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Organic Chemistry
Paula Yurkanis Bruice, 5th Edition
Prepared by Merritt B. Andrus

Chapter 1 1pKa ' 102; alcohols and water


#
cylindrically symmetrical. Two p orbitals
Electronic Structure and Bonding overlap side-to-side to form a pi 1p2 1pKa ' 152. The equilibrium constant for
bond (1.6). an acid-base reaction = 1reactant Ka2/
Acids and Bases 7. Methane has four identical covalent bonds 1product Ka2. When atoms are the same
1. Atoms consist of protons (p+), neutrons
formed using four hybrid 1sp32 orbitals, size, the more electronegative the atom
(n), and electrons 1e -2. Atomic number is
which result from mixing one 2s and three to which the hydrogen is attached, the
the number of p+; mass number is the
2p atomic orbitals. It has tetrahedral stronger the acid. Relative electroneg-
sum of p+ and n. Isotopes have the same
(109.5°) bond angles. Ethane has sp3 ativities: sp 7 sp2 7 sp3. When atoms
number of p+ with different numbers of n.
carbons and 109.5° bond angles. Ethene are very different in size, the strongest
The atomic weight of an element is the
(with a double bond) has sp 2 carbons and acid will have its hydrogen attached to
average weighted mass of its atoms (1.1).
120° bond angles. Ethyne (with a triple the largest atom. For example, acid
2. An atomic orbital (s, p, d, f) is the volume
bond) has sp carbons and 180° bond strength: HI 7 HBr 7 HCl 7 HF. The
of space around a nucleus where an
angles. All single bonds are s bonds; a stronger the acid, the weaker its
electron is most likely to be found. An
double bond consists of 1 s bond and 1 p conjugate base. Weak bases are stable
electron goes into the lowest energy
bond; a triple bond consists of 1 s bond bases. A Lewis acid accepts a share in a
orbital available (aufbau principle), with
and 2 p bonds. The more s character, the pair of e -; a Lewis base donates a share in
two e - in each orbital (Pauli exclusion
shorter and stronger the bond and the a pair of e -. Curved arrows are used to
principle). An e - will occupy an empty
larger the bond angle. (1.6–1.9, 1.14). show electron flow; the arrow begins
degenerate (same energy) orbital before
where the electrons originate and points
it will pair up with another e - (Hund’s
to where they end up (1.16–1.26).
rule). Core e - are in filled shells; valence H
e ! are used for bonding (1.2). Chapter 2
3. Atoms give up or accept e - to achieve an
An Introduction to Organic
outer shell of eight electrons (octet rule). C
Electropositive elements (on the left of H H Compounds
the periodic table) lose e - to form cations; 1. Hydrocarbons contain only C and H.
H Alkanes are hydrocarbons with only
electronegative elements (on the right)
gain e - to form anions. Ionic bonds are single bonds. Constitutional isomers
Methane have the same molecular formula but
formed by electrostatic attraction
between cations and anions.
p bond differ in the way the atoms are connected.
Electronegativity is a measure of an IUPAC (systematic) and common names
H H are used to name compounds. CH 2 = a
atom’s ability to attract e -. Atoms form
covalent bonds by sharing valence e -. methylene group. A primary (1°) carbon
Nonpolar covalent bonds are formed by is bonded to one other C; a secondary (2°)
C C carbon is bonded to 2 Cs; a tertiary (3°)
atoms with the same electronegativity;
polar covalent bonds are formed by carbon is bonded to 3 Cs. Substituents
atoms with different electronegativities. H H are indicted as prefixes, with the parent
A polar bond has a dipole with a dipole hydrocarbon numbered in the direction
s bond that puts the lowest number in the name
moment, D (debye). Electrostatic
potential maps show how charge is Ethene of the compound. Substituents are listed
distributed: red 1-2 and blue 1+2 (1.3). alphabetically; di, tri, tetra, are used for
4. Lewis structures represent compounds, identical alkyl groups, but are not
showing all bonding and lone pair e !. H alphabetized; sec and tert are also not
The formal charge on an atom = the C alphabetized, but iso and cyclo are. In a
number of valence e - minus 1/2 the C cycloalkane with two substituents, the
bonding e - minus the lone pair e -. H first cited substituent gets the lower
Carbocations have a positively charged number (2.1–2.3).
carbon; carbanions have a negatively a primary carbon a secondary carbon a tertiary carbon CH3
charged carbon; a carbon radical has a Ethyne
CH3CHCH2 CH3CH2CH CH3C
carbon with an unpaired e -. Kekulé 8. The O and N of water and ammonia are
CH3 CH3 CH3
structures depict bonds as lines. sp3 hybridized; H 2O has 104.5° bond an isobutyl group a sec-butyl group a tert-butyl group
Condensed structures use subscripts and angles; NH 3 has 107.3° bond angles. C+
few, if any, bonds (1.4). and C # are sp2; C- is sp3 (1.11, 1.12). 2. Alkyl halides and ethers are named as
5. An s atomic orbital is spherical; the 2s 9. A Br"nsted acid donates a proton 1H +2; a substituted alkanes; alcohols and amines
atomic orbital has a radial node. There are Br"nsted base accepts a proton, forming a are named using a functional group suffix.
three degenerate, perpendicular p orbitals; conjugate base and a conjugate acid, Substituents on the nitrogen are preceded
each has a node at its nucleus (1.5). respectively. The acid dissociation by an N. If a parent chain has a substituent,
6. Bond length is the distance between constant (Ka) is a measure of the acidity of the substituent gets the lowest number; if
nuclei; bond dissociation energy is a compound; pKa = -log Ka; the lower it has a functional group, the functional
the energy required to break a bond. the pKa, the stronger the acid. Protonated group gets the lowest number; if it has
Two atomic orbitals combine to form carboxylic acids and protonated both a substituent and a functional group,
two molecular orbitals, a bonding MO alcohols = strong acids 1pKa 6 02; the functional group gets the lowest
(s or p) and an antibonding MO (s* carboxylic acids = weak acids 1pKa ' 52; number. Only if the functional group gets
or p*). A sigma 1s2 bond is protonated amines = very weak acids the same number in either direction, is the
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chain numbered so the substituent gets 2. The sp2 carbons of an alkene and the four Chapter 4
the lower number (2.4–2.7). atoms attached to them are in a plane. Cis The Reactions of Alkenes
3. Alkyl halides and alcohols are 1°, 2°, or 3° isomers have the hydrogens on the same 1. Hydrogen halides add to alkenes to form
depending on whether the X or OH is on side of the double bond; in trans isomers alkyl halides. Carbocations are stabilized
a 1°, 2°, or 3° carbon. Amines are 1°, 2°, or they are on opposite sides. The E isomer by hyperconjugation (e - delocalization
3° depending on how many alkyl groups has the high priority groups (based on by overlap of adjacent s bond orbitals
are bonded to N (2.4, 2.6, 2.7). atomic numbers) on opposite sides of the with the empty p orbital); relative
4. The stronger the intramolecular forces double bond; the Z isomer has them on stabilities: 3° 7 2° 7 1°. The Hammond
holding molecules together, the higher the same side. Proceeding down a postulate states that the transition state is
the boiling point: hydrogen bonds are substituent breaks a tie (3.5). more similar in structure to the species to
stronger than dipole-dipole interactions, 3. The double bond of an alkene is its which it is more similar in energy (4.1–4.3).
which are stronger than van der Waals functional group (the center of 2. Electrophilic addition reactions are
forces, which increase with molecular reactivity). Curved arrows show the regioselective; the electrophile adds to
weight and decrease with branching (2.9). mechanism for this electrophilic the sp2 carbon bonded to the greater
5. Polar compounds dissolve in polar addition reaction (H + is an electrophile number of hydrogens in order to form
solvents; nonpolar compounds dissolve and the p bond is a nucleophile; the the more stable carbocation (4.4).
in nonpolar solvents. An oxygen can drag carbocation is an electrophile and Br - is a 3. The addition of water or an alcohol to an
about 3 carbons into water (2.9). nucleophile) (3.6). alkene requires an acid catalyst. Addition
6. Organic compounds exist in various of water forms an alcohol; addition of an
conformations due to bond rotation. slow fast alcohol forms an ether (4.5).

