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Chapter 1
#
Electronic Structure and Bonding
Acids and Bases
1. Atoms consist of protons (p+), neutrons
(n), and electrons 1e -2. Atomic number is
the number of p+; mass number is the
sum of p+ and n. Isotopes have the same
number of p+ with different numbers of n.
The atomic weight of an element is the
average weighted mass of its atoms (1.1).
2. An atomic orbital (s, p, d, f) is the volume
of space around a nucleus where an
electron is most likely to be found. An
electron goes into the lowest energy
orbital available (aufbau principle), with
two e - in each orbital (Pauli exclusion
principle). An e - will occupy an empty
degenerate (same energy) orbital before
it will pair up with another e - (Hund’s
rule). Core e - are in filled shells; valence
e ! are used for bonding (1.2).
3. Atoms give up or accept e - to achieve an
outer shell of eight electrons (octet rule).
Electropositive elements (on the left of
the periodic table) lose e - to form cations;
electronegative elements (on the right)
gain e - to form anions. Ionic bonds are
formed by electrostatic attraction
between cations and anions.
Electronegativity is a measure of an
atom’s ability to attract e -. Atoms form
covalent bonds by sharing valence e -.
Nonpolar covalent bonds are formed by
atoms with the same electronegativity;
polar covalent bonds are formed by
atoms with different electronegativities.
A polar bond has a dipole with a dipole
moment, D (debye). Electrostatic
potential maps show how charge is
distributed: red 1-2 and blue 1+2 (1.3).
4. Lewis structures represent compounds,
showing all bonding and lone pair e !.
The formal charge on an atom = the
number of valence e - minus 1/2 the
bonding e - minus the lone pair e -.
Carbocations have a positively charged
carbon; carbanions have a negatively
charged carbon; a carbon radical has a
carbon with an unpaired e -. Kekulé
structures depict bonds as lines.
Condensed structures use subscripts and
few, if any, bonds (1.4).
5. An s atomic orbital is spherical; the 2s
atomic orbital has a radial node. There are
three degenerate, perpendicular p orbitals;
each has a node at its nucleus (1.5).
6. Bond length is the distance between
nuclei; bond dissociation energy is
the energy required to break a bond.
Two atomic orbitals combine to form
two molecular orbitals, a bonding MO
(s or p) and an antibonding MO (s*
or p*). A sigma 1s2 bond is
Organic Chemistry
Paula Yurkanis Bruice, 5th Edition
Prepared by Merritt B. Andrus
cylindrically symmetrical. Two p orbitals
overlap side-to-side to form a pi 1p2
bond (1.6).
7. Methane has four identical covalent bonds
formed using four hybrid 1sp32 orbitals,
which result from mixing one 2s and three
2p atomic orbitals. It has tetrahedral
(109.5°) bond angles. Ethane has sp3
carbons and 109.5° bond angles. Ethene
(with a double bond) has sp 2 carbons and
120° bond angles. Ethyne (with a triple
bond) has sp carbons and 180° bond
angles. All single bonds are s bonds; a
double bond consists of 1 s bond and 1 p
bond; a triple bond consists of 1 s bond
and 2 p bonds. The more s character, the
shorter and stronger the bond and the
larger the bond angle. (1.6–1.9, 1.14).
H
C
H H
H Alkanes are hydrocarbons with only
Methane
p bond
H H
C C
H H
s bond
Ethene
H alphabetized; sec and tert are also not
C alphabetized, but iso and cyclo are. In a
C cycloalkane with two substituents, the
H first cited substituent gets the lower
Ethyne
8. The O and N of water and ammonia are
sp3 hybridized; H 2O has 104.5° bond
angles; NH 3 has 107.3° bond angles. C+
and C # are sp2; C- is sp3 (1.11, 1.12).
9. A Br"nsted acid donates a proton 1H +2; a
Br"nsted base accepts a proton, forming a
conjugate base and a conjugate acid,
respectively. The acid dissociation
constant (Ka) is a measure of the acidity of
a compound; pKa = -log Ka; the lower
the pKa, the stronger the acid. Protonated
carboxylic acids and protonated
alcohols = strong acids 1pKa 6 02;
carboxylic acids = weak acids 1pKa ' 52;
protonated amines = very weak acids
1
1pKa ' 102; alcohols and water
1pKa ' 152. The equilibrium constant for
an acid-base reaction = 1reactant Ka2/
1product Ka2. When atoms are the same
size, the more electronegative the atom
to which the hydrogen is attached, the
stronger the acid. Relative electroneg-
ativities: sp 7 sp2 7 sp3. When atoms
are very different in size, the strongest
acid will have its hydrogen attached to
the largest atom. For example, acid
strength: HI 7 HBr 7 HCl 7 HF. The
stronger the acid, the weaker its
conjugate base. Weak bases are stable
bases. A Lewis acid accepts a share in a
pair of e -; a Lewis base donates a share in
a pair of e -. Curved arrows are used to
show electron flow; the arrow begins
where the electrons originate and points
to where they end up (1.16–1.26).
Chapter 2
An Introduction to Organic
Compounds
1. Hydrocarbons contain only C and H.
single bonds. Constitutional isomers
have the same molecular formula but
differ in the way the atoms are connected.
IUPAC (systematic) and common names
are used to name compounds. CH 2 = a
methylene group. A primary (1°) carbon
is bonded to one other C; a secondary (2°)
carbon is bonded to 2 Cs; a tertiary (3°)
carbon is bonded to 3 Cs. Substituents
are indicted as prefixes, with the parent
hydrocarbon numbered in the direction
that puts the lowest number in the name
of the compound. Substituents are listed
alphabetically; di, tri, tetra, are used for
identical alkyl groups, but are not
number (2.1–2.3).
a primary carbon a secondary carbon a tertiary carbon CH3
CH3CHCH2 CH3CH2CH CH3C
CH3 CH3 CH3
an isobutyl group a sec-butyl group a tert-butyl group
2. Alkyl halides and ethers are named as
substituted alkanes; alcohols and amines
are named using a functional group suffix.
Substituents on the nitrogen are preceded
by an N. If a parent chain has a substituent,
the substituent gets the lowest number; if
it has a functional group, the functional
group gets the lowest number; if it has
both a substituent and a functional group,
the functional group gets the lowest
number. Only if the functional group gets
the same number in either direction, is the
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 2
chain numbered so the substituent gets
the lower number (2.4–2.7).
3. Alkyl halides and alcohols are 1°, 2°, or 3°
depending on whether the X or OH is on
a 1°, 2°, or 3° carbon. Amines are 1°, 2°, or
3° depending on how many alkyl groups
are bonded to N (2.4, 2.6, 2.7).
4. The stronger the intramolecular forces
holding molecules together, the higher
the boiling point: hydrogen bonds are
stronger than dipole-dipole interactions,
which are stronger than van der Waals
forces, which increase with molecular
weight and decrease with branching (2.9).
5. Polar compounds dissolve in polar
solvents; nonpolar compounds dissolve
in nonpolar solvents. An oxygen can drag
about 3 carbons into water (2.9).
6. Organic compounds exist in various
conformations due to bond rotation.
Newman projections depict staggered
(anti and gauche) and higher energy
eclipsed conformations. Cyclopropane
and cyclobutane have significant angle
strain; cyclopentane and cyclohexane are
nearly strain free. Cyclohexane adopts a
chair conformation with an axial and
equatorial bond on each carbon. Ring-flip
causes one chair conformer to convert into
another chair conformer; bonds that are
axial in one are equatorial in the other. A
substituent is more stable in an equatorial
position. A cis isomer has substituents on
the same side of the ring; a trans isomer
has them on opposite sides (2.10–2.14).
= axial bond
= equatorial bond
Chapter 3
Alkenes: An Introduction to
Reactivity. Thermodynamics and
Kinetic
1. Alkenes are hydrocarbons with a double
bond. The total number of p bonds and
rings is the degree of unsaturation. The
general molecular formula for a
hydrocarbon is CnH 2n + 2 minus 2
hydrogens for each degree of
unsaturation. The parent hydrocabon is
the longest carbon chain that contains the
double bond, numbered so that the start
of the double bond is given the lowest
possible number. Alkadiene is used for
two double bonds. Vinylic carbons are
double-bonded carbons; allylic carbons
are adjacent to vinylic carbons (3.1–3.2).
Br
CH3CHCH2CH CCH2CHCH3
CH3 CH2CH3 Br
2-bromo-4-ethyl-7-methyl-4-octene 6-bromo-3-chloro-4-methylcyclohexene
not
7-bromo-5-ethyl-2-methyl-4-octene 3-bromo-6-chloro-5-methylcyclohexene
because 4 < 5 because 4 < 5
2. The sp2 carbons of an alkene and the four
atoms attached to them are in a plane. Cis
isomers have the hydrogens on the same
side of the double bond; in trans isomers
they are on opposite sides. The E isomer
has the high priority groups (based on
atomic numbers) on opposite sides of the
double bond; the Z isomer has them on
the same side. Proceeding down a
substituent breaks a tie (3.5).
3. The double bond of an alkene is its
functional group (the center of
reactivity). Curved arrows show the
mechanism for this electrophilic
addition reaction (H + is an electrophile
and the p bond is a nucleophile; the
carbocation is an electrophile and Br - is a
nucleophile) (3.6).
slow
C C + H Br C C
+
H Br H
the electrophile a carbocation
adds to an sp2 intermediate
carbon of the
alkene
4. Energy changes are shown by a reaction
coordinate diagram. A transition state
has partially broken and partially formed
bonds; an intermediate has fully formed
bonds. The more stable the species, the
lower its energy. The change in Gibbs free
energy 1¢G°2 is exergonic 1-2 when
forming a more stable species, and
endergonic 1+2 when forming a less
stable species. ¢G° is related to the
equilibrium constant by -RT ln Keq.
The formation of products with stronger
bonds and greater freedom of movement
causes ¢G° to be negative;
¢G° = ¢H° - T¢S°. If a system at
equilibrium is disturbed, it will adjust to
offset the disturbance (Le Chatlelier’s
principle). The free energy of activation
( ¢G‡) is the difference between the free
energy of the transition state and the free
energy of the reactants. The greater ¢G‡,
the slower the reaction. The rate-
determining step has its transition state at
the highest point on the reaction
coordinate. The rate of a reaction is
directly proportional to a rate constant, k;
the smaller the rate constant, the slower
the reaction. The Arrhenius equation
relates the rate constant to the activation
energy 1Ea2 (3.7–3.8).
intermediate
Free energy
CH3CHCH2CH3
+
Br−
Cl
CH3CH CHCH3
HBr
CH3
not
Progress of the reaction
2
Chapter 4
The Reactions of Alkenes
1. Hydrogen halides add to alkenes to form
alkyl halides. Carbocations are stabilized
by hyperconjugation (e - delocalization
by overlap of adjacent s bond orbitals
with the empty p orbital); relative
stabilities: 3° 7 2° 7 1°. The Hammond
postulate states that the transition state is
more similar in structure to the species to
which it is more similar in energy (4.1–4.3).
2. Electrophilic addition reactions are
regioselective; the electrophile adds to
the sp2 carbon bonded to the greater
number of hydrogens in order to form
the more stable carbocation (4.4).
3. The addition of water or an alcohol to an
alkene requires an acid catalyst. Addition
of water forms an alcohol; addition of an
fast alcohol forms an ether (4.5).
−
+ Br C C
4. A carbocation can rearrange to a more
stable carbocation via a 1,2-hydride or 1,2-
the nucleophile
adds to the methyl shift, or by ring expansion (4.6).
carbocation
5. Halogens (Cl2 and Br2) add to alkenes to
form vicinal dihalides via a cyclic
bromonium ion intermediate. If the
reaction is carried out in water, a
halohydrin is formed with water adding
to the more substituted sp2 carbon. Since
the intermediate in these reactions is not a
carbocation, carbocation rearrangements
cannot occur (4.7).
6. Alkenes undergo oxymercuration-
reduction and alkoxymercuration-
reduction to form alcohols and ethers,
respectively. Carbocations are not formed
as intermediates, so carbocation
rearrangements do not occur (4.8).
7. Alkenes react with peroxyacids
1RCO3H2 to form epoxides. The reaction
is concerted (it does not have an
intermediate) (4.9).
8. Hydroboration-oxidation of an alkene
involves the concerted addition of borane
1BH 32 to form a trialkylborane that is
treated with H 2O2 and HO - to form an
alcohol. Borane is the electrophile that
adds to the less substituted sp2 carbon;
H - is the nucleophile that adds to the
other sp2 carbon (4.10).
CH3 CH3
1. BH3/THF
CH3CHCH CH2 2. HO−, H2O2, H2O
CH3CHCH2CH2OH
3-methyl-1-butene 3-methyl-1-butanol
9. Alkenes undergo catalytic (Pd/C, Pt/C,
Ni) hydrogenation to form alkanes. The
most stable alkene has the smallest heat of
hydrogenation. The greater the number
of alkyl substituents attached to the sp2
carbons, the more stable the alkene (4.11).
Chapter 5
Stereochemistry
−∆G˚
CH3CHCH2CH3 1. Constitutional isomers differ in the way
Br their atoms are connected. Stereoisomers
(cis-trans isomers and isomers with
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 3
asymmetric centers) differ in the way the
atoms are arranged in space. Cis-trans
isomers have either a double bond or a
cyclic structure (5.1).
2. A molecule is chiral if it is
nonsuperimposable on its mirror image.
A carbon bonded to four different
