TBR O Chem2

Organic
Chemistry
Part II
Sections V-VIII
Section V

Carbonyls and Alcohols
Section VI

Carbohydrates
Section VII

Nitrogen Compounds
Section VIII

Organic Chemistry
Laboratory Techniques

BERKELEY
Specializing in MCAT Preparation


ERKELEY
®

E • V • I • E • W
P.O. Box 40140, Berkeley, California 94704-0140
Phone:

(800)

622-8827

Internet:



(80 0)

M CAT-TBR



The Berkeley Review and The Berkeley Review logo are registered trademarks of The Berkeley Review.

This publication for The Berkeley Review® was written, edited, and composed on a desktop publishing system

using Apple Macintosh® computers and Microsoft® Word. Pages were created on theApple LaserWrite® Pro. Line

art was created using numerous graphics programs designed tor use on Macintosh computers. The majority of the
text type and display type was set in Times Roman and Palatine

Cover Design by MacGraphics.

Copyright © 2012, 2010, 2007, 2005, 2004, 2002, 2000, 1995, 1994, 1993, 1992 by The Berkeley Review. All rights
reserved.

No partof this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any

means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the

copyright owner.


Oxygen Containing Compounds
a)
b)
c)
d)

Section V

Alcohol Properties
Alcohol Reactivity
Alcohol Spectroscopy
Aldehyde and Ketone Properties

e) Aldehyde and Ketone Reactivity
f) Aldehyde and Ketone Spectroscopy

Carbonyls

g) Ketals and Acetals

and

i.

Protecting Groups

h) Carboxylic Acids and Derivatives

i.
Carboxylic Acids

Alcohols

ii.
iii.

by Todd Bennett

Esters
Lactones

iv. Acid Anhydrides
0

v.

O
Off

RX XCH3

vi.

/C\0
R

Carbonyl Reactivity

CH2

a) Attack at Carbonyl Carbon
O

O

b) Deprotonation of a-Protons

C

R

R

CH2

+1

CH2I

O

2more times
Off.

^5~"

a) Qrignard Reaction

||
/C\ CI3
R

O

c) Oxidation-Reduction Reactions
Name Reactions

O

/C\'CH2I
R'

Acid Halides
Amides

b) Aldol Condensation
c) Claisen Condensation
d) Transesterification

O

e) Wittig Reaction
Pinacol Rearrangement
g Iodoform Reaction
h) Wolff-Kishner Reaction

f)
Off.

R

O

o

C
R

/c\ OH + cl3

+ CI3 ^f=^
OH

C.
R

Iodoform Test

Synthetic Logic
0 + HCI3
O

yeUowoil

a)
b)
c)
d)

Reactions of Acetoacetic Ester
Reactions of Malonic Ester
Decarboxylation
Protecting Groups

Carbonyl Biochemistry
a) Biological Oxidation-Reduction
b) Biochemical Reagents

BERKELEY
Ur-E-V.KE'W®
Specializing in MCAT Preparation


Carbonyls & Alcohols
Section Goals
Recognize the carbonyl functional groups and types of compounds.

°!> especially ketones and aldehydes. You must know which compounds are most reactive towards

You must be able to recognize functional groups such as amides, anhydrides, acid halides, and
substitution (which isbasedon the leaving group strength), and mostelectrophilic (which is based
on the electron withdrawing or donating capacity of the functional group).
Be able to identify infrared peaks for carbonyl compounds.

Carbonyl compounds will have apeak in the infrared spectrum in the area of 1700± cm'1. This will

mostlikely be useful whencomparing twocarbonyl compounds, or identifying an unknown carbonyl

compound. You may wish toknow roughly where esters, aldehydes, and ketones fall inthe IR range.

©

Be able to identify common name reactions involving carbonyl compounds.

*

You must recognize common name reactions from carbonyl chemistry. Included inthis group should

be the Aldolcondensation, Grienardreaction, Wittie reaction, and the Claisen reaction. TheAldol
and Claisen reactions have biological significance, because they play a role in select biochemical
pathways such as glycolysis and beta oxidation.

Be able to recognize the acidity of alpha carbons.

The carbon alpha to thecarbonyl can bedeprotonated, ifit hasa proton bonded to it. The pKa ofa
standard ketone is the range 1/± 2. Once deprotonated, an enolate is formed. The enolate has an
equilibrium of its own with the enol structure. The conversion of a ketone into an enol is referred
to as tautomerization.

*

Be able to identify ketals, hemiketals, acetals and hemiacetals.
Although current accepted nomenclature does notdistinguish between ketals andacetals, youshould
be aware of the functional group. Acetals and ketals are best described as "double ethers." They
play a major role in sugar chemistry and protecting groups in carbonyl synthesis.

Understand the difference between thermodynamic and kinetic enolates.
Thethermodynamic enolate is formed under conditions ofhighertemperature wherethe pathway
of greateractivation energymaybe chosen. Thethermodynamic enolateis the moresubstitutedand

thus more stable intermediate which will lead tothe more stable final product. The kinetic enolate

is formed under conditions oflower temperature and greater steric hindrance where the pathway

of lower activation energy must be chosen. The kinetic enolate is the less substituted and thus less
stable intermediate which will lead to the less stablefinal product.

Know the mechanisms for acidic and basic carbonyl reactions.
The mechanism for transesterification ispresent inbiochemistry and organic chemistry, soit important
that you recognize the steps. Also recognize what catalyst is necessary to carry out the process.
©

Recognize common oxidizing and reducing agents.

n and/or the gain of bonds to hydrogen.

a nutshell, oxidation is defined as thegainofbondsto oxygen and/or the lossofbonds to hydrogen.
Oxidizing agentsincludeKMn04and K2Cr207. Reduction is definedas the lossofbonds to oxygen

Reducing agents include LiAlH4 and NaBI-14.

Know common reactions by both name and reagents.

The AAMC guide lists a series ofreactions that they expect you toknow byname. Iris a eood idea
tonot only know the general reaction, butalso the mechanism and reaction conditions. Highlights

of this list include the Aldol reaction, the Grignard reaction, the Witting reaction, the iodoform

reaction, transesterification, and the Wolff-Kishner reduction.

