chemistry 2213a fall 2012 western university topic 9...

Chemistry 2213a Fall 2012 Western University

Topic 9. Aldehydes & Ketones

A. Structure and Nomenclature

The carbonyl group is present in aldehydes and ketones and is the most important group in bio-organic chemistry.

carbonyl group aldehyde ketone

O O

RR

O

HR

Both the C and O are sp2, and their p orbitals overlap to form a

bond. Angles are 120°. Most importantly, the C=O is a polar double bond. It can react with both electrophiles and nucleophiles.

In IUPAC nomenclature, for a compound named as an aldehyde, the C=O is always position #1 (takes precedence over other groups) and the suffix al is used.

C

O

+

-

O

H

O

Br

Br H

propanal 3,3-dibromo-2-methylbutanal

Aldehydes & Ketones 2

When the aldehyde group is a substituent on a ring, the suffix carbaldehyde is added to the ring name, and the point of attachment is given #1.

CHO CHO

cyclopropanecarbaldehyde cis-2-methylcyclopentanecarbaldehyde

In ketones, the C=O is given the lowest possible number in the carbon chain and the suffix one is added.

O

3-methyl-2-butanone

O

4,4-dimethyl-2-cyclohexenone

In compounds with two or more functional groups, it may be necessary to name the carbonyl group as an ordinary substituent using oxo.

3-oxobutanal

H

OO


Carbonyl compounds don’t have a + hydrogen, so intermolecular hydrogen

bonding is not possible. However, the polar carbonyl group results in higher BP than ethers, but lower than that of alcohols.

O

O

OH

80°35° 118°

B. Spectroscopy

In IR spectroscopy, the carbonyl group has a strong, distinctive absorption between 1705 – 1780 cm

−1. (As we’ll see later, the C=O stretch appears in all

functional groups containing the C=O bond, including acids and derivatives).


In 1H NMR, the H aldehydes is shifted far downfield to about 9.5 – 10 ppm.

Although the carbonyl H (d) splits (and is also split by) the two H atoms c, the splitting is very small. Therefore, d looks like a singlet. Similarly, the signal for c looks like it is split only by the H atoms b.

Note that ketones do not have an H on the C=O, so the peak near 9.5 – 10 ppm does not appear.


C. Nucleophilic Addition Reactions

The reactivity of carbonyl compounds can be explained by the structure of the carbonyl group. The bond is polar not only because of a difference in electronegativity between the two atoms, but also because of resonance.

O

R'R

O

R'R

Nucleophiles will always add to the carbon, and electrophiles (typically a proton) will add to the oxygen. Therefore, only one regioisomer is formed.

C

OH

R'R

Nu

The mechanism of the reaction depends on whether the solution is acidic or basic. Regardless of the mechanism, these are termed nucleophilic addition

reactions because the RDS is the breaking of the bond by the nucleophile.


In basic solution, where anions exist, nucleophilic attack occurs first. The electrophile is weakly electrophilic, while the nucleophile is strongly nucleophilic. A neutrally charged species, such as water, is the proton donor.

O

R'RC

OH

R'R

NuNu

slow

C

O

R'R

Nu

fast

H OH

In acidic solution, where cations exist, protonation occurs to generate a strong electrophile prior to the addition of a weak nucleophile. Notice that a protonated C=O is just like a resonance-stabilized carbocation.

O

R'R

H

fastOH

R'R

Nu

OH

RR'

NuH

OH

RR'

NuH

slow

OH2 H2O

H2O H OH2

fast


Some important considerations:

o As in alkene reactions, an sp2 carbon changes to sp

3, and a stereocentre

may be formed, in which case both stereoisomers are formed in equal amounts.

o Carbonyl reactions are not as exothermic as alkene reactions, so the reaction is easily reversed (this is a very useful biochemical property).

o Aldehydes (less hindered) react faster than ketones.

1. Addition of carbon nucleophiles: Grignard Reaction

In the late 19th century, Victor Grignard discovered that alkyl halides (Cl, Br, or

I) reacted with Mg to form a highly polar, almost-ionic C–Mg bond.

R X+ -

etherMg R MgX

+-

R MgXf unctionally equivalent to

These organomagnesium compounds, called Grignard reagents, behave as negatively charged carbons.


Grignard reagents are therefore nucleophilic.

O

R'R''R MgX

+-ether

O

R'R''

R

MgX

The ionic product is easily converted to an alcohol using some sort of proton donor, such as acid in water.