substituents is an asymmetric center.
A molecule with one asymmetric center is
chiral; it can exist as a pair of
enantiomers (nonsuperimposable mirror
image molecules). Enantiomers have the
same physical and chemical properties
(5.2–5.6).
Br Br
C C
CH3CH2 H H
CH3 CH3
mirror
the two isomers of 2-bromobutane
enantiomers
3. The R,S system is used to name chiral
compounds by prioritizing the four
substituents attached to the asymmetric
center based on atomic number. When the
lowest priority substituent points to the
rear, an arrow starting at the highest
priority substituent and pointing at the
second highest priority substituent is
clockwise if the compound has the R
configuration, and counterclockwise if it
has the S configuration (5.7).
1 1
Br Br
C H4 4 C
H a vinyl halide; with excess reagent, a
CH3CH2
CH3 CH3
2
3 3
(S)-2-bromobutane (R)-2-bromobutane
4. Chiral molecules that rotate plane-
polarized light to the right are
dextrorotatory 1+2; those that rotate it to
the left are levorotatory 1-2.
A polarimeter measures observed
rotation, a, from which specific rotation
[a] can be calculated. A 50:50 mixture of
enantiomers is an optically inactive
1a = 02 racemic mixture. Enantiomeric
excess is measured by dividing the
observed specific rotation by the specific
rotation of the pure enantiomer (5.8–5.10).
5. Stereoisomers that are not mirror images
are diastereomers. Unlike enantiomers,
diastereomers possess different physical
and chemical properties. In compounds
with two asymmetric centers, the
configuration of one of the asymmetric
centers is the same in both diastereomers,
and the configuration of the other is not
the same in both. Compounds with two or
more asymmetric centers that possess a
plane of symmetry are achiral (optically
inactive) meso compounds (5.11–5.13).
6. Enantiomers can be separated (resolved)
by chiral chromatography (5.16).
7. In a stereoselective reaction, one
stereoisomer is formed in preference to
another. In a stereospecific reaction,
stereoisomeric (e.g., cis and trans)
reactants form different stereoisomers as
products. When a reactant without an
asymmetric center forms a product with
one asymmetric center, the product will
be a racemic mixture. Electrophilic
addition reactions that form carbocation
intermediates involve syn and anti
addition. Hydrogenation, epoxidation,
and hydroboration are syn additions;
halogenation is an anti addition. CIS-
SYN-ERYTHRO or -CIS (5.18, 5.19).
8. Enzymes and receptors can distinguish
between enantiomers. Enzyme-catalyzed
reactions are completely stereoselective—
CH2CH3
only one stereoisomer is formed.
Enzyme-catalyzed reactions are
stereospecific—the enzyme reacts with
only one stereoisomer (5.20, 5.21).
Chapter 6
The Reactions of Alkynes
1. Alkynes are hydrocarbons with a triple
bond. A terminal alkyne has the triple
bond at the end of a chain; otherwise, it is
an internal alkyne. A compound with a
double and a triple bond is named as an
alkenyne; the double bond has the
greater priority only if there is a tie. OH
and NH 2 groups have priority over
double and triple bonds (6.1, 6.2).
2. Electrophiles add to the least substituted
sp carbon. Addition of HCl or HBr forms
CH2CH3
2 geminal dihalide is formed. Addition of
Cl2 or Br2 forms a dihaloalkene; excess
reagent forms a tetrahaloalkane (6.5, 6.6).
3. The acid-catalyzed addition of water to
an alkyne forms an enol, which
tautomerizes to a ketone. HgSO4 is used
with terminal alkynes (6.7).
4. Borane adds to an alkyne to form a vinyl-
borane, which is oxidized to an enol. An
internal alkyne tautomerizes to a ketone: a
terminal alkyne requires disiamylborane
and forms an aldehyde (6.8).
OH
H2O, H2SO4
CH3C CH2 CH3CCH3
HgSO4
a ketone
CH3C CH
OH
1. disiamylborane
CH3CH CH CH3CH2CH
2. HO−, H2O2, H2O
an aldehyde
5. Catalytic hydrogenation of an alkyne
forms an alkane. With Lindlar
catalyst, a cis alkene is formed; with
Na 1or Li2 + NH 3, a trans alkene is
formed via radical anion and vinyl
radical intermediates (6.9).
6. A terminal alkyne 1pKa 252 is
deprotonated with NaNH 2 to form an
acetylide ion, which reacts with a 1° alkyl
halide to form a longer-chain alkyne.
3
Working from product to reactants, when
designing a synthesis, is called
retrosynthetic analysis (6.10–6.12).
Chapter 7
Delocalized Electrons and Their
Effect on Stability, Reactivity, and pKa
1. Delocalized e ! are shared by three or
more atoms. Benzene has delocalized e -:
all the C ¬ C bonds have the same length;
the three pairs of p e - are shared by all
six carbons. Resonance contributors use
localized e - to approximate the true
structure with delocalized e - (the
resonance hybrid) (7.1–7.3).
a.
b. c.
2. Rules for drawing resonance contributors:
move only p and lone-pair e -. Move e - to
a positively charged atom or to an atom
with a p bond. Each resonance
contributor has the same net charge. The
greater the predicted stability of the
resonance contributor, the more it
contributes to the hybrid. Destabilizing
features: incomplete octet, positively
charged electronegative atom, charge
separation (7.4, 7.5).
3. Delocalization (resonance) energy is the
gain in stability that results from having
delocalized e -. The greater the number of
relatively stable resonance contributors,
the greater the delocalization energy.
Relative stabilities: conjugated dienes 7
isolated dienes 7 cumulated dienes.
Allylic and benzylic cations are more
stable than 1° alkyl cations because of e -
delocalization (7.6–7.8).
4. A molecular orbital (MO) results from a
linear combination of atomic orbitals
(LCAO). Two e - are placed in each MO,
starting from the lowest energy MO. The
number of MOs equals the number of
AOs; a node is added for each ascending
O
MO. The highest occupied MO (HOMO)
is the highest energy MO that contains e -;
O the lowest unoccupied MO (LUMO) is
the lowest energy MO that does not
contain e - (7.8).
5. Carboxylic acids and phenol have some
e - delocalization, but their conjugate
bases have more, causing carboxylic
acids 1pKa ' 52 and phenol 1pKa ' 102
to be stronger acids than alcohols
1pKa ' 152, which have no e -
delocalization. Protonated aniline
1pKa ' 52 is more acidic than protonated
alkylamines 1pKa ' 102 due to an
increase in delocalization energy upon
losing a proton (7.9).
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 4
6. Conjugated dienes form 1,2- and 1,4-
addition products. At low temperatures,
where the reaction is not reversible, the
kinetic product (the one that is formed
faster) is favored. At higher temperatures,
where the reaction is reversible, the
thermodynamic product (the more stable
product) is favored. The 1,2-product is
always the kinetic product; either the 1,2-
or 1,4-product can be the thermodynamic
product; it will depend on which is the
more substituted alkene (7.10, 7.11).
7. A conjugated diene reacts with a
dieneophile (an alkene with an e!
withdrawing group) to form a cyclohexene
via a concerted Diels-Alder reaction. The
diene adopts an s-cis conformation for this
[4 # 2] cycloaddition reaction where the
HOMO of one reactant interacts with the
LUMO of the other. The reaction is
stereospecific; e.g., a cis dienophile forms
cis products. Bridged, bicyclic products
favor the endo configuration when the
substituent has p e - (7.12).
nucleophile electron-withdrawing group
H
4
CH2
O
3C CH CCH3 30 ºC
2C CH2
H CH2
1 electrophile
a 1,4-addition reaction to 1,3-butadiene
Chapter 8
Substitution Reactions of Alkyl
Halides
1. Substitution reactions involve
replacement of a leaving group with a
nucleophile. Alkyl halides have good
leaving groups 1I -, Br -, Cl -2 (8.1).
− d+ d−
Nu + C X
a nucleophile
2. The reaction of bromomethane with HO -
is a bimolecular nucleophilic
substitution reaction 1SN22, with a rate
law dependent on [RX] and [HO -] (a
second-order reaction). HO - attacks with
simultaneous departure of the leaving
group. Steric effects govern the relative
rates with 1° alkyl halides faster than 2°,
and 3° very slow. The reaction occurs with
inversion of configuration because the
nucleophile (HOMO) interacts with the
s* (LUMO) on the backside of the carbon
attached to X (8.2).
the configuration of the
product is inverted relative
to the configuration of
the reactant
CH3 CH3
C + HO− C + Br−
H H
CH3CH2 Br HO
CH2CH3
(R)-2-bromobutane (S)-2-butanol
3. Leaving group tendencies for RX:
I - 7 Br - 7 Cl -. Strong bases are better
nucleophiles, except if there is a large
difference in size and they are in a protic
solvent, because of the greater
polarizability of the large nucleophile and
its weaker solvation (in which case I - is a
better nucleophile than F -). Aprotic polar
solvents (DMSO, DMF) are used in S N2
reactions of alkyl halides with negatively
charged nucleophiles because such
solvents solvate only cations (8.3, 8.4).
4. The reaction of a 3° alkyl halide with H 2O
is a unimolecular nucleophilic
substitution reaction 1SN12, with a rate
law dependent only on [RX] (a first-order
reaction). The leaving group leaves,
forming a carbocation that is attacked by
the nucleophile. Formation of the
carbocation is the rate-limiting step, so 3°
alkyl halides are the most reactive;
carbocation rearrangements can occur.
Products with inverted and retained
configurations are obtained. Partial
racemization can occur because one face
of the carbocation can be partially
H
4
CH2
O blocked by the leaving group (8.5–8.7).
3C CH CCH3 5. Benzylic and allylic halides undergo both
2C CH2 S N1 and S N2 reactions. Vinyl and aryl
H CH2
1 halides undergo neither S N1 nor S N2
reactions (8.8).
6. High concentration of a good nucleophile
favors S N2; a poor nucleophile favors
S N1. If a reactant is charged, increasing
the polarity of the solvent decreases the
rate of the reaction; if neither of the
reactants is charged, increasing the
polarity of the solvent increases the rate
of the reaction (8.9, 8.10).
7. Bifunctional molecules can undergo
intramolecular reactions to form cyclic
products. Five- and six-membered rings
C Nu + X − are favored (8.11).
8. A common cellular methylating agent is
S-adenosylmethionine (SAM), a methyl
substitution sulfonium ion (8.12).
product
Chapter 9
Elimination Reactions of Alkyl
Halides
1. An E2 reaction of an alkyl halide involves
the simultaneous removal of a proton
from a b-carbon and the halide ion from
the a-carbon (dehydrohalogenation) to
form an alkene (a B-elimination). An E1
reaction is a two-step reaction; the
leaving group departs (the rate-limiting
step), forming a carbocation, which loses
a proton from the b-carbon. Leaving
group order in both E2 and E1:
I - 7 Br - 7 Cl - 7 F - (9.1, 9.3).
2. E2 and E1 reactions are regioselective: the
more stable (more substituted) alkene is
the major product (the hydrogen is
removed from the b-carbon bonded to the
fewest hydrogens; Zaitsev’s rule), because
the transition state is alkene-like.
4
However, alkyl fluorides, with a poor
leaving group, preferentially form the less
substituted alkene, because the transition
state is carbanion-like. The relative
stabilities of carbanions are 1° 7 2° 7 3°,
the reverse of carbocation stabilities (9.2).
3. E2 and E1 reactions are stereoselective:
the alkene with the bulkiest groups on
opposite sides of the double bond is
favored (9.5).
4. In E2 reactions of substituted
cyclohexanes, both groups that are
eliminated must be in axial positions
because of anti elimination (9.6).
5. Under S N1/E1 conditions: 1° alkyl
halides do not react because primary
carbocations are too unstable to be
formed; 2° and 3° alkyl halides undergo
both substitution and elimination. Under
SN2/E2 conditions: 1° alkyl halides favor
substitution; 2° undergo both
substitution and elimination; 3° undergo
only elimination (9.8).
6. Bulky, strong bases (tert-butoxide) favor
E2 over S N2 due to steric hindrance. High
temperatures favor E2 over S N2 due to a
greater ¢S° (9.8).
7. Ethers are formed from alkoxide ions and
1° alkyl halides (Williamson ether
synthesis). Na or NaH converts an
alcohol to an alkoxide ion. Geminal and
vicinal dihalides react with excess -NH 2
to form alkynes (9.9, 9.10).
Chapter 10
Reactions of Alcohols, Amines,
Ethers, Epoxides, and Sulfur-
Containing Compounds
1. Alcohols and ethers have poor leaving
groups due to the strong basicity of HO -
and RO -. If protonated, they become
good leaving groups that can be replaced
by halide ions. These are S N1 reactions
(so carbocation rearrangements can
occur) except in the case of 1° alkyl
halides, which are S N2 reactions (10.1).
a weakly basic leaving group
+H ∆
CH3 O H + HBr CH3 OH CH3 Br + H2O
weak base
−
poor leaving good leaving Br
group group
2. Alcohols react with PBr3, PCl3, or thionyl
chloride 1SOCl22 to form alkyl halides.
Alcohols react with sulfonyl chloride to
form sulfonate esters (10-2, 10-3).
3. Alcohols undergo dehydration when
heated with a strong acid 1H 2SO42 to
form alkenes. These are S N1 reactions,
except in the case of 1° alcohols, which are
S N2. POCl3 + pyridine dehydrates
alcohols without carbocation formation,
so there are no rearrangements (10.4).
4. 2° alcohols are oxidized to ketones; 1°
alcohols are oxidized to carboxylic acids
with chromic acid 1H 2CrO42 and to
aldehydes with PCC (10.5).
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 5