Organic Chemistry

Carbonyls and Alcohols

Introduction

Carbonyls and Alcohols
The carbon-oxygen bond is a major part oforganic and biological chemistry. A
significant part of organic chemistry on the MCAT involves compounds that
contain carbon-oxygen bonds. In the case of carbonyl compounds, the carbonoxygen 7C-bond is easily broken to form new bonds to the carbonyl carbon and
subsequently form a new compound. The carbon-oxygen a-bond found in
alcohols and sugars can undergo several reactions, but it is generally not as
reactive as the carbon-oxygen rc-bond. Our goalis to organize the vast multitude
of reactions involving carbonyl compounds and alcohols. Figure 5-1 shows
several types of carbonyl compounds and carbonyl derivatives with which you
should be familiar.

Types of Carbonyl Compounds
0

O

R

R

R

R'Ov

OR*

R'Ov

\/
R

OH

R'O

\/

H
Acetal

R

H

Aldehyde

Ketone

H
Hemiacetal

OR'

R'O

\/

R/CVR

R/CVR

Ketal

Hemiketal

O

O

O

O

II

II

II

II

OH[

R

R

R

OR'

Carboxylic Acid

O

If

If

R

NH2

R

/

R

N

R'

NHPh

R

Phenylhydrzine derivative

Lactone

if
H
Imide

Amide

Acid halide

R

Acid anhydride

Ester

it
.'N.

OH

\/

?

Lactam

If

R

R

/c\

CHn

Enolate Resonance Forms

Figure 5-1

Copyright © by The Berkeley Review

Exclusive MCAT Preparation


OrgSlIllC ChCllllStry

Carbonyls and Alcohols Oxygen Containing Compounds

Oxygen containing compounds, because of the highly electronegative nature of
oxygen, are very reactive. Much of organic chemistry revolves around alcohols
and carbonyls, so it is imperative to get a fundamental understanding of their
properties, reactivity,and spectroscopicevidence that supports their existence.

Alcohol Properties
Because of their ability to form hydrogen bonds, alcohols typically have high
boiling points and are generally miscible in water. Alcohols make good solvents
as they are often liquids at room temperature and they have a large range
between their melting and boiling points. Alcohols are hydrophilic, polar
molecules that become less hydrophilic (more lipophilic) as their carbon chain

length increases. The smaller alcohols (three carbons or less) are highly water
soluble, but as the size of the alkyl group increases, their water solubility
decreases. As with all compounds, their physical properties vary with mass and
branching, as well as the position of the hydroxyl group. As the molecular mass
increases, the boiling point increases, but the effect on the melting point is less
clear. As the branching increases, the boiling point decreases. Table 5-1 shows
the physical properties of several alcohols, from which the effects of mass,

branching, and positioning of the hydroxyl group on the physical properties can
be ascertained.

Isomer

IUPAC Name

Boiling

(Common Name)

Point

Melting Density
Point

(g/mL)

Water

Solubility
(g/lOOmL)

CH3OH

Methanol

64.6°C

-98°C

0.791

High

H3CCH2OH

Ethanol

78.4°C

-115°C

0.789

High

H3CCH2CH2OH

1-Propanol (n-Propanol)

97.2°C

-127°C

0.804

High

(H3Q2CHOH

2-Propanol (i-Propanol)

82.3°C

-90°C

0.786

High

H3C(CH2)3OH

1-Butanol (w-Butanol)

117.3C

-90°C

0.810

8.2

H3CCH(OH)CH2CH3

2-Butanol (sec-Butanol)

99.6°C

-115°C

0.806

12.8

(H3C)2CHCH2OH

2-Methyl-l-propanol (f-Butanol)

107.7°C

-122°C

0.802

11.3

(H3Q3COH

2-Methyl-2-propanol (f-Butanol)

82.0°C

24°C

0.789

High

H3C(CH2)4OH

1-Pentanol (n-Pentanol)

137.6°C

-79°C

0.814

2.1

H3CCH(OH)CH2CH2CH3

2-Pentanol

119.3°C

0.809

5.0

(H3CCH2)2CHOH

3-Pentanol

115.9°C

0.815

5.6

H3C(CH2)4CH3

1-Hexanol (n-Hexanol)

157.5°C

0.814

0.8

C6HnOH

Cyclohexanol

161.5°C

0.956

2.1

H3C(CH2)6CH2OH

n-Octanol

194.7°C

0.817 1

0.3

T able 5-1

Copyright©by The Berkeley Review

The Berkeley Review


OrgaiUC ChemiStry

Carbonyls and Alcohols Oxygen Containing Compounds

Example 5.1

Whattype of alcohol is the following molecule?
HiC

CH„

HO-

A. Primary alcohol
B. Secondary alcohol
C. Tertiary alcohol
D. Phenol
Solution

The compound has the alcohol functional group attached to a carbon that is
bonded to two other carbons. This is defined as a secondary alcohol, so the best
answer is choice B.

Alcohol Reactivity

Alcohols are nucleophilic reagents in organic chemistry. They are not good
nucleophiles in their protonated (neutral)state, but they can be deprotonated and
converted into their anion (alkoxide) form under basic conditions. Because

alkoxides (the deprotonated form of the alcohol) are strong bases, they are not
the ideal nucleophile, but they are generally better than alcohols. Alcohol
chemistry also involves oxidation into a carbonyl as we shall see later in this
section. Alcohols are commonly formed from the reduction of carbonyls, which
we shall also postpone for the moment. The common reactions to form and
consume alcohols that do not involve carbonyl compounds center around
nucleophilic substitution. Figure 5-2 shows nucleophilic substitution reactions
that convert alkyl halides into alcohols. Figure 5-3 shows nucleophilic
substitution reactions that convert alcohols into alkyl halides.

Alkyl halides to alcohols
R

R

h*%/ x

~2~~^ H*y

H

OH

+ X

H

R'

\

R»';?-Br

R'

1. RCO,"

/

2.0H-(ac,)»

H°~V"R +

H

„^ TT

+

2

H

R"

„„t.^—X
Rv /

„.