OH

R'R''

R

HOMgX

O

R'R''

R

MgX H / H2O

However, because carbanions are basic, they are destroyed by the presence of compounds that can act as acids. Acid is therefore only added in the second part of the sequence.

MgBr

Oether H / H2O

OH


The Grignard reaction is one of the most useful ways to create new carbon-carbon bonds. The starting materials (carbonyl compounds and alkyl halides) are readily available, and the product is formed in good yield.

There is also exceptional versatility: Two R groups come from the carbonyl compound, and one from the alkyl halide. It doesn’t matter which R groups are from the carbonyl compound or from the alkyl halide.

For example, two ways to make:

O

CH3MgBrether H / H2O

product

O

CH3

ether H / H2OproductMgBr

OH

CH3


Grignard reagents even react with carbon dioxide, to yield carboxylic acids, and with epoxides, to give alcohols.

Reaction with epoxides occurs because of the polar C–O bond in addition to the reactivity of the strained 3-atom ring.

R–MgXether H / H2O

RCOHO C O

O

R–MgXether H / H2O

C C

O -

+C C

OH

R


2. Addition of hydrogen nucleophiles: reduction

The addition of a hydride reduces an aldehyde or a ketone to an alcohol.

O

R'RC

OH

R'R

H

slow

C

O

R'R

H

fast

H OH OH

H

In the laboratory, there are two common hydride sources:

o Weaker: NaBH4 in alcohol solvent, followed by H2O

o Stronger: LiAlH4 in ether solvent, followed by H2O

Aldehydes and ketones can also be reduced by catalytic hydrogenation, similar to the hydrogenation of alkenes. However, metal hydrides usually do NOT reduce alkenes because C=C bonds are typically non-polar.


H2 / NiO

2 H2

OH

1. LiAlH4

O OH

2. H2O

+

3. Addition of oxygen (alcohol) nucleophiles

The two previous reactions involved the addition of a good nucleophile (carbanion or hydride) to a neutrally charged aldehyde or ketone (a weak electrophile).

Alcohols, which are weak nucleophiles, do not react very fast with aldehydes or ketones unless either an acid or a base catalyst is present.

O

R2R1

C

OH

R2R1

OR

ROHH or OH


The product of the reaction contains both OR and OH bonded to the same C, and is called a hemiacetal. The reaction is very readily reversible, even in nearly neutral solutions.

Either an acid or a base is needed because:

o Protonating the carbonyl group gives it a positive charge, making it a better electrophile that can attract even weak nucleophiles (ROH).

o Deprotonating an alcohol makes it a good nucleophile that can attack weak electrophiles (unprotonated C=O).

o That is, acid makes the C=O more reactive, while base makes the ROH more reactive.


Mechanism of base-catalyzed hemiacetal formation:


Mechanism of acid-catalyzed hemiacetal formation:


Hemiacetal and acetal formation is particularly favourable when five- or six-membered rings are formed.

1234HO5

H

OH 1

2

O

3

45

OH

H

The cyclic form of monosaccharides contains a hemiacetal.


Under acidic conditions, hemiacetals can react with a second equivalent of alcohol an SN1 reaction to yield an acetal, a carbon bonded to two OR groups.

C

OR

R2R1

OR

ROHH

C

OH

R2R1

OR

Acid protonates OH, making it an excellent leaving group (water). The second alcohol acts as the nucleophile.

The acid-catalyzed formation of an acetal is reversible, but in basic solution it is stable.

Sucrose is a disaccharide that has acetal groups on both of its two rings, linking them together.


Because acetals are formed by a series of reversible steps in acidic solution, the acetal can revert back to the starting aldehyde and alcohol. Acetals are base-stable.

OR

HR'

OR

acetal hemiacetal

OH

HR'

OR

O

HR'

HHOR

In the reversal, note that the C bonded to the two oxygens becomes the carbonyl, and the two oxygens become the OH groups of the alcohol.

4. Addition of nitrogen (amine) nucleophiles

Because amines are moderate nucleophiles, they can react with aldehydes and ketones in the absence of a catalyst.

O

R2R1

H2N–R

C

O

R2

R1 NHR

H

C

OH

R2

R1 NHR

aminol


In the presence of an acid, the reaction occurs in a manner identical to that of hemiacetal formation, except the nucleophile is an amine instead of an alcohol.

The addition product, an aminol, is unstable and decomposes to an imine in an E2-like reaction. The decomposition reaction is acid-catalyzed.

imine

NR

R2

R1–H2OC

OH

R2

R1 NR

aminol

H

Note that in the overall reaction, the double-bonded oxygen is replaced by a double-bonded nitrogen.