5. Amines have poor leaving groups due to step and the product of the second high
frequency
Frequency (n) in Hz low
frequency

the very strong basicity of -NH 2. propagation step (11.2). 1019 1017 1015 1013 1010 105

Ammonium ions are weaker acids 2. Radical stability: 3° 7 2° 7 1°. Relative

Cosmic Ultraviolet Visible Infrared Radio waves
g-rays X-rays Microwaves
rays light light radiation NMR

1pKa ~102 than hydronium ions 1pKa ~ -22, rates for chlorination at room temp: 5: 3.8: short
10−6 10−4 10−1 0.4 0.8
Wavelength (l) in µm
102 106 1010
long
so amines are stronger bases and better 1 for 3°, 2°, 1°. Probability and reactivity wavelength wavelength

nucleophiles than alcohols (10.6). factors are used to predict product

6. Ethers are cleaved with HI; the reaction is
S N1 (breaking to form the more stable
carbocation) unless the alkyl groups
cannot form a carbocation (primary,
vinyl, aryl); then it is S N2 (with iodide ion
attacking the least sterically hindered
carbon) (10.7).
7. Epoxides react with nucleophiles. Under
acidic conditions, the ring opens to put
the developing positive charge on the
more substituted carbon; under basic
conditions, the nucleophile attacks the
less sterically hindered carbon (10. 8).
O asymmetric center, the product will be a
distribution (11.3, 11.4).
3. Relative rates for bromination at 125 °C:
1600 : 82 : 1 for 1°, 2°, 3°. A bromine 4. Stretching vibrations involve changes in
radical is less reactive and more selective bond length and occur at a higher energy
than a chlorine radical (reactivity- than bending vibrations, which involve
selectivity principle (11.5). changes in bond angles. Absorption
4.
#
When HBr adds to alkenes in the
presence of peroxide, Br is the
bands indicate the kind of bonds present
in a compound. Those in the functional
electrophile, so it adds to the sp2 carbon group region 14000–1400 cm-12 detect
bonded to the most hydrogens—opposite functional groups; those in the fingerprint
to the regioselectivity of HBr addition region 11400 – 600 cm-12 are characteristic
without peroxide (11.6). of the molecule as a whole (12.7, 12.8).
5. If a radical substitution reaction or a
radical addition reaction forms an
100
2.5 2.6 2.7 2.8 2.9 3 3.5 4 4.5 5
Wavelength (µm)
5.5 6 7 8 9 10

CH3CH CH2 racemic mixture (11.7).