R"

1 •
acetone

t,ii»»^—
OH
Rx
/

R'

+HX

R'

Figure 5-2

Copyright © by The Berkeley Review

5

Exclusive MCAT Preparation


OrCJ£UllG ChCHllStry

Carbonyls and Alcohols Oxygen Containing Compounds
Alcohols to alkyl halides
O

R

,^-oh S

«

R

/s^ Cl

^—Cl

H^

H

Retention

H
R'

R'

h

r^;

PBr,

OH

Br

-i

H

Inversion

H

R"

R"

h

R^

OH

^L^.

h

Br

r^;

K

Racemization

R'

Figure 5-3
Spectroscopic Evidence for Alcohols

Alcohols can be detected using either infrared or NMR spectroscopy. In IR

spectra, hydroxyl groups present a distinct absorbance between 3200 and 3500

cm"1 that is medium in intensity and broad due to hydrogen bonding. In
XHNMR spectra, hydroxyl groups present asignal between 1and 5ppm that is
broad due to hydrogen bonding, although the broadness varies with the solvent.
They have no definite 6-value (it varies with concentration and solvent). The
peak slowly disappears with the addition of D2O to the NMR tube. The OH

group does notcouple well, so werarely consider splitting patterns foralcohols.

Figure 5-4 shows the 1HNMR spectrum for 2-propanol in carbon tetrachloride
solvent. Figure 5-5 shows the IR spectrum for 2-propanol obtained neat onsalt
plates.
H

H,C

OH

6H

CH,

1H
1H

1
3.0 ppm

2.0

1.0

Figure 5-4

Copyright ©by The Berkeley Review

6

The Berkeley Review


Ur£J£UllC t/llCllllStry

Carbonyls and Alcohols Oxygen Containing Compounds

PTVl
1392 cm-'

1455 cm-1 & 1365 cm-'

2984 cm

Figure 5-5

Aldehyde and Ketone Properties
Because aldehydes and ketones do not form hydrogen bonds, they typically have
boiling points only slightly higher than alkanes of equal mass. Because of the
polarity of the carbonyl bond, they are slightly miscible in water. Aldehydes and
ketones are aprotic, polar molecules that become less hydrophilic as their carbon

chain length increases. The smaller aldehydes and ketones (three carbons or less)
are generally water soluble but as the size of the alkyl group increases, their
water solubility decreases. Table 5-2 shows the physical properties of several
aldehydes and ketones, from which the effects of mass, branching, and
positioning of the carbonyl group on the physical properties can be ascertained.

Isomer

IUPAC Name

(Common Name)

Boiling Melting
Point

Point

Water

Solubility
(g/lOOmL)

HCHO

Methanal (Formaldehyde)

-21°C

-92°C

High

H3CCHO

Ethanal (Acetaldehyde)

21°C

-121°C

Infinite

H3CCH2CHO

Propanal (Propionaldehyde)

49°C

-81°C

16.3

H3C(CH2)2CHO

Butanal (n-Butyraldehyde)

76°C

-99°C

6.8

H3C(CH2)3CHO

Pentanal

103°C

-92°C

3.3

H3C(CH2)4CHO

Hexanal

128°C

-56°C

2.1

C6H5CHO

Benzaldehyde

178°C

-26°C

0.3

H3CCOCH3

Propanone (Acetone)

56°C

-94°C

Infinite

H3CCOCH2CH3

Butanone (Ethyl methyl ketone)

80°C

-86°C

25.6

H3CCO(CH2)2CH3

2-Pentanone

102°C

-78°C

5.7

(H3CCH2)2CO

3-Pentanone

1018C

-41'C

4.9

H3CCO(CH2)3CH3

2-Hexanone

128°C

-55°C

1.6

H3CCH2CO(CH2)2CH3

3-Hexanone

124°C

H3CCOCH2CH(CH3)2

4-Methyl-2-Pentanone

119°C

-85°C

1.9

C6Hi0O

Cyclohexanone

156°C

°C

2.2

C6H5COCH3

Acetophenone

202°C

21°C

Insoluble

1.3

Table 5-2

Copyright © by The Berkeley Review

Exclusive MCAT Preparation


OrCJcllllC l^IlCllllStry

Carbonyls and Alcohols Oxygen Containing Compounds

Example 5.2

What is the IUPACname for the following compound?
OH

r H
O

A.
B.
C.
D.

l-Aldo-4-pentanol
4-Hydroxypentanal
5-Oxo-2-pentanol
2-Hydroxypentaldehyde

Solution

The longest chain isfive carbons and the highest priority functional group is the
aldehyde. The functional group with the most oxidized carbon receives the

highest priority according toIUPAC convention. For naming aldehydes, the"e"
is dropped from the alkane chain of the samelengthand an "al" suffix is added.
This makes the compound pentanal, which makes choice B correct. The OH is
named hydroxy as a substituent.
Aldehyde and Ketone Reactivity

Aldehydes consist ofa carbonyl with a hydrogen bonded to the carbonyl carbon
along with either an alkyl group or in the case of formaldehyde, a second
hydrogen. Ketones consist of a carbonyl group with two alkyl substituents
attached. The chemistry occurs primarily at the electrophilic carbonyl center.
Aldehydes and ketones are reactive with most nucleophiles, but not by a
traditional nucleophilic substitution mechanism. Once a nucleophile attacks a
carbonyl carbon, it forms a four-ligand intermediate with a negative charge on
oxygen known as a tetrahedral intermediate. This intermediate will be shown in

the mechanism of many carbonyl reactions in this section. The chemistry of
aldehydes is similar to the chemistry of ketones except that analdehyde can be
oxidized into a carboxylic acid while ketones cannot be oxidized easily.
Oxidation in carbonyl chemistry can be viewed as either the gain ofbonds to
oxygen orthe loss of bonds to hydrogen. We shall thoroughly address carbonyl
reactions throughout this section.

Spectroscopic Evidence for Aldehydes and Ketones

Aldehydes have infrared absorbances inthe 1720 cm"1 to1740 cm-1 range. They
are unique in the IR from other carbonyls due to two medium C-H stretches

around2700 cm-1 and 2900 cm-1. Ketones haveinfrared absorbances in the 1710

cm-1 to 1725 cm-1 range. In *HNMR, aldehyde hydrogens are found between 9
and 10 ppm, which makes aldehydes easy to identify via *HNMR. Ketones and

aldehydes each have alpha protons which fall in the 2.0 to 2.5 ppm range in

!HNMR. Figure 5-6 shows the *HNMR spectrum for butanone in carbon
tetrachloride solvent. Figure 5-7 shows the IR spectrum for butanal obtained
neat on salt plates.