Newman projections depict staggered C C + H Br C C + Br C C
+
4. A carbocation can rearrange to a more
(anti and gauche) and higher energy H Br H
stable carbocation via a 1,2-hydride or 1,2-
the electrophile a carbocation the nucleophile
eclipsed conformations. Cyclopropane adds to an sp2 intermediate adds to the methyl shift, or by ring expansion (4.6).
and cyclobutane have significant angle carbon of the
alkene
carbocation
5. Halogens (Cl2 and Br2) add to alkenes to
strain; cyclopentane and cyclohexane are form vicinal dihalides via a cyclic
nearly strain free. Cyclohexane adopts a 4. Energy changes are shown by a reaction bromonium ion intermediate. If the
chair conformation with an axial and coordinate diagram. A transition state reaction is carried out in water, a
equatorial bond on each carbon. Ring-flip has partially broken and partially formed halohydrin is formed with water adding
causes one chair conformer to convert into bonds; an intermediate has fully formed to the more substituted sp2 carbon. Since
another chair conformer; bonds that are bonds. The more stable the species, the the intermediate in these reactions is not a
axial in one are equatorial in the other. A lower its energy. The change in Gibbs free carbocation, carbocation rearrangements
substituent is more stable in an equatorial energy 1¢G°2 is exergonic 1-2 when cannot occur (4.7).
position. A cis isomer has substituents on forming a more stable species, and 6. Alkenes undergo oxymercuration-
the same side of the ring; a trans isomer endergonic 1+2 when forming a less reduction and alkoxymercuration-
has them on opposite sides (2.10–2.14). stable species. ¢G° is related to the reduction to form alcohols and ethers,
equilibrium constant by -RT ln Keq. respectively. Carbocations are not formed
The formation of products with stronger as intermediates, so carbocation
bonds and greater freedom of movement rearrangements do not occur (4.8).
causes ¢G° to be negative; 7. Alkenes react with peroxyacids
¢G° = ¢H° - T¢S°. If a system at 1RCO3H2 to form epoxides. The reaction
= axial bond equilibrium is disturbed, it will adjust to is concerted (it does not have an
= equatorial bond offset the disturbance (Le Chatlelier’s intermediate) (4.9).
principle). The free energy of activation 8. Hydroboration-oxidation of an alkene
Chapter 3 ( ¢G‡) is the difference between the free involves the concerted addition of borane
Alkenes: An Introduction to energy of the transition state and the free 1BH 32 to form a trialkylborane that is
energy of the reactants. The greater ¢G‡, treated with H 2O2 and HO - to form an
Reactivity. Thermodynamics and the slower the reaction. The rate- alcohol. Borane is the electrophile that
Kinetic determining step has its transition state at adds to the less substituted sp2 carbon;
1. Alkenes are hydrocarbons with a double the highest point on the reaction H - is the nucleophile that adds to the
bond. The total number of p bonds and coordinate. The rate of a reaction is other sp2 carbon (4.10).
rings is the degree of unsaturation. The directly proportional to a rate constant, k;
general molecular formula for a the smaller the rate constant, the slower CH3 CH3
1. BH3/THF
hydrocarbon is CnH 2n + 2 minus 2 the reaction. The Arrhenius equation CH3CHCH CH2 2. HO−, H2O2, H2O
CH3CHCH2CH2OH
hydrogens for each degree of relates the rate constant to the activation 3-methyl-1-butene 3-methyl-1-butanol

unsaturation. The parent hydrocabon is energy 1Ea2 (3.7–3.8).


the longest carbon chain that contains the
double bond, numbered so that the start 9. Alkenes undergo catalytic (Pd/C, Pt/C,
of the double bond is given the lowest Ni) hydrogenation to form alkanes. The
possible number. Alkadiene is used for intermediate most stable alkene has the smallest heat of
two double bonds. Vinylic carbons are hydrogenation. The greater the number
double-bonded carbons; allylic carbons of alkyl substituents attached to the sp2
Free energy

CH3CHCH2CH3
are adjacent to vinylic carbons (3.1–3.2).
+
Br−
carbons, the more stable the alkene (4.11).