6. Allylic and benzylic halides are O OH
selectively halogenated at the allylic or

% Transmittance
site of nucleophilic attack site of nucleophilic attack under CH3CCH2CCH3
under acidic conditions basic or neutral conditions
benzylic positions. Bromination of allylic CH3
positions is best carried out with
8. Arene oxides can undergo nucleophilic NBS + peroxide + ¢; if the resonance
C O
attack or can rearrange (via an NIH shift) hybrid of the radical intermediate is not 0
O H
4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 1800 1600 1400 1200 1000
to form phenols. Arene oxides that form symmetrical, two substitution products Wavenumber (cm−1)

unstable carbocations are more apt to are formed (11.8).

undergo nucleophilic attack (10.9).
9. Crown ethers form inclusion compounds
with metal ions based on molecular
recognition. Crown ethers can be used as
phase-transfer catalysts (10.10).
10. Thiols (RSH) are more acidic 1pKa ~102
than alcohols. Thiolate anions react with
alkyl halides to form sulfides (RSR);
sulfides react with alkyl halides to form
sulfonium salts 1R3S # X !2 (10.11).
11. Lithium reacts with alkyl halides to form
alkyllithium compounds; magnesium
reacts with alkyl halides to form Grignard
reagents. These organometallic
compounds are good nucleophiles; they
react as if they were carbanions. For
example, they react with epoxides to form
(after acidification) alcohols. In the
presence of H +, OH, or NH, organometallic
compounds form alkanes (10.12).
12. Gilman reagents 1R 2CuLi2 are formed
from alkyllithium compounds and CuI.
They couple with vinyl, aryl, and alkyl
halides, replacing the halogen. Catalytic
palladium is used to facilitate coupling
reactions with alkenes (Heck), stannanes
(Stille), and organoboranes (Suzuki) and
aryl, benzyl, or vinyl halides (10.13).
Chapter 11
Radicals • Reactions of Alkanes
1. Alkanes undergo halogenation with Cl2
or Br2 and heat or light to form alkyl
halides in a chain reaction that has
initiation, propagtion, and termination
steps. The radical formed in the initiation
step is the reactant of the first propagation
Chapter 12
Mass Spectrometry, IR Spectroscopy,
and UV/Vis Spectroscopy
1. An e - beam removes an e - to form a
molecular ion (a radical cation), which
then fragments. A magnetic field focuses
cations toward a detector, giving a mass
spectrum, which plots abundance versus
mass-to-charge (m/z) (12.1).
2. The molecular ion corresponds to the
nominal molecular mass. The base peak is
the highest abundance ion. M+1 peaks can
be used to determine the number of
carbons. For a chlorine-containing com-
pound, the M+2 peak is 1/3 the M peak;
for a compound that contains bromine, the
M+2 peak is equal to the M peak. High
resolution MS can determine the exact
molecular mass. The e - beam is most likely
to dislodge a lone-pair e -. A bond between
carbon and a more electronegative atom
breaks heterolytically; a bond between
carbon and an atom of similar electroneg-
ativity breaks homolytically. a-cleavage
(cleavage of the bond a to the heteroatom)
occurs because the positive charge is then
shared by two atoms (12.2–12.5).
3. Spectroscopy uses electromagnetic
radiation to probe molecular structure.
Frequency 1n2 is directly proportional to
energy 1E = hn2; wavelength 1l2 is
inversely proportional to energy
(E = hc/l; c = speed of light).
IR spectroscopy uses wavenumbers (the
number of waves in 1 cm), which are
directly proportional to energy and have
units of cm-1 (12.6).
5
5. The greater the change in dipole moment
when a bond vibrates, the more intense
the absorption. The energy required to
stretch a bond depends on the bond
strength and the masses of the bonded
atoms; stronger bonds and lighter atoms
absorb at higher frequencies (Hook’s
law); triple bonds are stronger than
double bonds, which are stronger than
single bonds. Electron delocalization can
affect bond order. C-H stretch frequency
depends on the hybridization of C
1sp 7 sp2 7 sp32. Alkene substitution
patterns can be identified in the
fingerprint region (12.9–12.11).
6. O ¬ H (of RCOOH and ROH) and N ¬ H
show absorption bands at the same
frequency, but their shapes are different.
The absence of bands can rule out
functional groups. Stretches with no net
change in dipole moment are IR inactive
(12.12–12.14).
7. UV/Vis spectroscopy involves excitation
of an e - to a higher energy state: n : p*
and p : p* transitions; the latter are
lower in energy and have greater molar
absorptivities 1e2. The greater the lmax,
the lower the energy: UV radiation
(180–400 nm) is of higher energy than
visible light (400–780 nm). A chromophore
is the group in the molecule that causes the
absorption. Absorbance depends on the
concentration of the sample, the length of
the light path, and the e of the compound
(Beer-Lambert Law) (12.15–12.17).
8. The more conjugated double bonds, the
greater the lmax (due to raised energy of
the HOMO and lowered energy of the
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 6
LUMO) and the greater the e. Colored
compounds absorb visible light.
Auxochromes (OH and NH 2) attached to
chromophores increase both lmax and e
(12.18, 12.19).
Chapter 13
NMR Spectroscopy
1. Nuclear magnetic resonance (NMR)
establishes atom connectivity. When
NMR active nuclei 11H, 13C, 15N, 19F, 31P2
are subjected to an applied magnetic
field, they align either with the field
1A-spin state2 or against the field
1B-spin state2. The energy difference
between the spin states depends on the
strength of the magnetic field 1B o2 and
the gyromagnetic ratio (13.1).
2. Nuclei resonate at different frequencies
due to shielding by nearby electrons that
induce a local magnetic field that opposes
the applied magnetic field, thereby
changing the effective magnetic field
1Beffective = Bapplied - Blocal2. Protons in
e - rich environments are shielded and
resonate at lower frequencies (upfield);
those in e - poor environments are
deshielded and resonate at higher
frequencies (downfield) (13.3, 13.6).
these protons sense a
larger effective magnetic
field, so come into resonance
at a higher frequency
Intensity
deshielded nuclei
"downfield"
Frequency
3. Chemically equivalent protons resonate
at the same frequency; nonequivalent sets
of protons resonate at different
frequencies. The chemical shift 1D2 is
independent of spectrometer frequency;
d = distance of the signal in Hz from TMS
divided by spectrometer frequency in
MHz. Low frequency (shielded) signals
have small d values (13.4, 13.5).
4. In a similar environment, a signal for CH 3
is at a lower frequency than a signal for
CH 2, which is at a lower frequency than a
signal for CH. Induced ring currents
cause sp2-bound protons (aryl and vinyl)
and sp-bound protons to experience
diamagnetic anisotropy and resonate at
7–5 ppm and 2.4 ppm, respectively (13.7,
13.8).
O
H Z
H C
C H C C
O C
C OH
vinylic
Z = O, N, halogen
12 9.0 8.0 6.5 4.5
d (ppm)
5. Integration indicates the relative
number of protons responsible for each
signal. A signal has a multiplicity
according to the N # 1 rule, where N is
the number of neighboring equivalent
protons bonded to adjacent carbons.
Splitting occurs as a result of the
proton(s) that give rise to the signal being
coupled to adjacent nonequivalent
protons whose nuclear spins can align
either with or against the applied
magnetic field (13.9, 13.10).
c a b
ClCH2CH2CH2I
3.7 3.6 3.5 PPM 3.4 3.3
8 7 6 5
6. The coupling constant (J) is the distance
(in Hz) between adjacent peaks in a signal.
The coupling constant for H a being split
by H b is denoted by Jab. The signals of
coupled protons have the same coupling
constant. The number of observed peaks
in a signal can be explained by a splitting
diagram. When the coupling constants of
these protons sense a
two sets of nonequivalent adjacent
smaller effective magnetic protons are similar, the signal multiplicity
field, so come into resonance
at a lower frequency is the same as if the adjacent sets were
equivalent (13.12, 13.13).
7. Two hydrogens bonded to a carbon that is
shielded nuclei
bonded to two different groups are called
enantiotopic hydrogens; one is a pro-S-
hydrogen, the other a pro-R-hydrogen,
and the carbon is prochiral. Enantiotopic
"upfield" hydrogens are equivalent. If the
compound has an asymmetric center, the
two hydrogens are diastereotopic
hydrogens; they are not equivalent, so
they produce different signals (13.14).
8. NMR spectra show an average of various
conformers at room temperature.
Hydrogens involved in proton exchange
(OH, NH 2) are not split and do not split;
they appear as broadened singlets
(13.15, 13.16).
9. 13C NMR determines the types of
carbons present in a compound (0–200
ppm). The signals cannot be integrated
and are not split unless the spectrum is
run in a proton-coupled mode. The
multiplicity is determined by the N+1
rule, where N is the number of
hydrogens bonded to the carbon that
produces the signal (13.19).
O H
C C C C
C H H C C H C O
C C C saturated
2.5
allylic
1.5 0 200 150
Chapter 14
#
Aromaticity Reactions of Benzene
1. Aromatic compounds have large
delocalization energies: benzene is 36
kcal/mol more stable than hypothetical
‘cyclohexatriene.’ To be aromatic, a
compound must have an uninterrupted
cloud of p electrons (that is, it must be
cyclic, planar, and every ring atom must
have a p orbital), and the p cloud must
contain an odd number of pairs of p e -
(Hückel’s 4n # 2 rule) (14.1, 14.2).
2. Cyclobutadiene and cyclooctatetraene,
with an even number of pairs of p e -, are
not aromatic. The cyclopentadienyl anion
2
and the cyloheptatrienyl cation, each
with three pairs of p e -, are aromatic.
2
Pyridine, pyrrole, furan, and thiophene
2 (heterocyclic compounds) are aromatic
(14.1, 14.2).
3.2 PPM 2.3 2.2 2.1 PPM
4 3 2 1 0
d (ppm)
frequency
N O S
N H
pyridine pyrrole furan thiophene
3. The pKa of cyclopentadiene is unusually
low (15) due to its aromatic conjugate
base. Cycloheptatrienyl bromide ionizes
readily due to its aromatic cation.
Antiaromatic compounds, with an
uninterrupted cloud of p electrons that
contains an even number of pairs of p e -,
are less stable than analogous compounds
with localized e -. Frost circle diagrams
are used to assign relative energies to the
MOs of cyclic compounds (14.5–14.7).
4. Some monosubstituted benzenes have
names that incorporate the substituent
(toluene, phenol, aniline, benzenesulfonic
acid, anisole, styrene, benzaldehyde,
benzoic acid, benzonitrile). A benzene
substituent is a phenyl group (Ph-); a
phenyl methyl substituent is a benzyl
group 1PhCH 2-2 (14.8).
5. Aromatic compounds undergo
electrophilic aromatic substitution
reactions, which replace a hydrogen with
an electrophile. Halogenation employs
Br2 + FeBr3 or Cl2 + FeCl3 (14.9–14.11).
+ H Br
+ −
+ Br Br FeBr3 Br B
+ HB+
−
+ FeBr4
6. Nitration employs nitric acid and sulfuric
acid; the nitronium ion 1+NO22 is the
electrophile. Sulfonation uses sulfuric
acid; the sulfonium ion 1+SO3H2 is the
electrophile. This reaction is reversible at
C N
C Cl 100 °C (14.12, 14.13).
Br
7. Friedel-Crafts acylation employs an acyl
C
sp3 carbon chloride or an acid anhydride + AlCl3 (the
C O
100 50 0
acylium ion is the electrophile) and forms a
d (ppm) phenyl ketone. Friedel-Crafts alkylation
6
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 7
employs an alkyl halide + AlCl3 (a
carbocation is the electrophile); an
alkylbenzene is the product. A carbocation
generated from an alkene or an alcohol can
also be used. Carbocations can rearrange;
therefore, a benzene ring with a straight-
chain alkyl group is synthesized by
Friedel-Crafts acylation, followed by
reduction with H 2, Pd/C, or
Zn1Hg2 + HCl + ¢ (Clemmensen), or
H 2NNH 2 + NaOH + ¢ (Wolff-
Kishner). Alkylbenzenes with straight-
chain alkyl groups can also be prepared by
Stille and Suzuki reactions (14.13–14.18).
8. Bromination of an alkylbenzene at the
benzylic position allows subsequent
substitution and elimination reactions.
Oxidation with KMnO4 or Na 2Cr2O7/H +
converts alkyl groups to COOH groups.
Mild oxidation of a 1° or 2° benzyl alcohol
with MnO2 produces benzaldehyde or a
phenyl ketone, respectively.
Nitrobenzenes are reduced to anilines
with Sn + HCl followed by HO - or with
H 2, Pd/C (14.19).
Chapter 15
Reactions of Substituted Benzenes
1. Disubstituted benzenes can be named
using ortho (1,2), meta (1,3), and para
(1,4) designations. Substituents are listed
alphabetically, or one of the substituents
is incorporated into the parent name. In
polysubstituted benzenes, the
substituents are numbered in the
direction that results in the lowest
possible numbers (15.1).
NH2
Cl
CH3
NO2
2-chlorotoluene
ortho-chlorotoluene
4-nitroaniline
para-nitroaniline
ortho-ethylphenol
not not
ortho-chloromethylbenzene para-aminonitrobenzene ortho-ethylhydroxybenzene
2. Groups that donate e - either by resonance
or by hyperconjugation activate a benzene
ring toward electrophilic aromatic
substitution; groups that withdraw e -
either by resonance or by inductive
electron withdrawal deactivate it. The
position to which a substituent directs an
incoming substituent depends on which
of the three possible carbocation
intermediates is the most stable.
Activating groups and the mildly
deactivating halogens are ortho-para
directors; all groups more deactivating
than the halogens are meta directors. All
ortho-para directors (except alkyl, aryl,
RCH “ CHR) have a lone pair on the
atom attached to the ring; all meta
directors have a positive or partial
positive charge on the atom attached to
the ring (15.2, 15.3).
3. Deactivating substituents stabilize the
conjugate bases of phenols, carboxylic
acids, and anilinium ions, making the
acids more acidic (lowering their pKa);
activating substituents make the
compounds less acidic (15.4).
4. The relative amounts of ortho and para
products depend on the size of the
directing and incoming substituents.
Benzene rings with highly activating
substituents are monohalogenated with-
out a catalyst and polyhalogenated with
it. A benzene ring with a meta-directing
substituent cannot undergo a Friedel-
Crafts reaction. Anilines form ammonium
ions (strongly deactivating meta
directors) with Lewis acids (15.5, 15.6).
5. When a disubstitued benzene ring
undergoes an electrophilic aromatic
substitution reaction, a strongly activating
substituent wins out over a weakly acti-
vating or deactivating substituent (15.8).
6. Arenediazonium salts 1ArN2 +2,
produced from aniline using nitrous acid
1NaNO2 + HCl2 undergo substitution
with CuCl, CuBr, CuCN (Sandmeyer
reaction), KI, HBF4 (Schiemann
reaction), and form phenols with
Cu 2O, Cu1NO322, H 2O. The diazonium
group can be replaced by an H with
H 3PO2. ArN2 + reacts with strongly
activated benzene rings via electrophilic
aromatic substitution to form colored azo
compounds. Diazonium ion formation
results from reaction of a 1° aniline (or
amine) with a nitrosonium ion
1+N=O2; 2° anilines form N-
nitrosoamines; with 3° anilines, the
nitrosonium ion is an electrophile that
replaces an H of benzene (15.9–15.11).
7. Aryl halides with strongly electron-
OH
CH2CH3 withdrawing substituents in the ortho
and/or para positions undergo
nucleophilic aromatic substitution
2-ethylphenol
reactions 1SNAr2 with good nucleophiles
not
(HO -, RO -, amines). Halobenzenes react
with NaNH 2 to form anilines via a
benzyne intermediate (15.12, 15.13).
8. Polycyclic benzenoid hydrocarbons with
fused rings (naphthalene, anthracene,
phenanthrene, etc.) undergo reactions
similar to the ones that benzene
undergoes (15.14).
Chapter 16
Carbonyl Compounds I
1. Carbonyl compounds have a carbonyl
group 1C=O2. Carboxylic acid
derivatives have an acyl group 1RC=O2
bonded to OH, Cl, OC1=O2R, OR, NH2,
NHR, NR 2; these groups can be substi-
tuted by another group. Acyl groups
bonded to H or R do not posses a group
that can be substituted by another group.
The parent name for carboxylic acid is
alkanoic acid. The positions adjacent to
the carbonyl carbon are a, b, g, d, e in
common nomenclature (16.1).
7
O O
C C
CH3CH2CH2CH2 OH CH3CH2CH2CH2CH2 OH
pentanoic acid hexanoic acid
valeric acid caproic acid
O O
C C
CH2 CH OH OH
propenoic acid benzenecarboxylic acid
acrylic acid benzoic acid
2. Nomenclature: an acyl halide is an
alkanoyl halide, an acid anhydride is a
alkanoic anhydride, an ester is an alkyl
alkanoate (where the alkyl prefix refers to
the group bonded to the carboxyl oxygen),
a lactone (a cyclic ester) is a
2-oxacycloalkanone, an amide is an
alkanamide with N-alkyl as a prefix , if
necessary; a lactam (a cyclic amide) is a
2-azacycloalkanone, a nitrile is an
alkanenitrile (16.1).
3. The carbonyl carbon and carbonyl
oxygen are sp2 hybridized; carboxylic
acids, esters, and amides are stabilized by
e - delocalization. Elevated boiling points
of carboxylic acids and amides are due to
hydrogen bonds and dipole-dipole
interactions (16.2, 16.3).
4. Carboxylic acid derivatives undergo
nucleophilic acyl substitution reactions
via a tetrahedral intermediate that expels
the weakest base. The order of reactivity:
acyl chloride 7 acid anhydride 7
ester ' acid 7 amide. More reactive
carboxylic acid derivatives are converted
to less reactive ones (16.5–16.7).
a group is
expelled
O sp2 sp3 O
−
O sp2
k1 k2
C + Z
−
k−1
R C Y
k−2
C + Y
−
R Y R Z
Z
nucleophile attacks
a tetrahedral intermediate
the carbonyl carbon
5. Acyl halides react with carboxylate ions to
form acid anhydrides, with alcohols to
form esters, with water to form carboxylic
acids, and with excess amine to form
amides. Acid anhydrides react with
alcohols to form esters, with water to form
carboxylic acids, and with excess amine to
form amides. The reaction of esters with
excess water to form carboxylic acids or
with excess alcohol to form a new ester
requires a catalyst; H + (Fischer
esterification) or HO - for hydrolysis, and
H + or RO - for transesterification. Esters
undergo aminolysis with amines to form
amides (16.8–16.12).
6. Hydrolysis of an ester with a 3° alkyl
group occurs via a carbocation (16.11).
7. Triesters of glycerol (fats and oils) are
hydrolyzed under basic conditions
(saponification) to form sodium
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 8