Copyright ©by The Berkeley Review

8

The Berkeley Review


ljr£}£llllC (jtlCiniStry

Carbonyls and Alcohols Oxygen Containing Compounds
O

HgC

2 ppm

A

CH^CHg

Oppm

1 ppm

Figure 5-6

O

X

H

CH2CH2CH3

1117 cm'1

1457 cm'1 1388 cm''

J2738 cm-

and
1726 cm"

1362 cm-1

Figure 5-7

Example 5.3

Pentanal canbe distinguished from 3-pentanone by all ofthe following EXCEPT:

A. a signal at9-10ppm in the aHNMR.
B. fivesignals in the *HNMR rather than two signals.
C. an IR absorbance at 1826 cm"1.
D. an ultraviolet absorbance at 230 ran instead of 240 nm.
Solution

An aldehyde hydrogen isfound between 9ppm and 10 ppm in the 1HNMR, so
choice A is a valid way to distinguish an aldehyde from a ketone. Choice A is
eliminated. Pentanal has five unique hydrogens while 3-pentanone has two
unique hydrogens, so the two compounds can be distinguished by their

respective number ofsignals in the 1HNMR. Choice Biseliminated. Aldehydes
and ketones have different 7i-bonds, so they have different carbonyl absorbances
in the ultraviolet absorbance region. This eliminates choice D. Aldehydes and

ketones have different IR absorbances, but they are observed around 1700 cm"1,
not at 1826 cm"1. This makes choiceC an invalid technique, which makes choice
C the best answer.

Copyright © by The Berkeley Review

Exclusive MCAT Preparation


Ur£)21111C CllCllllStry

Carbonyls and Alcohols Oxygen Containing Compounds

Ketals, Hemiketals, Acetals, and Hemiacetals
Ketals and hemiketals are derivatives of ketones while acetals and hemiacetals

are derivatives of aldehydes. Ketals occur when a ketone loses the carbonyl
group and gains two alkoxy functional groups (R-O). The oxidation state of

carbon does not change, because the carbon still has two bonds to oxygen, but
now it is two sigma-bonds to two different oxygen atoms rather than a sigmabond and pi-bond to the sameoxygen. A hemiketal occurs when the ketonehas

itscarbonyl group converted into a hydroxyl group and gains one alkoxy group.
Acetals are similar to ketals, except it is the aldehyde that loses its carbonyl
group to gain the two alkoxy groups. Hemiacetals are similar to hemiketals,

except it again is an aldehyde, rather than a ketone, that converts its carbonyl
group into a hydroxyl group while gaining an alkoxy group. Figure 5-8 shows
the formation of the four compounds.
O

R"0

xsR"OH/OH~

Ketone

R^RHemiketal

O

R"0

II

xsR"OH/H+,

R

R'

R

R'O

xsR'OH/OH
H

"H

Hemiacetal

O

R'O

II

OH
O

V/
R

Aldehyde

R'

K
Ketal

O

II

C

\/

Ketone

R

OH

xsTOH/H*" .
H

OR'

V/
R

Aldehyde

H
Acetal

Figure 5-8

Acetals and ketals are useful as protecting groups in organic synthesis. Acetals

and ketals can be formed and removed only under acidic conditions, where as
hemiacetals and hemiketals are formed only under basic conditions butremoved
under any conditions.

Copyright ©by The Berkeley Review

10

The Berkeley Review


Or£)£llllC ChCmiStry

Carbonyls and Alcohols Oxygen Containing Compounds

Figure 5-9 shows a general mechanism for ketal formation under acidic
conditions. It is the same mechanism for the formation of an acetal from an

aldehyde, except that an aldehyde is the reactant, rather than a ketone.
R' — Q".

HH
+ 2 R'OH

-^

^:

H.O

*0—R'

+

R

R

deprotonate

R' —

OH

H
R1•—o+

:o—R'

R

R

make

R'

R'

:o

•o
-<—*-

R

R

R'
R

J

R

OH

make

1 break
HO

R'

H

HO

deprotonate
R

R

Figure 5-9

The steps of the mechanism are labeled to emphasize the predictable nature of
acid-catalyzed mechanisms. When you draw a mechanism foran acid catalyzed
reaction, the intermediates must carry positive charges and no molecule should
ever carry a negative charge. With the exception of rearrangement steps in
selected cases, acid catalyzed mechanisms follow this same pattern of: 1)

protonate (making the leaving group a better leaving group), 2) break (the
leaving group leaves), 3) make (the nucleophile attacks the carbocation), and 4)
deprotonate (returning the molecule to a neutral state). Base catalyzed
mechanisms follow the exact opposite pattern of: 1) deprotonate (to make a
strongnucleophile), 2) make/break (where the nucleophile attacks and dislodges
the leaving group), and 3) protonate (returning the molecule to a neutral state).
Copyright © by The Berkeley Review

11

Exclusive MCAT Preparation


vlrCJ£llllC CllCIIllStry

Carbonyls and Alcohols Oxygen Containing Compounds

These mechanisms should be kept as simplistic as possible. The mechanism for
the formation of a hemiacetal from an aldehyde and alcohol in the presence of
strong base is shown in Figure 5-10.
•

QR'

H

^~^Base

"ITS

+

•

•

•

H~ Q'' ;°—R'

R'O —H

deprotonate

R'

\ :qL

~R

R'O—h*^ ^rotonate

/fH

•

•

Q.

•

•

«0

R'

make/break

R'

R'p:

R-

-R

Figure 5-10

When you draw the mechanism for a base catalyzed reaction, be sure that the

intermediates carry negative charges and no molecule ever carries a positive
charge. Ketals and acetals serve as protecting groups for carbonyl groups in

synthesis involving ketones and aldehydes. Hemiacetals and hemiketals arenot

useful as protecting groups, but they are important in sugar chemistry.
Example 5.4

Addition of ethanol at apH of 4to propanal yields which organic product?
A-

B.

Et(V ^OEt
Et

H

C.

EtO.
EtO

.OEt
H

D.