Br
Cl
Chapter 5
CH3CHCH2CH CCH2CHCH3 CH3CH CHCH3
HBr
Stereochemistry
CH3 CH2CH3 Br CH3 −∆G˚

2-bromo-4-ethyl-7-methyl-4-octene 6-bromo-3-chloro-4-methylcyclohexene
CH3CHCH2CH3 1. Constitutional isomers differ in the way
not not Br their atoms are connected. Stereoisomers
7-bromo-5-ethyl-2-methyl-4-octene 3-bromo-6-chloro-5-methylcyclohexene
because 4 < 5 because 4 < 5 Progress of the reaction (cis-trans isomers and isomers with
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asymmetric centers) differ in the way the 7. In a stereoselective reaction, one Working from product to reactants, when
atoms are arranged in space. Cis-trans stereoisomer is formed in preference to designing a synthesis, is called
isomers have either a double bond or a another. In a stereospecific reaction, retrosynthetic analysis (6.10–6.12).
cyclic structure (5.1). stereoisomeric (e.g., cis and trans)
2. A molecule is chiral if it is reactants form different stereoisomers as
nonsuperimposable on its mirror image. products. When a reactant without an
A carbon bonded to four different asymmetric center forms a product with Chapter 7
substituents is an asymmetric center. one asymmetric center, the product will Delocalized Electrons and Their
A molecule with one asymmetric center is be a racemic mixture. Electrophilic Effect on Stability, Reactivity, and pKa
chiral; it can exist as a pair of addition reactions that form carbocation 1. Delocalized e ! are shared by three or
enantiomers (nonsuperimposable mirror intermediates involve syn and anti more atoms. Benzene has delocalized e -:
image molecules). Enantiomers have the addition. Hydrogenation, epoxidation, all the C ¬ C bonds have the same length;
same physical and chemical properties and hydroboration are syn additions; the three pairs of p e - are shared by all
(5.2–5.6). halogenation is an anti addition. CIS- six carbons. Resonance contributors use
SYN-ERYTHRO or -CIS (5.18, 5.19). localized e - to approximate the true
Br Br 8. Enzymes and receptors can distinguish structure with delocalized e - (the
between enantiomers. Enzyme-catalyzed resonance hybrid) (7.1–7.3).
C C reactions are completely stereoselective—
CH3CH2 H H CH2CH3
CH3 CH3 only one stereoisomer is formed.
a.
mirror Enzyme-catalyzed reactions are
the two isomers of 2-bromobutane stereospecific—the enzyme reacts with b. c.
enantiomers only one stereoisomer (5.20, 5.21).
3. The R,S system is used to name chiral
compounds by prioritizing the four
substituents attached to the asymmetric Chapter 6 2. Rules for drawing resonance contributors:
center based on atomic number. When the The Reactions of Alkynes move only p and lone-pair e -. Move e - to
lowest priority substituent points to the 1. Alkynes are hydrocarbons with a triple a positively charged atom or to an atom
rear, an arrow starting at the highest bond. A terminal alkyne has the triple with a p bond. Each resonance
priority substituent and pointing at the bond at the end of a chain; otherwise, it is contributor has the same net charge. The
second highest priority substituent is an internal alkyne. A compound with a greater the predicted stability of the
clockwise if the compound has the R double and a triple bond is named as an resonance contributor, the more it
configuration, and counterclockwise if it alkenyne; the double bond has the contributes to the hybrid. Destabilizing
has the S configuration (5.7). greater priority only if there is a tie. OH features: incomplete octet, positively
and NH 2 groups have priority over charged electronegative atom, charge
1 1 double and triple bonds (6.1, 6.2). separation (7.4, 7.5).
Br Br 2. Electrophiles add to the least substituted 3. Delocalization (resonance) energy is the
C H4 4 C sp carbon. Addition of HCl or HBr forms gain in stability that results from having
H a vinyl halide; with excess reagent, a
CH3CH2
CH3 CH3
CH2CH3 delocalized e -. The greater the number of
2
3 3
2 geminal dihalide is formed. Addition of relatively stable resonance contributors,
(S)-2-bromobutane (R)-2-bromobutane Cl2 or Br2 forms a dihaloalkene; excess the greater the delocalization energy.
reagent forms a tetrahaloalkane (6.5, 6.6). Relative stabilities: conjugated dienes 7
4. Chiral molecules that rotate plane- 3. The acid-catalyzed addition of water to isolated dienes 7 cumulated dienes.
polarized light to the right are an alkyne forms an enol, which Allylic and benzylic cations are more
dextrorotatory 1+2; those that rotate it to tautomerizes to a ketone. HgSO4 is used stable than 1° alkyl cations because of e -
the left are levorotatory 1-2. with terminal alkynes (6.7). delocalization (7.6–7.8).
A polarimeter measures observed 4. Borane adds to an alkyne to form a vinyl- 4. A molecular orbital (MO) results from a
rotation, a, from which specific rotation borane, which is oxidized to an enol. An linear combination of atomic orbitals
[a] can be calculated. A 50:50 mixture of internal alkyne tautomerizes to a ketone: a (LCAO). Two e - are placed in each MO,
enantiomers is an optically inactive terminal alkyne requires disiamylborane starting from the lowest energy MO. The
1a = 02 racemic mixture. Enantiomeric and forms an aldehyde (6.8). number of MOs equals the number of
excess is measured by dividing the AOs; a node is added for each ascending
OH O
observed specific rotation by the specific H2O, H2SO4 MO. The highest occupied MO (HOMO)
CH3C CH2 CH3CCH3
rotation of the pure enantiomer (5.8–5.10). HgSO4
a ketone
is the highest energy MO that contains e -;
5. Stereoisomers that are not mirror images CH3C CH O the lowest unoccupied MO (LUMO) is
OH
are diastereomers. Unlike enantiomers, 1. disiamylborane the lowest energy MO that does not
CH3CH CH CH3CH2CH
diastereomers possess different physical 2. HO−, H2O2, H2O
an aldehyde contain e - (7.8).
and chemical properties. In compounds 5. Carboxylic acids and phenol have some
with two asymmetric centers, the 5. Catalytic hydrogenation of an alkyne e - delocalization, but their conjugate