Imines can be converted back to their parent carbonyl and amine compounds in the presence of water and acid.

NCH2CH3 H2OH+


Like alkenes, imines can be reduced.

N

R2

R1

R

H2

Pt, Pd, or NiN

R2

R1

R

H

H

The reaction of a carbonyl compound with an amine, followed by reduction of the imine, converts a carbonyl to a saturated amine. This process is called reductive amination.

D. Other Reactions 1. Oxidation of aldehydes

Aldehydes are easily oxidized to carboxylic acids using common reagents such as H2CrO4 or KMnO4.

O

HR

[O]O

OHR


The Tollen’s Test for aldehydes relies on their easy oxidizability (Expt 5). The oxidizing agent is Ag

+ found in Tollens’ reagent Ag(NH3)2OH.

When Ag+ oxidizes the aldehyde, it is reduced to Ag

0, which precipitates in the

form of metallic silver. This is often observed in the form of a silver mirror on the glass.

Ketones are resistant to common oxidizing agents. This is the principal difference between aldehydes and ketones.

2. Keto-enol tautomerism

As seen in Chapter 5, the addition of water to alkynes results in the formation of an enol, which tautomerizes to the more-stable keto tautomer.

H2SO4

HgSO4

H3CC CH

+ H2O

OH

CH3

O

keto tautomerenol tautomer

Keto-enol tautomerism involves the movement of a proton bonded to the

-carbon, which is the carbon directly adjacent to the carbonyl group.


Although the keto form is more favourable due to the stronger C=O double bond, aldehydes and ketones can tautomerize to enols under acidic or basic conditions.

Keto-enol tautomerism is important in the chemistry of nucleic acids, where the nucleobases of DNA can adopt enol forms. This is important from a biological standpoint, as it allows of proper base pairing.

Under acidic conditions, the carbonyl group is protonated and then the -hydrogen is removed.

O

CH2R

H

OH

CH2R

OH2

H2OH H

OH

CH2R

H3O


Under basic conditions conditions, the -hydrogen is removed, and then the C=O is protonated.

O

CH2R

H

O

CH2R

OH

OH

H

O

CH2R

H OH

OH

CH2R

OH

Resonance stabilization makes the -hydrogens of carbonyl compounds sufficiently acidic that they can be removed.

O

CH3H3CC CH H CH3CH2OH

pKa = 25 pKa = 19 pKa = 16

Because keto-enol tautomerism is an equilibrium, enol tautomers are always present, even though they may exist in very low concentrations. For example, for acetaldehyde (ethanal) one molecule out of 1.7 × 10

6 is in the enol form.


If the -carbon is a stereocentre, an enantiomerically pure compound slowly converts to a racemic mixture via enol formation. This racemization is accelerated by acid or base.

O

H

CH3

O

CH3

H

OH

CH3

A visual test for methyl ketones, called the iodoform test (Expt 5), relies on -hydrogen acidity. These react with I2 in base to give a carboxylic acid salt and the yellow ppt CHI3.

RCCH3

O

RCOH

O CHI3I2NaOH

iodoform ppt


Topic Summary

Textbook pages covered: 462–478, 481–489, 491–493

Suggested Quick Quiz questions: all

Suggested problems: 14, 16, 17, 20, 22, 24, 26, 28, 30, 34, 35, 36, 40, 41, 43, 44, 46 a/b/c/e/f/i/j/k/l/n/o/p/q/r, 48, 51, 52, 53, 54.

Suggested questions from final exams:

o 2008: 35–39 2009: 36–42

o 2010: 33–38 2011: 33–38

Past Test Questions

What is a correct IUPAC name for benzyl isopropyl ketone?

o 3,3-dimethyl-1-phenylpropan-2-one

o 3-methyl-1-phenylbutan-2-one

o 2-methyl-1-phenylpropan-1-one

o 2-methyl-4-phenylpropan-3-one

o 1-phenylisopentanone


Which Grignard reaction gives the product shown in good yield?

OH

?1. Ether

2. H3O+

OMgBr

OMgBr

OMgBr

OMgBr

OMgBr


Which one of the following compounds is an acetal?

O

OO

O

O

O

O O

O

During the course of the following multi-step process, the change in hybridization of the indicated atom is most accurately described as…

o sp2 sp sp

3 sp

2

o sp2 sp

3 sp

2

o sp3 sp sp

3

o sp2 sp

3 sp

2 sp

3

o sp2 sp sp

3

OH+ / CH3OH

OCH3

OCH3

chemistry 2213a fall 2012 western university topic 9...

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