HO.
Et

.OEt
H

HO^
Et

^OH
H

Solution

Addition of an alcohol to an aldehyde under acidic conditions (pH =4is acidic)
yields an acetal. The only acetal in the choices is choice A. Choice B has too

many ethoxy groups, choice Cis ahemiacetal, and choice Disa geminal diol.
Example 5.5

Addition of sodium methoxide inmethanol to acetone yields:
A. isopropyl alcohol.
B. acetaldehyde.
C.

aketal.

D. a hemiketal.
Solution

Addition ofan alcohol to a ketone under basic conditions yields ahemiketal. The
methoxide anion attacks the carbonyl carbon of acetone to generate the
tetrahedral anion intermediate, which then deprotonates the methanol to form
thehemiketal and regenerate themethoxide anion. The best answeris choice D.

Copyright ©by The Berkeley Review

12

The Berkeley Review


OrCjaniC CJoCmiStry

Carbonyls and Alcohols Oxygen Containing Compounds

Acetals and Ketals as Protecting Groups
Protecting groups are used in synthesis to prevent a reagent from reacting at a
site where it is undesirable to have a reaction. We shall only discuss protecting
groups for aldehydes and ketones at this time. Both of these carbonyl

compounds employ the same reaction to add the protecting group, forming
either an acetal or ketal. As we have seen, aldehydes and ketones, in the
presence of alcohols and acid, form acetals (from aldehydes) and ketals (from
ketones). Because acetals and ketals are less reactive than aldehydes and
ketones, they are an ideal protecting group. The alcohol that is typically used to
form the protected carbonyl compound is a vicinal diol (a 1,2-diol), such as
ethylene glycol (HOCH2CH2OH). Figure 5-11 shows the protecting of
cyclohexanone using ethylene glycol.

HO

+

H20

cone. H+

Cyclohexanone

Protected as a Ketal
Figure 5-11

The mechanism for forming the protected ketone is the same generic acidcatalyzed mechanism shown in Figure 5-9, only instead of using two molecules
of alcohol, a vicinal diol is used, so the second "make" step involves the second
hydroxyl group of the vicinal diol rather than a new alcohol.
Example 5.6

The addition of ethylene glycol (HOCH2CH2OH) in the presence of acid
provides a protecting group for ketones. Which of the following is the protected
form of 2-pentanone?

00

00

00

0.0

Solution

The original ketone (2-pentanone)has two bonds from carbon 2 to oxygen, so the
product must also have two bonds from carbon 2 to oxygen. This eliminates all
of the answer choices except choice B. The product of a diol and a ketone in
anhydrous, acidic conditions is a cyclic ketal.
There is not much to using an acetal or ketal protecting group. The last thing to
consider is when to use a protecting group in synthesis. As a guideline, any time

that you have a molecule with more than one reactive site, you must protect the
sites at which you wish to have no reaction. The exception to this rule is when
the site you wish to react at is significantly more reactive than any other sites on
the molecule.

Copyright ©by The Berkeley Review

13

Exclusive MCAT Preparation

Or£}
Carbonyls and Alcohols Oxygen Containing Compounds

Carboxylic Acids and Their Derivatives

Carboxylic acid derivatives are differentfrom aldehydes and ketones in that the

carbonyl carbon has a functional group thatpossibly can actas a leaving group.
Much of the chemistry of carboxylic acids and acid derivatives centers around
changing the group on the carbonyl carbon. We shall address each functional
group starting with the carboxylic acid and look at their chemical reactions.
Carboxylic Acids

Carboxylic acids are weak acids with a pKa between 2 and 5. They are readily
converted into esters, anhydrides, oracid halides. They carry outsimilar organic
reactions as esters, but are less reactive than esters. Carboxylic acids can be

formed by saponification (treating an ester with strong base in water), by treating
a methyl ketone (RCOCH3) with I2 and strong base, by oxidizing primary
alcohols and aldehydes in water, or by hydrolyzing a nitrile oran amide using
strong acid athigh temperatures. These reactions are shown inFigure 5-12.
Saponification:

O

R

O

xsH2Q/OH ^

A

OR'

R

O

R

OR'

R

Ester

R

CH3

A

R

R

Aldehyde

OH

O

¥L2Cr207/l?
R

Primary alcohol

A

OH

Carboxylic acid

O

\

A

Carboxylic acid

H

R-^OH

O

xs^O/H*

^
A
NHR'

Secondary amide

R

A

+

R'NH,

+

NH,

OH

Carboxylic acid

Nitrile hydrolysis

O

xsHp/H*
R

Iodoform

O

KMnQ4/OH^

X

R

• I3CH
O"

Carboxylate

O

Amide hydrolysis:

HOR'

O

I2/OH

A

H

+

OH

Carboxylic acid

Methyl ketone

Oxidation:

A

O

Oxidation:

HOR'

O

xsRgO/H*"

A

Iodoform reaction:

+

O"

Carboxylate

Ester

Ester hydrolysis:

A

C=N
R
Nitrile

A

OH

Carboxylic acid
Figure 5-12

Copyright ©by TheBerkeley Review

14

The Berkeley Review


Or£)£llllC tUlCHliStry

Carbonyls and Alcohols Oxygen Containing Compounds

Carboxylic acids can be reduced into primary alcohols or converted into other
compounds such as acid halides, acid anhydrides, or esters. Figure 5-13 shows

four reactions of carboxylicacids with which you are expected to be familiar.
O

H

R

Cl

R

X

O

o

A

OH

Primary alcohol

Acid halide

R

H

O

AA

R

OR'

O

R

Acid anhydride

Ester

Figure 5-13

Example 5.7
Treatment of benzoic acid with ethanol and acid yields which of the following
compounds?
D.

OH

OH

OEt
EtO

OEt

Solution

Addition of an alcohol to a carboxylic acid under acidic conditions with enough
heat to overcome the activation barrier yields a new ester by way of a
transesterification reaction. The final product is an ester with an ethoxy group in
place of the hydroxyl group of the carboxylic acid, along with a water molecule
side product. Choice B is the best answer.
Esters

Esters are carbonyl compounds with an alkyl group and an alkoxy group
attached to the carbonyl carbon. Esters have a leaving group (the alkoxy group),
so they undergo more reactions than ketones or aldehydes. Their reactivity
correlates with the pKa of the conjugate acid of the leaving group. Leaving
groups that are more stable (are less basic and their conjugate acids have a lower
pKa value) are better leaving groups. Esters can easily exchange their alkoxy
group in the presence of acid and an alcohol in what is referred to as a
transesterification reaction.