carboxylates (soaps), which form reduced to 1° alcohols and amides are Chapter 18
micelles in water ordered by reduced to amines. Diisobutylaluminum Carbonyl Compounds III
hydrophobic interactions (16.14). hydride reduces esters to aldehydes at 1. Aldehydes, ketones, and esters have
8. Reactions of carboxylic acids with amines -78 °C (17.6). acidic a-hydrogens, because the electrons
form ammonium carboxylate salts. 5. Ketones and aldehydes add cyanide ion left behind when the proton is removed
Amides react with water and alcohols to form cyanohydrins. Aldehydes and are delocalized onto oxygen, forming an
under acidic conditions to form ketones react with 1° amines to form enolate. Aldehydes and ketones (pKa 16-
carboxylic acids and esters, respectively. imines (Schiff base) and with 2° amines 20) are more acidic than esters (pKa 25).
Dehydrating reagents 1P2O5, POCl32 to form enamines (a,b-unsaturated b-Dicarbonyl compounds
convert amides without a substituent on tertiary amines). Imines and enamines ( B-keto esters, B-diketones) have
the N to nitriles (16.15–16.17). can be hydrolyzed to carbonyl enhanced acidity (pKa 6-10). Keto and
9. Alkyl halides are converted to 1° amines compounds and amines under acidic enol tautomers are in equilibrium.
using the reaction of phthalimide anion conditions. Hydroxylamine forms Enolization can be catalyzed by acid or by
with an alkyl halide to form an oximes; hydrazine forms hydrazones. base (18.1–18.4).
N-substituted imide, which is hydrolyzed Imines and enamines are reduced to
(Gabriel synthesis). Nitriles, formed by amines with H 2, Pd/C, or with sodium O O O
−
O
an S N2 reaction of an alkyl halide with triacetoxyborohydride (reductive C C C C
RCH R RCH R RCH R RCH R
cyanide ion, are hydrolyzed with acid amination) (17.7, 17.8). H
−
+ H2O E+ E
and heat to produce carboxylic acids. −
HO
enolate ion A-substituted product