configuration of one of the asymmetric forms an alkane. With Lindlar bases have more, causing carboxylic
centers is the same in both diastereomers, catalyst, a cis alkene is formed; with acids 1pKa ' 52 and phenol 1pKa ' 102
and the configuration of the other is not Na 1or Li2 + NH 3, a trans alkene is to be stronger acids than alcohols
the same in both. Compounds with two or formed via radical anion and vinyl 1pKa ' 152, which have no e -
more asymmetric centers that possess a radical intermediates (6.9). delocalization. Protonated aniline
plane of symmetry are achiral (optically 6. A terminal alkyne 1pKa 252 is 1pKa ' 52 is more acidic than protonated
inactive) meso compounds (5.11–5.13). deprotonated with NaNH 2 to form an alkylamines 1pKa ' 102 due to an
6. Enantiomers can be separated (resolved) acetylide ion, which reacts with a 1° alkyl increase in delocalization energy upon
by chiral chromatography (5.16). halide to form a longer-chain alkyne. losing a proton (7.9).
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6. Conjugated dienes form 1,2- and 1,4- 3. Leaving group tendencies for RX: However, alkyl fluorides, with a poor
addition products. At low temperatures, I - 7 Br - 7 Cl -. Strong bases are better leaving group, preferentially form the less
where the reaction is not reversible, the nucleophiles, except if there is a large substituted alkene, because the transition
kinetic product (the one that is formed difference in size and they are in a protic state is carbanion-like. The relative
faster) is favored. At higher temperatures, solvent, because of the greater stabilities of carbanions are 1° 7 2° 7 3°,
where the reaction is reversible, the polarizability of the large nucleophile and the reverse of carbocation stabilities (9.2).
thermodynamic product (the more stable its weaker solvation (in which case I - is a 3. E2 and E1 reactions are stereoselective:
product) is favored. The 1,2-product is better nucleophile than F -). Aprotic polar the alkene with the bulkiest groups on
always the kinetic product; either the 1,2- solvents (DMSO, DMF) are used in S N2 opposite sides of the double bond is
or 1,4-product can be the thermodynamic reactions of alkyl halides with negatively favored (9.5).
product; it will depend on which is the charged nucleophiles because such 4. In E2 reactions of substituted
more substituted alkene (7.10, 7.11). solvents solvate only cations (8.3, 8.4). cyclohexanes, both groups that are
7. A conjugated diene reacts with a 4. The reaction of a 3° alkyl halide with H 2O eliminated must be in axial positions
dieneophile (an alkene with an e! is a unimolecular nucleophilic because of anti elimination (9.6).
withdrawing group) to form a cyclohexene substitution reaction 1SN12, with a rate 5. Under S N1/E1 conditions: 1° alkyl
via a concerted Diels-Alder reaction. The law dependent only on [RX] (a first-order halides do not react because primary
diene adopts an s-cis conformation for this reaction). The leaving group leaves, carbocations are too unstable to be
[4 # 2] cycloaddition reaction where the forming a carbocation that is attacked by formed; 2° and 3° alkyl halides undergo
HOMO of one reactant interacts with the the nucleophile. Formation of the both substitution and elimination. Under
LUMO of the other. The reaction is carbocation is the rate-limiting step, so 3° SN2/E2 conditions: 1° alkyl halides favor
stereospecific; e.g., a cis dienophile forms alkyl halides are the most reactive; substitution; 2° undergo both
cis products. Bridged, bicyclic products carbocation rearrangements can occur. substitution and elimination; 3° undergo
favor the endo configuration when the Products with inverted and retained only elimination (9.8).
substituent has p e - (7.12). configurations are obtained. Partial 6. Bulky, strong bases (tert-butoxide) favor
racemization can occur because one face E2 over S N2 due to steric hindrance. High
nucleophile electron-withdrawing group
of the carbocation can be partially temperatures favor E2 over S N2 due to a
H
4
CH2
O
H
4
CH2
O blocked by the leaving group (8.5–8.7). greater ¢S° (9.8).
3C CH CCH3 30 ºC
3C CH CCH3 5. Benzylic and allylic halides undergo both 7. Ethers are formed from alkoxide ions and
2C CH2 2C CH2 S N1 and S N2 reactions. Vinyl and aryl 1° alkyl halides (Williamson ether
H CH2 H CH2
1 electrophile 1 halides undergo neither S N1 nor S N2 synthesis). Na or NaH converts an
a 1,4-addition reaction to 1,3-butadiene reactions (8.8). alcohol to an alkoxide ion. Geminal and
6. High concentration of a good nucleophile vicinal dihalides react with excess -NH 2
favors S N2; a poor nucleophile favors to form alkynes (9.9, 9.10).
Chapter 8 S N1. If a reactant is charged, increasing
Substitution Reactions of Alkyl the polarity of the solvent decreases the
rate of the reaction; if neither of the Chapter 10
Halides reactants is charged, increasing the Reactions of Alcohols, Amines,
1. Substitution reactions involve
polarity of the solvent increases the rate Ethers, Epoxides, and Sulfur-
replacement of a leaving group with a
of the reaction (8.9, 8.10). Containing Compounds
nucleophile. Alkyl halides have good
7. Bifunctional molecules can undergo
leaving groups 1I -, Br -, Cl -2 (8.1). 1. Alcohols and ethers have poor leaving
intramolecular reactions to form cyclic groups due to the strong basicity of HO -
− d+ d−
products. Five- and six-membered rings and RO -. If protonated, they become
Nu + C X C Nu + X − are favored (8.11). good leaving groups that can be replaced
8. A common cellular methylating agent is by halide ions. These are S N1 reactions
S-adenosylmethionine (SAM), a methyl (so carbocation rearrangements can
a nucleophile substitution sulfonium ion (8.12). occur) except in the case of 1° alkyl
product halides, which are S N2 reactions (10.1).
2. The reaction of bromomethane with HO - Chapter 9
a weakly basic leaving group
is a bimolecular nucleophilic Elimination Reactions of Alkyl
+H ∆
substitution reaction 1SN22, with a rate Halides CH3 O H + HBr CH3 OH CH3 Br + H2O
weak base
law dependent on [RX] and [HO -] (a