Copyright © by The Berkeley Review

15

Exclusive MCAT Preparation


Or£J£UllC CoCmiStry

Carbonyls and Alcohols Oxygen Containing Compounds

Example 5.8

What is the majororganic product for the following reaction?
O

+ HoCOH/rf

H3CH2C

A.

OCH2CH3

B.

O

X„

Et'

C.

O

"OCH3

X1

EKT

'OCH,

HO

X

Et*"

D.

OEt
"OCH,

H3CO

X

Et'

OCH3
"OEt

Solution

At high temperature under acidic conditions, an alcohol can undergo a
transesterification reaction when mixed with an ester. The final product is the
new ester with the methoxy group attached instead ofthe ethoxy group. Ethanol
is the organic side product. ChoiceA is the best answer.
In Example5.8, a C-O bond and an O-H bond were both broken in the reactants

andformed in the products. This implies that the enthalpy (AH) for the reaction
is close to 0. Going from an ester and non-cyclic alcohol to an ester and noncyclic alcohol generates a change in entropy (AS) of roughly 0, because the
reaction starts and finishes with roughly the same degrees of freedom. This
implies that the change infree energy for transesterification isaround 0 (AG =AH
- TAS). Thismeans that the equilibrium constantfor a transesterification reaction

is approximately 1. The reaction can be driven to products by focusing on Le
Chatelier's Principle. Itwill proceed inhigh yield ifthe products are removed or
a reactant is constantly added. This also has biological significance in that
transesterification can be used for shuttles in the cell membrane. For the

formation of a lactone (cyclic ester), there is a ring formed and an alcohol
molecule produced from a linear system. Depending on the reaction, there can
be either again or aloss in entropy, so lactone formation is less predictable.
Lactones

Lactones are cyclic esters, as shown in Figure 5-1. Lactones undergo the same
chemistry as esters, only entropy is a factor in the reaction's favorability.
Lactones can be synthesized by treating cyclic ketones with peroxyacids
(RCO3H) in what is known as the Baeyer-Villiger reaction. Lactone chemistry is
easier to understand when you recognize that the compound isan ester. Figure
5-14 shows the formation of a lactone from an intramolecular transesterification
reaction of a hydroxyester.

H+
RO

ROH

OH

Figure 5-14

Copyright ©by The Berkeley Review

16

The Berkeley Review


Ur£J21IllC CJlClHiStry

Carbonyls and Alcohols Oxygen Containing Compounds

Acid Anhydrides

Acid anhydrides are formed by a condensation reaction (dehydration) of two
carboxylic acids at elevated temperatures (as shown in Figure 5-13). Therefore,
when you add water to an acid anhydride, it breaks into two carboxylic acids. It
is easiest to predict the product if you focus on the inorganic side product (H2O
in this case) more than the organic product. If you circle and remove an H from
one reactant and an OH from the second reactant and then connect the two

leftover fragments, then you can derive the organic product rather effortlessly.
This is shown in Figure 5-15 as a short-cut method for deducing the product of
dehydration of two carboxylic acids.
O

O

OO

OO

X^~X ^ A A - A A
Cfa HOJ
Find the water

R'

R
O
R*
Connect the atoms

R
O
R'
Viva la anhydride

Figure 5-15
Example 5.9

What is the major product from the following reaction?
O

Q
-•

\
A.

/

r^ur
OH

H3C
iW-

OH

Diketone

B. Acid anhydride
C.

Ester

D. Aldehyde
Solution

Addition of heat to carboxylic acids yields an acid anhydride by driving off
water. Thefinal products are an acid anhydride and a watermolecule. Choice B
is the best answer There are three possible acid anhydrides that can form. One
of the three possible acid anhydrides that may form is drawn below. The other
two acid anhydrides that can form result from the condensation of each acid
uponitself. Probability saysthat the productbelow is themost likely.
O

H„qi

O

O

O

O

O

X,A-X
^ XX
XnX
CfHHOj CH3HnC6^
O
CH3"*"
HnC6^
O
Water is found

Atoms are connected

CH3

Anhydrides are good

Acid Halides

Acid halides are similar to esters, but with a halide (Cl, Br and I) in place of the

alkoxy group. They are the most reactive of all the carbonyl compounds, because
the halide is a great leaving group. They undergo the samesubstitutionreactions
as other carbonyl compounds that have a leaving group, but they react faster.
For some reactions, acid halides can be too reactive.

They are a useful

intermediate product in many synthetic pathways, such as the conversion of a
carboxylic acid into an amide for instance, where the carboxylic acid is first
converted to the more reactive acid halide which then goes on to form the amide.

Copyright ©by The Berkeley Review

17

Exclusive MCAT Preparation


Or£}2UllC CllCllllStry

Carbonyls and Alcohols Oxygen Containing Compounds

Example 5.10

What are the two products formed when propanoyl chloride, H3CCH2COCI, is
treated with methyl amine, H3CNH2?
A. N-methyl propanamide and hydrochloric acid

B. l-amino-2-butanoneand hydrochloric acid
C. Propanal and chloromethylamine

D. Carbondioxide and N,N-ethylmethylamine
Solution

An amine is a good nucleophile capable of attacking the carbonyl carbon and

displacing the chloride anion to form an amide, choice A. Amides are biological
structures thatyou arerequired to know according to theMCAT Student Manual.
This reaction can be used asa precursor to synthesizing an amine. Amides can

bereduced to anamine using LiAlH4 in ether followed by neutralization with a

weak acid. There are problems with direct synthesis of primary amines using

ammonia and an alkyl halide due to multiple additions. The point here is that
amides can be products themselves, orintermediates inamine synthesis.
Amides

Amides are carbonyls with an amine group bonded to the carbonyl carbon.
Amides form the backbone ofproteins, and they arefound in most ofthebases of
nucleic acids (i.e., DNA and RNA). An amide bond that links amino acids
together is referred to as a peptide bond. Amides can be reduced into amines

using a strong reducing agent such as lithium aluminum hydride, LiAlH4.
Example 5.11

Which of the following compounds doesNOT contain an amidebond?
A. Guanine

B. Uracil

C.