Catalytic hydrogenation of a nitrile forms H H

a 1° amine (16.18, 16.19). C C
2. Ketones and aldehydes react with
10. Carboxylic acids are activated in the lab C O + R NH2 C N + H2O
halogens under acidic conditions to form
with SOCl2, PCl3, or PBr3, which converts R a-halo carbonyl compounds; under basic
them to acyl halides. Carboxylic acids are an aldehyde or a primary amine an imine conditions multihalogenation occurs.
activated in the cell with ATP to form acyl
a ketone a Schiff base
Methyl ketones react with HO - and I 2 to
phosphates, acyl pyrophosphates, or acyl form carboxylate ions and iodoform
a, b-position
adenylates, or by being converted to H (haloform reaction) (18.5).
thioesters. Diacids include oxalic, C R C R 3. Carboxylic acids react with P + Br2 and
malonic, succinic, glutaric, adipic, and C O + NH C N + H2O water to form a-bromocarboxylic acids
phthalic acids (16.20–16.23). R R (Hell-Volhard-Zelinski reaction) (18.6).
an aldehyde or a secondary amine an enamine
a ketone 4. LDA removes an a-hydrogen to form an
Chapter 17 enolate, which undergoes alkylation with
6. As a result of steric and electronic effects, 1° alkyl halides. The a-carbon can also be
Carbonyl Compounds II
ketones form less hydrate than do alkylated (or acylated) via an enamine
1. An aldehyde is named as an alkanal, and
aldehydes. Aldehydes react with alcohols (18.8–18.10).
a ketone as an alkanone (17.1).
2. Aldehydes and ketones undergo +H + to form acetals via a hemiacetal 5. a,b-Unsaturated carbonyl compounds
intermediate; ketones form ketals. Acetals undergo conjugate addition with
nucleophilic addition reactions. Steric
effects and crowding in the tetrahedral and ketals are hydrolyzed (with H + ) back b-dicarbonyl anions (Michael reaction)
to aldehydes and ketones. or with enamines (Stork enamine
intermediate cause aldehydes to be more
1,2-Diols and 1,3-diols 1+acid2 form reaction) (18.11).
reactive than ketones (17.2, 17.3).
cyclic acetals that can be used as a 6. Aldehydes and ketones react with HO - to
protecting group. Thioketals are formed form b-hydroxyaldehydes and
a nucleophile that is a strong base
O O− OH
from thiols, which are reduced with H 2 b-hydroxyketones (aldol addition), as a
C + Z
−
R C R'
HB+
R C R'
and Raney Ni to alkanes (17.9–17.12). result of the addition of an enolate of one
R R'
Z
B
Z
molecule to the carbonyl carbon of
O OH OCH3 another. Heating with acid or base causes
HCl CH3OH, HCl
the reaction is irreversible product of nucleophilic
addition
C + CH3OH R C H R C H + H2O loss of water (aldol condensation).
because Z is too basic to R H
be expelled OCH3 OCH3 Enolates formed with LDA react with
an aldehyde a hemiacetal an acetal
aldehydes and ketones (added slowly),
3. Grignard reagents react with forming aldol products (mixed aldol
formaldehyde to form 1° alcohols 7. Phosphonium ylides react with addition) (18.12–18.14).
(following protonation of the alkoxide aldehydes and ketones to form alkenes
OH
ion); aldehydes form 2° alcohols, ketones (Wittig reaction). A prochiral carbonyl O O
O
O
1. CH3CH2CH2CH CHCH2CH2CH3
form 3° alcohols, and reaction with carbon carbon, with Re and Si faces, reacts with LDA − add slowly
dioxide forms a carboxylic acid. Acyl achiral nucleophiles to form R and S 2. H2O

chlorides and esters add two equivalents products. Retrosynthetic analysis allows
of Grignard reagent to form 3° alcohols. for multistep planning by disconnection 7. An ester with two !-hydrogens reacts
Acetylide ions also form nucleophilic and synthons, and synthetic equivalent with RO - (corresponding to its alkoxy
addition products with aldehydes and identification (17.13–17.15). group) to form a b-keto ester (Claisen
ketones (17.4, 17.5). 8. A,B-Unsaturated carbonyl compounds condensation) after acidification.
4. Aldehydes and ketones react with NaBH 4 undergo conjugate addition with weakly A mixed Claisen condensation leads to
to form 1° and 2° alcohols, respectively. Acyl basic nucleophiles (cyanide ion, thiols, primarily one product if an ester with
chlorides add two equivalents of hydride amines, Gilman reagents); with strongly a-hydrogens is added slowly to an ester
ion to form 1° alcohols. Esters, carboxylic basic nucleophiles (Grignard reagents and without a-hydrogens. An intramolecular
acids, and amides are too unreactive to be hydride ion), reactive carbonyl groups Claisen condensation (Dieckmann
reduced by NaBH 4; LiAlH 4 must be used. undergo direct addition, and less reactive condensation) forms cyclic b-keto esters;
Two equivalents of hydride ion add to these carbonyl groups undergo conjugate 5- and 6-membered rings are favored.
compounds: esters and carboxylic acids are addition (17.16–17.18). Intramolecular aldol additions also favor
8
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 9

Chapter 20
#
5- and 6-membered ring products. HC O HC O CH2OH CH2OH

A Michael addition combined with an More About Amines Heterocyclic

H C OH H OH C O C O
HO C H HO H HO C H HO H
intramolecular aldol condensation forms
a compound with a 2-cyclohexenone ring
Compounds H C OH H OH H C OH H OH

1. Amines are bases and nucleophiles. H C OH H OH H C OH H OH

(Robinson annulation) (18.15–18.17).
8. 3-Oxocarboxylic acids lose CO2
(decarboxylate) when heated. Malonic
ester is alkylated, hydrolyzed with acid,
and decarboxylated to form a carboxylic
acid (malonic ester synthesis); acetoacetic
ester is alkylated, hydrolyzed, and
decarboxylated to form a methyl ketone
(acetoacetic ester synthesis) (18.18–18.20).
malonic ester synthesis
O O
C C 1. CH3CH2O−
C2H5O CH2 OC2H5 2. RBr
R CH2
3. HCl, H2O, ∆
diethyl malonate
malonic ester
from the alkyl halide
Chapter 19
More About Oxidation-Reduction
Reactions
1. Reduction increases the number of C ¬ H
bonds or decreases the number of
C ¬ O, C ¬ N, or C ¬ X bonds
1X = halogen2. Oxidation decreases the
number of C ¬ H bonds or increases the
number of C ¬ O, C ¬ N, or C ¬ X bonds.
Reducing agents are oxidized; oxidizing
agents are reduced. There are three
mechanisms for addition of H 2: H # + H #
(catalytic hydrogenation);
e - + H + + e - + H + (dissolving-metal
reduction); and H - + H + (metal-hydride
reduction) (19.1).
2. Chromic acid oxidation converts 1°
alcohols to carboxylic acids and 2° alcohols
to ketones. Swern oxidation (with DMSO,
oxalyl chloride, Et3N) converts them to
aldehydes and ketones, respectively (19.2).
3. Tollens reagent oxidizes aldehydes to
carboxylic acids (Tollens test). Peroxyacid
oxidizes aldehydes to carboxylic acids
and ketones to esters (Baeyer-Villiger
Heterocyclic compounds possess one or
wedge-and-dash
more heteroatoms (N, O, S) in a ring.
Cyclic amines are named as
azacycloalkanes or use common names:
aziridine, azetidine, pyrrolidine,
piperidine (20.1).
2. Quaternary ammonium ions react with
hydroxide ion and heat to form alkenes
(Hofmann elimination reaction). The
transition state has carbanion character,
O
so the less substituted amine is the major
C
OH product (the hydrogen is removed from
from malonic ester the b-carbon bonded to the most
hydrogens). Amines react with excess
methyl iodide to form quaternary
ammonium iodides (exhaustive
methylation), which are converted by
Ag2O to quaternary ammonium
hydroxides (20.4).
3. Quaternary ammonium ions are used as
phase-transfer catalysts (20.5).
4. 3° amines are oxidized to amine oxides
with peroxide, which eliminate when
heated to form the least substituted
alkene (Cope elimination). 2° amines are
oxidized to hydroxylamines and 1°
amines to nitro compounds (20.6).
5. Aromatic 5-membered ring
heterocycles (pyrrole, furan,
thiophene) are more reactive than
benzene toward electrophilic aromatic
substitution; they form 2-substituted
products. The pyridinium ion, with an
sp2 N, is more acidic 1pKa ~52 than an
alkylammonium ion. Pyridine is less
reactive than nitrobenzene toward
electrophilic aromatic substitution,
which occurs at the 3-position. Pyridine
is more reactive than benzene toward
nucleophilic aromatic substitution,
which occurs at the 2- and 4-positions
CH2OH CH2OH CH2OH CH2OH
Fischer projection wedge-and-dash Fischer projection
structure structure
D-glucose D-fructose
a polyhydroxy aldehyde a polyhydroxy ketone
2. Under basic conditions, monosaccharides
are converted to a mixture of aldoses and
ketoses through enolate intermediates.
Sugars are reduced to alditols with
NaBH 4 and are oxidized by Br2 or
Ag +/NH 3 to aldonic acids and by nitric
acid to aldaric acids. Monosaccharides
form osazones with excess
phenylhydrazine (Sec. 21.5–21.7).
3. The Kiliani-Fischer synthesis increases
the chain by one carbon, forming C-2
epimers. The Wohl degradation decreases
the chain by one carbon (21.8, 21.9).
4. Pentoses and hexoses exist in solution as
furanoses and pyranoses, which are
hemiacetals or hemiketals. The anomers
are in equilibrium in solution: a (right in a
Fischer projection, down in a Haworth
projection, axial in a chair conformer); b
(left in a Fischer, up in a Haworth,
equatorial in a chair). The optical rotation
changes when a pure anomer is placed in
solution (mutarotation). b -D-Glucose
(64% at equilibrium) has all its groups in
equatorial positions (21.11, 21.12).
5. Hemiacetals or hemiketals of sugars
react with ROH + H +, forming acetals
and ketals (glycosides: furanosides and
pyranosides); the new bond to OR is a
glycosidic bond. The mechanism
involves an oxocarbenium ion. The
a-glycoside is the major product due to
favorable n-s* e - overlap (the anomeric
effect) (21.13, 21.14).
CH2OH CH2OH
a glycosidic bond

oxidation). Migration tendencies: (20.8, 20.9). HO

O CH3CH2OH HO
O
OH HCl OCH2CH3
H 7 tert-alkyl 7 sec-alkyl = HO
OH
HO
OH
H H
phenyl 7 primary alkyl 7 methyl (19.3). -D-glucose ethyl -D-glucoside
4. Enantioselective reactions (which form -D-glucopyranose ethyl -D-glucopyranoside

more of one enantiomer than another) use Chapter 21 +

enzymes or enantiomerically pure Carbohydrates CH2OH
catalysts (19.4). 1. Carbohydrates are polyhydroxy HO
O
H
5. Alkenes react with basic, cold KMnO4 or aldehydes (aldoses) or polyhydroxy HO
OH
with OsO4 to form vicinal diols. Cyclic ketones (ketoses). Monosaccharides ethyl -D-glucoside
OCH2CH3

alkenes form cis-1,2-diols via syn addition have one sugar unit, disaccharides have ethyl -D-glucopyranoside

