiv. of lithium metal

Stirring magnesium metal with an alkyl or aryl halide results in the formation of aGrignard reagent, named after Victor Grignard. The reaction must be carried out indiethyl ether, and the ether must be dry . Grignard reagents are nucleophilic at carbon,hence, their utility. Grignard reagents are also basic and will react readily with evenweak acids.

How to Think About a Grignard Reagent

R CH 2 Mg Br R CH 2 Mg Br

One can think of the Grignard reagent as ionic. In reality the C-Mg bond has bothcovalent and ionic character , but enough ionic character to make the carbon "behave"as though it had a negative charge. The carbon is nucleophilic .

Compounds that have carbon-metal bond are referred to as organometallic

compounds .

Reactions of Grignard Reagents

Protonation

MgBr + H 2O + Mg(OH)Br

butane a salt

C-C Bond Formation

R 1 MgBr

R 2

C

O

R 3

+ R 2 C

O

R 3

R 1

O

H

H H

R 2 C

O

R 3

R 1

HO

HH

+

MgBr

an alkoxide salt

protonation

Cl

MgClBr

an alcohol

Like amines, there exist 1 o, 2o, and 3 o alcohols. Using the reaction above, any alcoholcan be synthesized starting from the appropriate Grignard reagent and carbonylcompound. Many Grignard reagents are commercially available, as are many differentcarbonyl compounds (aldehydes and ketones).

Examples:

Br MgBr

OHMg

Et 2O 2) H 3O+

1) CH 3CHO

Br Mg

Et 2O

MgBr 1)

O

2) H 3O+

OH

a 2 o alcohol

a 3o

alcohol





1)

2) H 3O+

MgBr H

CH

O

OH

Reaction with Epoxides

Br

OCH 3

H3 CO

Mg

Et 2O

MgBr

OCH 3

H3CO

1)

2) H 3O+

O

OCH 3

H3CO

OH

Recall that epoxides react with strong nucleophiles via a S N2 reaction. This is a way toadd the fragment --CH 2CH 2OH to a molecule.

Lithium (At. No. = 3)

1s 22s 1

Li+ + 1e -

1s 2

filled valence shell

Li0

Lithium is an alkaline metal . It readily forms salts, e.g., LiCl, LiBr, LiOH, etc. Themetal forms salts by readily giving up a single electron to achieve an inert gaselectronic configuration.

Preparation of Organolithium Reagents

2 Li 0 R CH 2 LiR CH 2 Br ether

+organolithium reagent

-20 oC+ LiBr

need 2 equiv. of lithium metal

Lithium, At. = 3, readily gives up a single electron to achieve the inert gas electronicconfiguration. Note that 2 equivalents of lithium are needed for each molecule ofstarting halide. Also note that a salt is produced in addition to the organolithumreagent.

Reactions of Organolithium Reagents

Protonation

Li + H 2O + LiOH

butane lithiumhydroxide

butyllithium

Aldrich: 2.5 M soln inhexanes, 430.00/100 mL

C-C Bond Formation

LiCH 3

O

+ 2) NH 4Cl (aq)

1) reactOH

3o , benzylic alcohol

Note: aqueous ammonium chloride, NH 4Cl, = source of H +--very common.

H3C Li

H

O

+2) NH 4Cl (aq)

1) react H3 C

OH

To make sure you get the correct structure, map the carbons of the starting materials withthose in the product; there should be a one-to-one correspondence.

Basicity of Organolithium Reagents

Li

Li

Li CH3 Li

decreasing basicity

3o -butyllithium 2o -butyllithium 1 o -butyllithium methyllithium

Explain the above. Hint: are alkyl groups electron-donating or electron-withdrawing?





Oxidation-Reduction in Organic Chemistry

ELECTRON FLOW IS EVERYTHING IN CHEMISTRY—AND IN LIFE!

Glucose CO 2 + H 2O + Energy(foodstuff) rxn by which organisms obtain energy

Glucose is oxidized. What does this mean and how can you tell glucose is oxidized.

Consider: Fe 0 + Cu 2+ Fe 2+ + Cu 0

2 e -'s flow from Fe 0 to Cu 2+ to give the products shown.

Fe 0 loses electrons: it is oxidized .

Cu 2+ gains electrons: it is reduced .

Fe 0 is a reducing agent.

Cu 2+ is an oxidizing agent.

Determination of Oxidation States

Rules:

C H C O

+1 -1

C C C Br 0 -1

examples

H C

H

H

H

+1

+1

+1

+14 - y = 0, y = 4, thus, OX c = -4

note: This is not a charge, merelya bookkeeping device.

H C

H

H

OH

+1

+1

-1

2 - y = 0, y = 2, thus, OXc = -2

In going from CH 4 to CH 3OH, OX c has gotten more positive (-4 → -2), have takenelectrons away from carbon, an oxidation has occurred.

H C

H

H

OH

H

C

H

O

+1

+1

+1

-12 X (-1) = -2

+1

+1

OX c = -2 OX c = 0

This time, carbon went from -2 to 0, more positive an oxidation.