Isoleucine

D. Cytochrome
Solution

Most amino acids do not contain an amide bond, although polymers of amino
acid (polypeptide chains) do. It is in proteins that amino acids form peptide

(amide) bonds. The peptide bonds of proteins are broken down in acidic
aqueous environments to regenerate the individual amino acids. Guanine and

uracil are bases in RNA, and they contain amide bonds (as drawn below). It is

the amide functional group that forms the hydrogen bonding in base pairing.
Cytochrome is an enzyme (protein), so it contains amide bonds in its peptide
linkages. The bestanswer is choice C, isoleucine, an amino acid.
9

O

£N^O
X"
H

Copyright ©by The Berkeley Review

Otx"
N^N^NHa
H

Uracil

Guanine

(pyrimidine base)

(purine base)

18

The Berkeley Review


Or£{£I]llC ChCmiStry

Carbonyls and Alcohols

Carbonyl Reactivity

Carbonyl reactions can be categorized in one of three ways. The fist type of
reaction involves a nucleophile attacking the electrophilic carbon. The second
type of reaction involves the deprotonation of an alpha proton and the
subsequent nucleophilicity of the anion that is generated. The last type of
reaction falls into the realm of oxidation-reduction chemistry, although most
mechanisms for carbonyl redox reactions involve a nucleophile attacking the
carbonyl carbon. If you keep things simple in terms of the three types of

reactions, you should be able to summarize all of carbonyl chemistry and work
through any questions they may present.
Attack at Carbonyl Carbon
Because carbonyl compounds contain a C=0 bond, they are good electrophiles.
We shall consider ketones and aldehydes first, but other carbonyl compounds

also act as electrophiles. The difference in reactivity between a ketone and a
carboxylic acid derivative, such as an ester, centers around the presence of a
leaving group on the carbonyl carbon. The C=0 bond is polar with a partial
positive charge on the carbon atom and a partial negative charge on the oxygen
atom. It is the partial positive charge on the carbon that makes a carbonyl such a
wonderful electrophile. Figure 5-16 shows a generic carbonyl reaction, where a
carbonylcompound is attacked by a nucleophile to form a tetrahedral intermediate.
O

II

Nuc

Nuc:'

Carbonyl

O"

\ /
Tetrahedral Intermediate

Figure 5-16

We have already seen aldehydes and ketones serving as electrophiles in the
formation of acetals, hemiacetals, ketals and hemiketals. As far as electrophilic

chemistry of carbonyls is concerned, there is no major variation between
reactions. In other words, it is best to view carbonyl reactions as all basically the

same with slight variations of the nucleophile. The tetrahedral intermediate in
Figure5-16 represents every genericintermediate in carbonyl addition reactions.

Forcarbonyl compounds that have leavinggroups, the reactivity of the carbonyl
compound is based on the strength of the leaving group. Stronger leaving
groups make for a more reactive (more electrophilic) carbonyl compound. The
strength of a leaving group can be inferred from the pKa of its conjugate acid.
Leaving groups are considered to be good when they form a stable compound
upon leaving. So, as the leavinggroup gets stronger, it gets morestable, which
makes it less basic, and thus makes its conjugate acid stronger. This means that
goodleavinggroups generally have conjugate acids with low pKa values. Figure
5-17 shows a carbonyl reactivity chart (relative reactivity of substituted
carbonyls) for an acid halide, an acid anhydride, an ester, and an amide. The
conjugate acid of each leaving group is shown in the same diagram.

Copyright ©by The Berkeley Review

19

Exclusive MCAT Preparation


Organic Chemistry

carbonyisandAicohois

Carbonyl Reactivity

Thebetter Xis at leavingfromH, the better it will be at leavingfrom C,
so thebestleaving group hasa conjugate acid with the lowest pKa.
O

H^
iA

xr

R

pKa = -10 to -7

verygood

R

R

pKa - 3 to5

very strong acid leaving group

cr
good leaving group

average acid strength

O

H

O

H

OR'
R

R

NHR1

yC\\

OR'

pKa = 14tol7

semi-poor

weak acid

leaving group

R

pKa = 33 to 35
very weak acid

NHR'

very poor
leaving group

Relative Reactivity:
O

R

O

X

R

O

O

O

R

R'

O

R'

OR'

NHR'

Figure 5-17

The relative reactivity implies that anacid halide can easily be converted into an
anhydride, ester, or amide. An acid anhydride can easily be converted into an
ester or amide, but it is difficult to convert the anhydride into an acid halide.

This technique is a good predictor of the reactivity of all carboxylic acid
derivatives. The generic reaction and its tetrahedral intermediate are shown in
Figure 5-18.
O^v

®q

0

R pL.G.

^

R

l.g.

\©
Nuc

O

II
,c.
R

©

+ L.G.
©

Nuc

:Nuc

Figure 5-18

Carbonylsubstitutionreactions proceed via a tetrahedral intermediate as shown

inFigure 5-18. Ifthe leaving group is not a good one, then the reaction cannot go
further than the tetrahedral intermediate and will ultimately shift back to the
carbonyl reactant. This results in an equilibrium between theoriginal carbonyl
and the tetrahedral intermediate. This isobserved with ketones and aldehydes
when they are present inasolvent that has nucleophilic capability.

Copyright ©by TheBerkeley Review

20

The Berkeley Review


Or£{21111C ChCmiStry

Carbonyls and Alcohols

Carbonyl Reactivity

Example 5.12

Whichof the following is the MOST electrophiliccarbonylcompound?
A. Amide
B.