(19.5). two, oligosaccharides have 3–10, and

6. Vincinal diols undergo oxidative polysaccharides have many.
cleavage with periodate to form D-glyceraldehyde (a triose) has the
aldehydes and ketones. Ozone reacts with R-configuration. Naturally occurring
alkenes (ozonolysis); ketones and sugars are D-sugars—the bottom-most
aldehydes are formed when the ozonide is asymmetric center in a Fischer projection
treated with Zn or 1CH 322S; ketones and has the OH group on the right. Erythrose
carboxylic acids are formed when it is and threose are tetroses; ribose is a
treated with peroxide (19.6-19.7). pentose; glucose and fructose are
7. Ozone reacts with alkynes to form hexoses. Mannose is the C-2 epimer of
carboxylic acids. Oxidation reactions and glucose; galactose is the C-4 epimer.
others allow for functional group Ketoses have a keto group at C-2
interconvertion (19.8, 19.9). (21.1–21.4).
9
6. Straight-chain sugars, hemiacetals, and
hemiketals are reducing sugars; acetals and
ketals are non-reducing sugars (21.15).
7. Starch is composed of amylose and
amylopectin; both are polysaccharides of
glucose. Amylose has a-1,4¿- glycosidic
linkages; amylopectin has a-1,4¿ and
a-1,6¿-linkages. Glycogen has more
branches than amylopectin. Cellulose is a
polysaccharide of glucose with
b-1,4¿-linkages; chitin has N-acetyl groups
at the 2-positions of cellulose (21.17).
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 10
Chapter 22
Amino Acids, Peptides, and Proteins
1. Peptides and proteins are polymers of
amino acids. Dipeptides have two
amide-linked amino acids; tripeptides
have three and polypeptides have many;
proteins have 40–400. Naturally
occurring amino acids have the
L-configuration (22.1, 22.2).
O O
C C
R CH OH NHCH
+
NH3
a protonated
R R′
amino acids are linked together by amide bonds
A-aminocarboxylic acid
an amino acid
2. The pKa of the carboxylic acid group of an
amino acid is ' 2; that of the ammonium
group is ' 9. At physiological pH (7.3),
amino acids are zwitterions (22.3).
O O
C C
R CH OH R CH
+
NH3 +
NH3 + H+
pH = 0 a zwitterion
pH = 7
3. The isoelectric point (pI), the pH at which
the amino acid has no net charge, is found
by averaging the pKa’s for neutral side
chain amino acids, and by averaging the
like charge pKa’s for amino acids with
ionizable side chains (except Cys and
Tyr). Electrophoresis separates amino
acids based on pI values; paper and thin-
layer chromatography separates them
based on polarity. Ion-exchange
chromatography separates and quantifies
amino acids based on charge and polarity.
Ninhydrin reacts with amino acids to
form a colored product (22.4, 22.5).
4. Amino acids are synthesized from
carboxylic acids by a-bromination
followed by reaction with NH 3; by
reductive amination of a-keto acids; by
the N-phthalimidomalonic ester
synthesis; or by the acetamidomalonic
ester synthesis. A racemic mixture of
amino acids can be separated via a kinetic
resolution with an enzyme (22.6, 22.7).
5. Peptide bonds have double bond character
due to electron delocalization. In writing
an amino acid sequence, the N-terminal
amino acid is on the left, the C-terminal is
on the right. Disulfide bonds are formed
between cysteine side chains (22.8).
O R a-carbon
C CH
CH N CH
a-carbon R H
resonance contributors
6. t-BOC protects amino groups; DCC
activates carboxyl groups. Automated
solid-phase peptide synthesis
synthesizes polypeptides from the
C-terminal end (22.10, 22.11).
7. The primary structure of a protein is the
sequence of amino acids and the location
of the disulfide bridges. 2-Mercapto-
ethanol cleaves disulfide bonds. Dilute
acid partially hydrolyzes peptides into
smaller fragments. Edman’s reagent
identifies the N-terminal amino acid.
Peptidases, enzymes that hydrolyze
peptide bonds, include carboxypeptidase
A and B (exopeptidases), which cleave
amide bonds
the C-terminal amino acid, and
O O endopeptidases: trypsin, chymotrypsin,
C C and elastase. Cyanogen bromide cleaves
NHCH NHCH O− at the C-side of Met (22.12, 22.13).
R′′
8. Secondary structure describes the
repetitive conformations assumed by
segments of the protein backbone: an
A-helix (right-handed coil with 3.6 amino
acids/turn); a B-pleated sheet (extended
hydrogen bonded conformation in
parallel or antiparallel orientation); and
a coil (loop) conformation (22.14).
O molecular recognition. In the lock-and-key
a. b.
C
O− R CH O−
NH2 + H+
pH = 11
hydrogen
bond
9. Tertiary structure, the 3D structure of the
protein, is maintained by disulfide bonds,
hydrogen bonds, hydrophobic
interactions, and electrostatic attractions.
Quaternary structure describes the
arrangement of protein subunits.
Denaturation by pH change, urea,
detergent, solvents, or by heat or agitation
forms a random coil (22.15–22.17).
Chapter 23
Catalysis
1. A catalyst increases the rate of a reaction
(without being consumed) by decreasing
the free energy of activation ( ¢G‡) (23.1).
‡
∆Gcatalyzed ‡
∆Guncatalyzed
a one-step
mechanism
Free energy
a two-step
mechanism
O− R
C +
CH
N 3. Vitamin B2 (riboflavin) is a precursor for
R H
Progress of the reaction
2. An acid catalyst increases the rate of a
reaction by donating a proton: before the
slow step in specific-acid catalysis; during
10
the slow step in general-acid catalysis.
A base catalyst increases the rate by
removing a proton: before the slow step in
specific-base catalysis; during the slow
step in general-base catalysis (23.2, 23.3).
3. A nucleophilic (covalent) catalyst
increases the rate by forming a new
covalent bond with the reactant, resulting
in formation of a more reactive species
(23.4).
4. Metal-ion catalysis makes a group more
susceptible to nucleophilic attack, makes
a group a better leaving group, or makes
water a better nucleophile by lowering its
pKa (23.5).
5. Intramolecular reactions occur with
faster rates compared with intermolecular
reactions. Intramolecular catalysis occurs
when the catalyst and the reaction center
are in the same molecule (23.6).
6. Enzymes (biological catalysts) bind their
substrate in an active site based on
model, the substrate fits into the active
site like a key fits into a lock; in the
induced-fit model, the enzyme changes its
conformation to become complementary
to the shape of the substrate after binding
it. The catalytic ability of an enzyme
results from bringing reacting and
catalytic groups together. A pH-activity
profile can be used to assess participation
of ionizable groups (23.8, 23.9).
Chapter 24
The Organic Mechanisms of the
Coenzymes
1. Cofactors are metal ions or organic
molecules (coenzymes) that some
enzymes need to catalyze a reaction. An
enzyme with its cofactor is a holoenzyme;
without its cofactor it is an apoenzyme.
All the water-soluble vitamins (except
vitamin C) and water-insoluble vitamin K
are precursors for coenzymes (24.1).
2. Vitamin B3 (niacin) is a precursor for
NAD # and NADP # that are oxidizing
agents and for NADH and NADPH that
are reducing agents (24.2).
a basic group of an
amino acid side chain
O H B
O H B– C
C R R
O O
H
4 oxidation of substrate
H H
3 CNH2 CNH2
5 reduction of coenzyme
6 2
1
N+ N
R R
FAD and FMN that catalyze oxidation
reactions. FAD catalyzes the oxidation of
thiols to disulfides and amines to imines;
FADH2 is a reducing agent (24.3).
4. Vitamin B1 is the precursor to thiamine
pyrophosphate (TPP) that catalyzes the
transfer of a two-carbon unit (24.4).
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 11
5. Biotin, from vitamin H, catalyzes the
carboxylation of the a-carbon of pyruvate
and acetyl-CoA (24.5).
6. Pyridoxal phosphate (PLP), from vitamin
B6, catalyzes amino acid transformations
including decarboxylation,
transamination, racemization, and
Ca —Cb bond cleavage (24.6).
7. Coenzyme B12, from vitamin B12, is a
cobalt-coordinated porphyrin compound
that catalyzes certain isomerization
reactions (24.7).
8. A substituted tetrahyrofolate (THF), from
folic acid, transfers a one-carbon unit
(methyl, methylene, formyl) to its
substrate. 5-Fluorouracil is a suicide
inhibitor. Methotrexate and wafarin are
competitive inhibitors (24.8, 24.9).
9. Vitamin KH2, from vitamin K, carboxy-
lates the g-carbon of glutamate (24.9).
Chapter 25
The Chemistry of Metabolism
1. Metabolism consists of catabolic
reactions that break down compounds to
release energy and anabolic reactions
that require energy to synthesize
compounds. Catabolism has four stages:
stage 1 involves the hydrolysis of fats,
carbohydrates, and proteins; in stage 2
the products of the first stage are
converted to pyruvate, acetyl-CoA, or
citric acid cycle intermediates; stage 3 is
the citric acid cycle; ATP is synthesized in
stage 4 (25.1).
2. ATP is used in phosphoryl transfer
reactions. ATP hydrolysis is favored due to
electrostatic repulsion, enhanced solvation,
and e - delocalization. ATP, because of its
negative charges, is not reactive unless
bound to an enzyme (25.2–25.5).
3. Fatty acids are converted to acetyl-CoA
by a repeating 4-step pathway
1B-oxidation2: oxidation by FAD,
addition of water, oxidation by NAD +,
and cleavage with CoASH (25.6).
4. Glucose is converted to pyruvate via a 10-
reaction pathway (glycolysis), including
a reverse aldol addition that forms
dihydroxyacetone phosphate and
glyceraldehyde-3-phosphate (25.7).
5. Under aerobic conditions, oxygen oxidizes
NADH to NAD +: under anaerobic
conditions, pyruvate oxidizes NADH to
NAD + and forms lactate. Pyruvate is
converted to acetyl-CoA by the pyruvate
dehydrogenase system. In yeast, pyruvate
is converted to ethanol (25.8).
6. Amino acids, each following a different
route, are converted to acetyl-CoA,
pyruvate, and citric acid cycle
intermediates, depending on the amino
acid. For example, phenylalanine is
converted to tyrosine, which is
transaminated to p-hydroxyphenyl-
pyruvate, which is converted to