CH 4 CH 3OH CH2 O

HC

O

OH

CO 2

more oxidized

more reduced

alkane alcohol aldehyde

carboxylic acid

carbondioxide

glucose is at this oxidation level.This is the CO 2 you exhale.

This represents the oxidation of methane to carbon dioxide. Note that in each step thenumber of bonds to hydrogen is reduced and the number of bonds to oxygen is increased.

1) Assign an oxidation number toeach atom attached to carbon byconsidering electronegativities.

2) If multiple bond, multiplyoxidation number by the bondoxidation number by bondmultiplicity.

3) Determine oxidation state ofcarbon by difference—should sumto zero.





In general: To oxidize a molecule you need an electron sink, i.e., somewhere to put theelectrons that are being given up. This is a very important consideration in organicsynthesis and in biological chemistry. Cells use NAD + as an electron sink.

Oxidation of Alcohols

Strategy: Use a metal in high oxidation state (M n+) as an electron sink.

General Mechanism

C O

H

R 1

R 2

H

Mx+C O

H

R 1

R 2

H

Mx+

C O

R 1

R 2

H

Mx+

B

C O

R 1

R 2

+ M x-2

ligand transfer proton lossor transfer

E2 rxn

Mx+ is a metal with oxidation state = +x; it acts as the electron sink.

The electrons in the O-M bond are dumped onto the metal.

The alcohol is oxidized and the metal is reduced.

You have formally lost a molecule of H 2.

Chromium Reagents ( M = Cr)

Oxidation States: 6, 3, 2; +3 is most common O.S. for Cr.

Chromic Acid:

Cr O

O

O

+ H 2O Cr

O

OH

O

OH+6 +6

chromium trioxide chromic acid

+ H 2OCr

O

OH

O

OH+6

C

H

R

H

O Cr

O

O

OHC

H

R

H

O

H

+6

B

CH R

O

Cr

O

OHOH +

+

chromate ester

aldehyde

+4

Cr(+4) continues theoxidation process,eventually resulting inCr(+3)

1) ligand exchange to formchromate ester.

2) have weak C-O-Cr bonddue to high O.S. on Cr; H on

oxygen is acidic.3) elimination occurs to givealdehyde; Cr is rduced.

Specific Reagents:

Jones Reagent in acetone : a solution of chromic acid and H 2SO 4 in water, An oxidationis carried out by titrating a solution of the alcohol in acetone at 0 oC to RT. Get a two-

phase system.

Na 2Cr 2O 7/K 2Cr 2O 7: generally used in sulfuric or acetic acid using ether as a solvent.

OH K2Cr 2O7, H 2SO 4

ether-H 2O

O

Problem with above : must run reaction in acidic medium, not for acid sensitivecompounds; get over-oxidation of 1 o alcohols to carboxylic acids via the hydrate.

C O

H

H

R

H

C O

H

R

C O

H

R

OH

H

C OR

OH

hydrate

-"H 2"-"H 2" + H 2O

carboxylic acidaldehyde





Example:

OHK2Cr 2O7, H 2SO 4

ether-H 2OOH

O

CrO 3/pyridine : obviates problem above by conducting reaction under anhydrousconditions. Good for converting 1 o alcohols to aldehydes; no over-oxidation.

O OH

MeMe

Me

CrO 3 /pyridine

O

MeMe

Me

H

O

Pyridinium Chlorochromate (PCC) ,CrO 3Cl - C5H5 NH +/CH 2Cl2: done underanhydrous conditions. A good way to convert 1 o alcohols to aldehydes.

OH O

H

PCC

CH 2Cl 2

Manganese Dioxide

General Reaction: MnO 2 oxidizes selectively allylic and benzylic alcohols. It is usedas a suspension in ether, hexane, CH 2Cl2, DMF, or DMSO.

OH

OH

H3CO

H3CO94%

OH

O

H3 CO

H3 CO

OH2

acetone, 5h, RT

MnO 2

OH2

note benzylic OH selectivity

CH 2Cl 2

MnO 2

OH

OH

OH

O

H note allylic OH selectivity

76% J. Org. Chem . 1994 , 3113*

OH

OH allylic OH

saturate OH

CH 2Cl 2

MnO 2

OH

OH

note allylic OH selectivity

Mechanism: must account for the benzylic/allylic selectivity.

OH + Mn

O

O

IV proton transfer O Mn

O

OH

H H

ligand exchange withloss of an oxo ligand same oxidation state

IV

IIIO Mn

OH

H OH

benzylic radical, resonancestabilized

O

H

IIMn

OH

OH

+

an "oxo ligand"MnO + H 2O

thermodynamically driven

M O

Mn is reduced

M = metal atom

The benzylic (or allylic radical) accounts for the selectivity we see. Remember: reaction

mechanisms should explain all features of a reaction. Make sure you follow the oxidationstate of manganese through this mechanism.

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