Ester

C. Aldehyde
D. Acid anhydride
Solution

The reactivity of a carbonyl is dictated by the leaving group on the carbon of the
carbonyl. As the acidity of the conjugate acid of the leaving group increases, so
does the reactivity of that particular carbonyl. In the choices above, the conjugate
acids of the leaving groups are an amine, an alcohol, H2, and a carboxylic acid
respectively. The most acidic is the carboxylic acid, so the anhydride is the most
reactive carbonyl.
Deprotonation of oc-Protons

The hydrogen on the alpha carbon (the carbon adjacent to the carbonyl carbon) is
acidic (its pKa is approximately 19), so it can be removed using a strong base.
Enolates are formed when a hydrogen on the alpha carbon is deprotonated. The
enolate can regain a proton at either the carbon or the oxygen. If it is protonated

at the oxygen, an enol is formed. There is an equilibrium between the ketone and
enol. The conversion from a ketone into an enol is known as tautomerization,

because a ketone and its enol are tautomers, structural isomers that vary in the

position of a 7t-bond and a hydrogen. The tautomerization of acetone is shown in
Figure 5-19.
Ketone

Carbanion

Enolate

Enol

CH,
! base

Figure 5-19

The carbanion that forms is a good nucleophile. When an alkyl halide is added
to the solution, the carbanion can attack the alkyl halide in a nucleophilic
substitution reaction to form a new carbon-carbon bond. This results in a longer

ketone. The halide can be any halide, but the reaction works best with an alkyl
iodide compound. Alkyl bromides and chlorides yield more O-alkylation side
products than alkyl iodides. The generic reaction is shown in Figure 5-20.
Ketone

Carbanion

Longer Ketone

Figure 5-20

Copyright ©by The Berkeley Review

21

Exclusive MCAT Preparation


OrgaillC ChemiStry

CarbonylsandAlcohols

Carbonyl Reactivity

When the carbonyl is asymmetric, the possibility of two different enolates arises
(each formed by deprotonating a different alpha hydrogen). If one of the two
alpha carbons is more substituted, then it is both more sterically hindered and

more stable. This creates a situation where the reaction can be dictated by
temperature and base size. At low temperature with a bulky base, the less

hindered (less substituted) alpha carbon gets deprotonated to form the so called
kinetic enolate (lower energy transition state). This is referred to as kinetic control.

At a higher temperature with a small base, the more hindered (more substituted)

alpha carbon gets deprotonated to form the so called thermodynamic enolate
(leading to themore stable product). This is referred to as thermodynamic control.
We shall apply this concept to aldol condensation reactions of asymmetric
ketones later on in this section.

Example 5.13

What is the final product after acetone is treated first with NaH, followed by
iodoethane, and subsequently followed by workup?
A. 2-Methyl-2-butanol
B. 3-Methyl-2-butanone
C. 2-Pentanone
D. 2-Butanone
Solution

This reaction is similar to the generic reaction in Figure 5-20. The carbon chain

length isincreased by two carbons (from three to five) when the electrophile is
ethyl iodide. This eliminates choice D. The product is a ketone, so choice A is
eliminated. The final product is 2-pentanone, as shown below, which makes
choice C the best answer.

:o:

II

H1>

:o:

__
CH3

:o:

II

II

B£

H^^I base

CH3

^ ^
n2^

H2C

^CH3

H3CH2C
L

2-Pentanone

/

H3C

Oxidation and Reduction

Oxidation and reduction are recurring in organic chemistry, soworking from a
logic-based foundation is key. If the oxophilic carbon (carbon containing abond
to oxygen) hashydrogens, it canbe oxidized. Primary alcohols are oxidized into

aldehydes, which can be further oxidized into carboxylic acids. Secondary
alcohols are oxidized into ketones. Tertiary alcohols cannot be oxidized (the

alcohol carbon has no hydrogen to lose). Reduction is defined as the opposite of
oxidation, so the reverse ofeach reaction just mentioned represents reduction.
To make the processes more clear, we shall define oxidation and reduction in

terms of bonds to oxygen and bonds to hydrogen. More than just oxygen
containing compounds do redox chemistry. When two cysteine residues form a
crosslink, they undergo dehydrogenation (loss of hydrogen), an oxidative
process. When the rc-bond in a fatty acid is hydrogenated to form an aliphatic
chain, it has undergone a reductive process.

Copyright ©by The Berkeley Review

22

The Berkeley Review

OrgaillC ChCmistry

Carbonyls and Alcohols

Carbonyl Reactivity

Oxidation is defined as an increase in oxidation state, which is caused by either
losing a bond to a lesselectronegative atom (inmostcases hydrogen) or gaininga
bond to a more electronegative atom (in most cases oxygen). Reduction is
definedas a decreasein oxidation state, which is caused by either gaining a bond
to a less electronegative atom (in most cases hydrogen) or losing a bond to a
more electronegative atom (in most cases oxygen).
Oxidation

Reduction

Gain of bonds to O

Loss of bonds to O

Loss of bonds to H

Gain of bonds to H

Increase in oxidation state

Decrease in oxidation state

Determining oxidation states using the method learned in general chemistry is a
matter of assigning oxygen a -2 (because it is more electronegative than the atoms
to which it bonded, and it makes two bonds) and a +1 to hydrogen (because it is
less electronegative than the atoms to which it bonded, and it makes one bond).
The oxidation state of any remaining atoms is found by difference. In organic
chemistry, oxidation states for specific atoms can easily be found by considering
electron sharing in each bond. If the bond is between two atoms of unequal
electronegativity, then the more electronegative atom is assigned a -1 and the less
electronegative atom is assigned a +1. The oxidation state of an atom is found
by summing the numbers from all of the bonds and any formal charge it may
have. Figure 5-21 shows this method as it applies to the oxidation state of carbon
2 in 2-propanol and acetone.

[O]

^

0C0?0CH3

lost a bond to H

gained a bond to O
Figure 5-21
Each of the four bonds to carbon is analyzed for its relative electronegativity

compared to the atoms to which it is bonded. Bonds to hydrogen give a negative
to carbon and a positive to hydrogen, because carbon is more electronegative
than hydrogen. Bonds to oxygen give a positive to carbon and a negative to
oxygen, because carbon is less electronegative than oxygen. Both carbons in a
carbon-carbon bond get zero, because there is no difference in electronegativity.

In a secondary alcohol,the oxophiliccarbon has an oxidationstate of 0 while in a
ketone, the oxophilic carbon has an oxidation state of +2. This means that the
carbon was oxidized by two electrons, which is predictable, because it has lost a
bond to hydrogen (oxidizing it by one electron) and has gained a bond to oxygen
(oxidizing it by another electron). Figure 5-22 shows that oxygen and hydrogen
do not change oxidation state when going from 2-pentanol to acetone.
O

A -2

@

H3C"0~0C0^CH2
Figure 5-22

Oxygen has a -2 oxidation state, as is expected. Hydrogen has a +1 oxidation
state as expected. Oxidation states should be made this simple.

Copyright ©by The Berkeley Review

23

Exclusive MCAT Preparation