fumarate and acetyl-CoA (25.9).
7. The citric acid cycle is series of 8
reactions that convert acetyl-CoA to 2
CO2 and CoASH. Each round forms 3
NADH, 1 FADH 2, and 1 ATP (25.10).
8. In the fourth stage of catabolism
(oxidative phosphorylation), each
NADH is oxidized to NAD + and 3 ATP;
each FADH 2 is oxidized to FAD and 2
ATP (25.11).
9. Anabolism is the reverse of catabolism:
acetyl-CoA, pyruvate, and other
intermediates are converted into fatty
acids, monosaccharides, and amino
acids (25.12).
Chapter 26
Lipids
1. Lipids, biological compounds soluble in
nonpolar solvents, include fatty acids
(saturated and unsaturated), waxes (long
chain esters), and fats and oils
(triacylglycerols) (26.1–26.3).
2. Membranes are composed of
phosphoacylglycerols (phospholipids),
which form lipid bilayers. Cholesterol
decreases fluidity. Vitamin E is an
antioxidant (Sec. 26.4).
3. Prostaglandins regulate physiological
responses, such as inflammation and
pain. They are synthesized from
arachidonic acid and contain a
cyclopentane ring with a 7-carbon
carboxylic acid side chain and an
adjacent (trans) 8-cabon hydrocarbon
side chain (26.5).
4. Terpenes contain multiples of 5 carbons
linked head-to-tail (isoprene rule).
Monoterpenes have 10 carbons;
sesquiterpenes have 15. Squalene is a
triterpene (30 carbons) and is the
precursor of cholesterol, which is the
precursor of all steroids. The carotenoids
(lycopene and carotene) are tetraterpenes.
Vitamin A is a diterpene that plays an
important role in vision (26.6, 26.7).
head head
tail tail
A-farnesene
a sesquiterpene found in the
waxy coating on apple skins
5. Acetyl-CoA and malonyl-CoA are
converted to isopentenyl pyrophosphate
for the synthesis of terpenes.
Isomerization forms dimethylallyl
pyrophosphate, from which isopentenyl
pyrophosphate displaces pyrophosphate
to form a 10-carbon compound; additional
reactions with isopentenyl pyrophosphate
make larger terpenes (26.8).
6. Steroids are hormones with 4 fused rings
and angular methyl groups.
B-Substituents are on the same side as the
angular methyl groups; a-substituents are
on the opposite side (26.9).
11
Chapter 27
Nucleosides, Nucleotides, and
Nucleic Acids
1. Deoxyribonucleic acid (DNA) and
ribonucleic acid (RNA) are nucleic
acids—phosphodiesters with purine
and pyrimidine bases. The bases in
DNA are adenine, guanine, cytosine,
and thymine; RNA has uracil instead
of thymine. Nucleosides =
base + ribose;
nucleotides = base + ribose +
phosphate . The primary structure
of a nucleic acid is the sequence of its
bases. DNA is double stranded (the
double helix) with major and minor
grooves. Stacking interactions between
the bases add stability. The 2¿-OH
group of RNA causes it to be easily
cleaved (27.1–27.4).
a. c.
b.
2. DNA is synthesized in the 5¿ : 3¿
direction by complementary base
pairing dictated by hydrogen bonds:
A pairs with T; G pairs with C.
One strand of DNA is made continuously
and the other is made in pieces
(semiconservative replication). The
template strand of DNA is read in the
3¿ : 5¿ direction to make RNA in the
5¿ : 3¿ direction (transcription); thus,
RNA has the same base sequence as
the sense strand of DNA, with Us in
place of Ts. Messenger RNA is the
template for protein synthesis
(translation); a codon (a 3 base sequence
of RNA) determines the amino acid
brought in. Ribosomal RNA forms
ribosomes, on which protein synthesis
takes place. Each transfer RNA carries an
amino acid (27.5–27.8).
H H
CH3 O H N N N H O N
N H N N N H N N
N N
sugar
N
O
sugar
sugar
N
O H N
sugar
thymine adenine cytosine
H
guanine
3. Synthetic oligonucleotides can be made
using phosphoramidite monomers or H-
phosphonate monomers (27.13).
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 12
Chapter 28
Synthetic Polymers
1. A polymer is made from monomers via
polymerization. Chain-growth
(addition) polymers are made by
attaching monomers to a radical, cation,
or anion propagating site (28.1).
CH2 CH CH2 CH CH2 CH CH2
styrene
a chain-growth polymer
2. Chain-growth polymerization includes
initiation, propagation, and termination
steps. Head-to-tail addition is favored
due to steric and electronic factors. The
mechanism of polymerization depends on
the initiator and the stability of the
propagating site: radical initiators have
bonds that break homolytically; H + is the
initiator in cationic polymerization;
organolithium compounds initiate
anionic polymerization. Hydrogen atom
removal from the main chain causes
branching. Living polymers contain
reactive ends that can continue
polymerization. Alkoxides or acids are
used to initiate ring-opening
polymerization with epoxides and
oxacyclobutanes (28.2).
3. An isotactic polymer has groups on the
same side; a syndiotactic polymer has
alternating groups. The groups in an
atactic polymer are random.
Ziegler-Natta catalysts (aluminum-
titantium complexes) control the
structure of the polymer (28.3).
4. Butadienes polymerize to form rubber
and neoprene. Heating with sulfur causes
cross-linking. Two or more different
monomers produce copolymers
(alternating, block, graft, or random)
(28.4, 28.5).
5. Step-growth (condensation) polymers,
formed by condensation of bifunctional
compounds, include polyamides and
aramides, polyesters, and
polyurethanes that form when a
diisocyanate reacts with a diol. Epoxy
resins involve a prepolymer and a
hardener (28.6).
O O
+ ∆
H3N(CH2)5CO− NH(CH2)5C
−H2O
6-aminohexanoic acid
Chapter 29
Pericyclic Reactions
1. The three types of pericyclic reactions
involve concerted cyclic reorganization of
e -. Electrocyclic reactions are
intramolecular with a s bond formed
between the ends of a conjugated system.
In cycloaddition reactions, two p bond-
containing compounds react to form a
cyclic compound. Sigmatropic Chapter 30
rearrangements are intramolecular: a s The Organic Chemistry of Drugs
bond breaks, a new s bond forms, and the 1. A brand name can be used only by the
p bonds rearrange. A thermal reaction holder of the patent; a generic name can
occurs without the absorption of light; a be used by anyone. Natural products are
photochemical reaction occurs with the traditional sources for lead compounds
absorption of light. The conservation of (30.1, 30.2).
orbital theory (in-phase orbitals overlap)
repeating unit explains the relationship between the
CH CH2 CH CH2 CH structure and configuration of the
H 3C O OCH3
reactant, the conditions, and the H 3C
N
polystyrene
n
configuration of the product (29.1-29-2). O N O
2. Electrocyclic reactions: For a reactant H 3C
O O
with an even number of conjugated
cocaine improved lead compound
double bonds ring closure is conrotatory lead compound
under thermal conditions and disrotatory
under photochemical conditions (TE-AC). 2. Related compounds with improved
With an odd number of conjugated properties are formed by molecular
double bonds, ring closure is disrotatory modification (30.3).
under thermal conditions and 3. A random screen is the search for a drug
conrotatory under photochemical
without structural information. Many
conditions (29.3). drugs have been discovered
accidentally (nitroglycerin, Librium,
Viagra) (30.5).
4. Drugs bind to specific receptors by
disrotatory H 3C CH3
ring closure hydrogen bonding, electrostatic
H3C HH CH3 H H interactions, and hydrophobic
(2E,4Z,6E)-octatriene cis-5,6-dimethyl-1,3-cyclohexadiene
interactions (30.6).
5. Drugs can inhibit enzymes through
covalent modification (suicide
3. Cycloaddition reactions: If the sum of the
inhibitor). Two drugs can have
reacting p bonds is even, bond formation
synergistic (additive) or antagonistic
is antarafacial under thermal conditions
effects; two drugs can be used to
and suprafacial under photochemical
overcome drug resistance. Therapeutic
conditions (TE-AC); if the sum is odd,
index, the ratio of toxic dose to
bond formation is suprafacial under
therapeutic dose, is a measure of drug
thermal conditions and antarafacial under
safety (30.7, 30.8).
photochemical conditions. Cycloaddition
6. In rational drug design, the chemical or
reactions that form 4-, 5-, or 6-
physical property of a series of drugs is
memberered rings must occur by
correlated with biological activity
suprafacial bond formation (29.4).
(QSAR). Molecular modeling allows for
4. Sigmatropic rearrangements: If the sum
evaluation of the fit of a potential drug
of the pairs of electrons in the reacting
with its receptor (30.9, 30.10).
system is even, rearrangement is
7. Combinatorial synthesis uses libraries of
antarafacial under thermal conditions and
compounds for the synthesis of analogs
suprafacial under photochemical
(13.11).
conditions ((TE-AC); if the sum is odd,
8. Nucleoside analogs are important
rearrangement is suprafacial under
antiviral drugs (30.12).
thermal conditions and antarafacial under
photochemical conditions. Migration on
the same p-face is suprafacial and to the
opposite face is antarafacial. Sigmatropic
rearrangements that form 4-, 5-, or 6- © 2007 Pearson Education, Inc.,
memberered transition states must be Upper Saddle River, NJ.
O O
suprafacial. In suprafacial rearrangement, All rights reserved. This material
NH(CH2)5C NH(CH2)5C
n carbon migrates using one of its p lobes is protected under all copyright
nylon 6
a polyamide (retained configuration) if the HOMO is laws as they currently exist. No
symmetric and both p lobes (inversion of portion of this material may be reproduced, in
configuration) if it is antisymmetric (29.5). any form or by any means. without permission
5. UV light promotes [2 + 2] cycloaddition of in writing from the publisher.
two adjacent thymine bases in DNA
leading to mutations. Luminescence
results from a retro [2+2] cycloaddition
reaction. Vitamin D is produced from
ergosterol, which undergoes a light-
mediated electrocyclic reaction, followed
by [1,7] sigmatropic rearrangement (29.6).
12