1. An E2 reaction of an alkyl halide involves poor leaving good leaving Br
group group
second-order reaction). HO - attacks with the simultaneous removal of a proton
simultaneous departure of the leaving from a b-carbon and the halide ion from 2. Alcohols react with PBr3, PCl3, or thionyl
group. Steric effects govern the relative the a-carbon (dehydrohalogenation) to chloride 1SOCl22 to form alkyl halides.
rates with 1° alkyl halides faster than 2°, form an alkene (a B-elimination). An E1 Alcohols react with sulfonyl chloride to
and 3° very slow. The reaction occurs with reaction is a two-step reaction; the form sulfonate esters (10-2, 10-3).
inversion of configuration because the leaving group departs (the rate-limiting 3. Alcohols undergo dehydration when
nucleophile (HOMO) interacts with the step), forming a carbocation, which loses heated with a strong acid 1H 2SO42 to
s* (LUMO) on the backside of the carbon a proton from the b-carbon. Leaving form alkenes. These are S N1 reactions,
attached to X (8.2). group order in both E2 and E1: except in the case of 1° alcohols, which are
I - 7 Br - 7 Cl - 7 F - (9.1, 9.3). S N2. POCl3 + pyridine dehydrates
the configuration of the 2. E2 and E1 reactions are regioselective: the alcohols without carbocation formation,
product is inverted relative
to the configuration of more stable (more substituted) alkene is so there are no rearrangements (10.4).
the reactant
CH3 CH3 the major product (the hydrogen is 4. 2° alcohols are oxidized to ketones; 1°
C + HO− C + Br− removed from the b-carbon bonded to the alcohols are oxidized to carboxylic acids
H H
CH3CH2 Br HO
CH2CH3 fewest hydrogens; Zaitsev’s rule), because with chromic acid 1H 2CrO42 and to
(R)-2-bromobutane (S)-2-butanol the transition state is alkene-like. aldehydes with PCC (10.5).
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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 distribution (11.3, 11.4).
S N1 (breaking to form the more stable 3. Relative rates for bromination at 125 °C:
carbocation) unless the alkyl groups 1600 : 82 : 1 for 1°, 2°, 3°. A bromine 4. Stretching vibrations involve changes in
cannot form a carbocation (primary, radical is less reactive and more selective bond length and occur at a higher energy
vinyl, aryl); then it is S N2 (with iodide ion than a chlorine radical (reactivity- than bending vibrations, which involve
attacking the least sterically hindered selectivity principle (11.5). changes in bond angles. Absorption
carbon) (10.7).
7. Epoxides react with nucleophiles. Under
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
acidic conditions, the ring opens to put electrophile, so it adds to the sp2 carbon group region 14000–1400 cm-12 detect
the developing positive charge on the bonded to the most hydrogens—opposite functional groups; those in the fingerprint
more substituted carbon; under basic to the regioselectivity of HBr addition region 11400 – 600 cm-12 are characteristic
conditions, the nucleophile attacks the without peroxide (11.6). of the molecule as a whole (12.7, 12.8).
less sterically hindered carbon (10. 8). 5. If a radical substitution reaction or a
radical addition reaction forms an
O asymmetric center, the product will be a 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). 5. The greater the change in dipole moment
9. Crown ethers form inclusion compounds Chapter 12 when a bond vibrates, the more intense
with metal ions based on molecular Mass Spectrometry, IR Spectroscopy, the absorption. The energy required to
recognition. Crown ethers can be used as stretch a bond depends on the bond
and UV/Vis Spectroscopy
phase-transfer catalysts (10.10). strength and the masses of the bonded
1. An e - beam removes an e - to form a
10. Thiols (RSH) are more acidic 1pKa ~102 atoms; stronger bonds and lighter atoms
molecular ion (a radical cation), which
than alcohols. Thiolate anions react with absorb at higher frequencies (Hook’s
then fragments. A magnetic field focuses
alkyl halides to form sulfides (RSR); law); triple bonds are stronger than
cations toward a detector, giving a mass
sulfides react with alkyl halides to form double bonds, which are stronger than
spectrum, which plots abundance versus
sulfonium salts 1R3S # X !2 (10.11). single bonds. Electron delocalization can
mass-to-charge (m/z) (12.1).
11. Lithium reacts with alkyl halides to form affect bond order. C-H stretch frequency
2. The molecular ion corresponds to the
alkyllithium compounds; magnesium depends on the hybridization of C
nominal molecular mass. The base peak is
reacts with alkyl halides to form Grignard 1sp 7 sp2 7 sp32. Alkene substitution
the highest abundance ion. M+1 peaks can
reagents. These organometallic patterns can be identified in the
be used to determine the number of
compounds are good nucleophiles; they fingerprint region (12.9–12.11).
carbons. For a chlorine-containing com-
react as if they were carbanions. For 6. O ¬ H (of RCOOH and ROH) and N ¬ H
pound, the M+2 peak is 1/3 the M peak;
example, they react with epoxides to form show absorption bands at the same
for a compound that contains bromine, the
(after acidification) alcohols. In the frequency, but their shapes are different.
M+2 peak is equal to the M peak. High
presence of H +, OH, or NH, organometallic The absence of bands can rule out
resolution MS can determine the exact
compounds form alkanes (10.12). functional groups. Stretches with no net
molecular mass. The e - beam is most likely
12. Gilman reagents 1R 2CuLi2 are formed change in dipole moment are IR inactive
to dislodge a lone-pair e -. A bond between
from alkyllithium compounds and CuI. (12.12–12.14).
carbon and a more electronegative atom
They couple with vinyl, aryl, and alkyl 7. UV/Vis spectroscopy involves excitation
breaks heterolytically; a bond between
halides, replacing the halogen. Catalytic
carbon and an atom of similar electroneg- of an e - to a higher energy state: n : p*
palladium is used to facilitate coupling
ativity breaks homolytically. a-cleavage and p : p* transitions; the latter are
reactions with alkenes (Heck), stannanes lower in energy and have greater molar
(cleavage of the bond a to the heteroatom)
(Stille), and organoboranes (Suzuki) and absorptivities 1e2. The greater the lmax,
occurs because the positive charge is then
aryl, benzyl, or vinyl halides (10.13). the lower the energy: UV radiation
shared by two atoms (12.2–12.5).
3. Spectroscopy uses electromagnetic (180–400 nm) is of higher energy than
radiation to probe molecular structure. visible light (400–780 nm). A chromophore
Chapter 11 Frequency 1n2 is directly proportional to is the group in the molecule that causes the
Radicals • Reactions of Alkanes energy 1E = hn2; wavelength 1l2 is absorption. Absorbance depends on the
1. Alkanes undergo halogenation with Cl2 inversely proportional to energy concentration of the sample, the length of
or Br2 and heat or light to form alkyl (E = hc/l; c = speed of light). the light path, and the e of the compound
halides in a chain reaction that has IR spectroscopy uses wavenumbers (the (Beer-Lambert Law) (12.15–12.17).
initiation, propagtion, and termination number of waves in 1 cm), which are 8. The more conjugated double bonds, the
steps. The radical formed in the initiation directly proportional to energy and have greater the lmax (due to raised energy of
step is the reactant of the first propagation units of cm-1 (12.6). the HOMO and lowered energy of the
5
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Chapter 14
#
LUMO) and the greater the e. Colored 5. Integration indicates the relative
compounds absorb visible light. number of protons responsible for each Aromaticity Reactions of Benzene
Auxochromes (OH and NH 2) attached to signal. A signal has a multiplicity 1. Aromatic compounds have large
chromophores increase both lmax and e according to the N # 1 rule, where N is delocalization energies: benzene is 36
(12.18, 12.19). the number of neighboring equivalent kcal/mol more stable than hypothetical
protons bonded to adjacent carbons. ‘cyclohexatriene.’ To be aromatic, a
Splitting occurs as a result of the compound must have an uninterrupted
Chapter 13 proton(s) that give rise to the signal being cloud of p electrons (that is, it must be
NMR Spectroscopy coupled to adjacent nonequivalent cyclic, planar, and every ring atom must
1. Nuclear magnetic resonance (NMR) protons whose nuclear spins can align have a p orbital), and the p cloud must
establishes atom connectivity. When either with or against the applied contain an odd number of pairs of p e -
NMR active nuclei 11H, 13C, 15N, 19F, 31P2 magnetic field (13.9, 13.10). (Hückel’s 4n # 2 rule) (14.1, 14.2).
are subjected to an applied magnetic 2. Cyclobutadiene and cyclooctatetraene,
field, they align either with the field with an even number of pairs of p e -, are
1A-spin state2 or against the field not aromatic. The cyclopentadienyl anion
1B-spin state2. The energy difference c a b
ClCH2CH2CH2I 2
and the cyloheptatrienyl cation, each
between the spin states depends on the with three pairs of p e -, are aromatic.
strength of the magnetic field 1B o2 and 2
Pyridine, pyrrole, furan, and thiophene
the gyromagnetic ratio (13.1). 2 (heterocyclic compounds) are aromatic
2. Nuclei resonate at different frequencies (14.1, 14.2).
due to shielding by nearby electrons that
3.7 3.6 3.5 PPM 3.4 3.3 3.2 PPM 2.3 2.2 2.1 PPM

8 7 6 5 4 3 2 1 0
induce a local magnetic field that opposes d (ppm)
frequency
the applied magnetic field, thereby
changing the effective magnetic field
1Beffective = Bapplied - Blocal2. Protons in 6. The coupling constant (J) is the distance N O S
(in Hz) between adjacent peaks in a signal. N H
e - rich environments are shielded and
resonate at lower frequencies (upfield); The coupling constant for H a being split pyridine pyrrole furan thiophene
those in e - poor environments are by H b is denoted by Jab. The signals of
deshielded and resonate at higher coupled protons have the same coupling 3. The pKa of cyclopentadiene is unusually
frequencies (downfield) (13.3, 13.6). constant. The number of observed peaks low (15) due to its aromatic conjugate
in a signal can be explained by a splitting base. Cycloheptatrienyl bromide ionizes
diagram. When the coupling constants of readily due to its aromatic cation.
these protons sense a these protons sense a
two sets of nonequivalent adjacent Antiaromatic compounds, with an
larger effective magnetic smaller effective magnetic protons are similar, the signal multiplicity uninterrupted cloud of p electrons that
field, so come into resonance field, so come into resonance
at a higher frequency at a lower frequency is the same as if the adjacent sets were contains an even number of pairs of p e -,
equivalent (13.12, 13.13). are less stable than analogous compounds
Intensity

7. Two hydrogens bonded to a carbon that is with localized e -. Frost circle diagrams
deshielded nuclei shielded nuclei
bonded to two different groups are called are used to assign relative energies to the
enantiotopic hydrogens; one is a pro-S- MOs of cyclic compounds (14.5–14.7).
hydrogen, the other a pro-R-hydrogen, 4. Some monosubstituted benzenes have
and the carbon is prochiral. Enantiotopic names that incorporate the substituent
"downfield"
Frequency
"upfield" hydrogens are equivalent. If the (toluene, phenol, aniline, benzenesulfonic
compound has an asymmetric center, the acid, anisole, styrene, benzaldehyde,
two hydrogens are diastereotopic benzoic acid, benzonitrile). A benzene
3. Chemically equivalent protons resonate hydrogens; they are not equivalent, so substituent is a phenyl group (Ph-); a
at the same frequency; nonequivalent sets they produce different signals (13.14). phenyl methyl substituent is a benzyl
of protons resonate at different 8. NMR spectra show an average of various group 1PhCH 2-2 (14.8).
frequencies. The chemical shift 1D2 is conformers at room temperature. 5. Aromatic compounds undergo
independent of spectrometer frequency; Hydrogens involved in proton exchange electrophilic aromatic substitution
d = distance of the signal in Hz from TMS (OH, NH 2) are not split and do not split; reactions, which replace a hydrogen with
divided by spectrometer frequency in they appear as broadened singlets an electrophile. Halogenation employs
MHz. Low frequency (shielded) signals (13.15, 13.16). Br2 + FeBr3 or Cl2 + FeCl3 (14.9–14.11).
have small d values (13.4, 13.5). 9. 13C NMR determines the types of
4. In a similar environment, a signal for CH 3 carbons present in a compound (0–200
is at a lower frequency than a signal for ppm). The signals cannot be integrated + H Br
+ −
CH 2, which is at a lower frequency than a and are not split unless the spectrum is + Br Br FeBr3 Br B
+ HB+

signal for CH. Induced ring currents run in a proton-coupled mode. The −
+ FeBr4

cause sp2-bound protons (aryl and vinyl) multiplicity is determined by the N+1
and sp-bound protons to experience rule, where N is the number of 6. Nitration employs nitric acid and sulfuric
diamagnetic anisotropy and resonate at hydrogens bonded to the carbon that acid; the nitronium ion 1+NO22 is the
7–5 ppm and 2.4 ppm, respectively (13.7, produces the signal (13.19). electrophile. Sulfonation uses sulfuric
13.8). acid; the sulfonium ion 1+SO3H2 is the
electrophile. This reaction is reversible at
O H C N
O
H Z C C C C C Cl 100 °C (14.12, 14.13).
H C Br
C H C C C H H C C H C O 7. Friedel-Crafts acylation employs an acyl
O C C
C OH
vinylic
Z = O, N, halogen
C C C saturated sp3 carbon chloride or an acid anhydride + AlCl3 (the
C O
12 9.0 8.0 6.5 4.5 2.5
allylic
1.5 0 200 150 100 50 0
acylium ion is the electrophile) and forms a
d (ppm) d (ppm) phenyl ketone. Friedel-Crafts alkylation
6
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employs an alkyl halide + AlCl3 (a 3. Deactivating substituents stabilize the O O


carbocation is the electrophile); an conjugate bases of phenols, carboxylic C C
alkylbenzene is the product. A carbocation acids, and anilinium ions, making the CH3CH2CH2CH2 OH CH3CH2CH2CH2CH2 OH
generated from an alkene or an alcohol can acids more acidic (lowering their pKa);
pentanoic acid hexanoic acid
also be used. Carbocations can rearrange; activating substituents make the valeric acid caproic acid
therefore, a benzene ring with a straight- compounds less acidic (15.4).
chain alkyl group is synthesized by 4. The relative amounts of ortho and para
Friedel-Crafts acylation, followed by products depend on the size of the O O
reduction with H 2, Pd/C, or directing and incoming substituents. C C
Zn1Hg2 + HCl + ¢ (Clemmensen), or Benzene rings with highly activating CH2 CH OH OH
H 2NNH 2 + NaOH + ¢ (Wolff- substituents are monohalogenated with-
propenoic acid benzenecarboxylic acid
Kishner). Alkylbenzenes with straight- out a catalyst and polyhalogenated with acrylic acid benzoic acid
chain alkyl groups can also be prepared by it. A benzene ring with a meta-directing
Stille and Suzuki reactions (14.13–14.18). substituent cannot undergo a Friedel- 2. Nomenclature: an acyl halide is an
8. Bromination of an alkylbenzene at the Crafts reaction. Anilines form ammonium alkanoyl halide, an acid anhydride is a
benzylic position allows subsequent ions (strongly deactivating meta alkanoic anhydride, an ester is an alkyl
substitution and elimination reactions. directors) with Lewis acids (15.5, 15.6). alkanoate (where the alkyl prefix refers to
Oxidation with KMnO4 or Na 2Cr2O7/H + 5. When a disubstitued benzene ring the group bonded to the carboxyl oxygen),
converts alkyl groups to COOH groups. undergoes an electrophilic aromatic a lactone (a cyclic ester) is a
Mild oxidation of a 1° or 2° benzyl alcohol substitution reaction, a strongly activating 2-oxacycloalkanone, an amide is an
with MnO2 produces benzaldehyde or a substituent wins out over a weakly acti- alkanamide with N-alkyl as a prefix , if
phenyl ketone, respectively. vating or deactivating substituent (15.8). necessary; a lactam (a cyclic amide) is a
Nitrobenzenes are reduced to anilines 6. Arenediazonium salts 1ArN2 +2, 2-azacycloalkanone, a nitrile is an
with Sn + HCl followed by HO - or with produced from aniline using nitrous acid alkanenitrile (16.1).
H 2, Pd/C (14.19). 1NaNO2 + HCl2 undergo substitution 3. The carbonyl carbon and carbonyl
with CuCl, CuBr, CuCN (Sandmeyer oxygen are sp2 hybridized; carboxylic
reaction), KI, HBF4 (Schiemann acids, esters, and amides are stabilized by
Chapter 15 reaction), and form phenols with e - delocalization. Elevated boiling points
Reactions of Substituted Benzenes Cu 2O, Cu1NO322, H 2O. The diazonium of carboxylic acids and amides are due to
1. Disubstituted benzenes can be named group can be replaced by an H with hydrogen bonds and dipole-dipole
using ortho (1,2), meta (1,3), and para H 3PO2. ArN2 + reacts with strongly interactions (16.2, 16.3).
(1,4) designations. Substituents are listed activated benzene rings via electrophilic 4. Carboxylic acid derivatives undergo
alphabetically, or one of the substituents aromatic substitution to form colored azo nucleophilic acyl substitution reactions
is incorporated into the parent name. In compounds. Diazonium ion formation via a tetrahedral intermediate that expels
polysubstituted benzenes, the results from reaction of a 1° aniline (or the weakest base. The order of reactivity:
substituents are numbered in the amine) with a nitrosonium ion acyl chloride 7 acid anhydride 7
direction that results in the lowest 1+N=O2; 2° anilines form N- ester ' acid 7 amide. More reactive
possible numbers (15.1). nitrosoamines; with 3° anilines, the carboxylic acid derivatives are converted
nitrosonium ion is an electrophile that to less reactive ones (16.5–16.7).
replaces an H of benzene (15.9–15.11).
7. Aryl halides with strongly electron- a group is
NH2 OH
Cl CH2CH3 withdrawing substituents in the ortho expelled

and/or para positions undergo O sp2 sp3 O



O sp2
CH3 k1 k2
NO2 nucleophilic aromatic substitution C + Z

k−1
R C Y
k−2
C + Y

R Y R Z
2-chlorotoluene
ortho-chlorotoluene
4-nitroaniline
para-nitroaniline
2-ethylphenol
ortho-ethylphenol
reactions 1SNAr2 with good nucleophiles Z
not not not
ortho-chloromethylbenzene para-aminonitrobenzene ortho-ethylhydroxybenzene
(HO -, RO -, amines). Halobenzenes react nucleophile attacks
a tetrahedral intermediate
the carbonyl carbon
with NaNH 2 to form anilines via a
benzyne intermediate (15.12, 15.13).
2. Groups that donate e - either by resonance 8. Polycyclic benzenoid hydrocarbons with 5. Acyl halides react with carboxylate ions to
or by hyperconjugation activate a benzene fused rings (naphthalene, anthracene, form acid anhydrides, with alcohols to
ring toward electrophilic aromatic phenanthrene, etc.) undergo reactions form esters, with water to form carboxylic
substitution; groups that withdraw e - similar to the ones that benzene acids, and with excess amine to form
either by resonance or by inductive undergoes (15.14). amides. Acid anhydrides react with
electron withdrawal deactivate it. The alcohols to form esters, with water to form
position to which a substituent directs an Chapter 16 carboxylic acids, and with excess amine to
incoming substituent depends on which Carbonyl Compounds I form amides. The reaction of esters with
of the three possible carbocation 1. Carbonyl compounds have a carbonyl excess water to form carboxylic acids or
intermediates is the most stable. group 1C=O2. Carboxylic acid with excess alcohol to form a new ester
Activating groups and the mildly derivatives have an acyl group 1RC=O2 requires a catalyst; H + (Fischer
deactivating halogens are ortho-para bonded to OH, Cl, OC1=O2R, OR, NH2, esterification) or HO - for hydrolysis, and
directors; all groups more deactivating NHR, NR 2; these groups can be substi- H + or RO - for transesterification. Esters
than the halogens are meta directors. All tuted by another group. Acyl groups undergo aminolysis with amines to form
ortho-para directors (except alkyl, aryl, bonded to H or R do not posses a group amides (16.8–16.12).
RCH “ CHR) have a lone pair on the that can be substituted by another group. 6. Hydrolysis of an ester with a 3° alkyl
atom attached to the ring; all meta The parent name for carboxylic acid is group occurs via a carbocation (16.11).
directors have a positive or partial alkanoic acid. The positions adjacent to 7. Triesters of glycerol (fats and oils) are
positive charge on the atom attached to the carbonyl carbon are a, b, g, d, e in hydrolyzed under basic conditions
the ring (15.2, 15.3). common nomenclature (16.1). (saponification) to form sodium
7
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
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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).
Heterocyclic compounds possess one or CH2OH CH2OH CH2OH CH2OH
8. 3-Oxocarboxylic acids lose CO2 wedge-and-dash Fischer projection wedge-and-dash Fischer projection
more heteroatoms (N, O, S) in a ring. structure structure
(decarboxylate) when heated. Malonic D-glucose D-fructose
Cyclic amines are named as a polyhydroxy aldehyde a polyhydroxy ketone
ester is alkylated, hydrolyzed with acid,
azacycloalkanes or use common names:
and decarboxylated to form a carboxylic
aziridine, azetidine, pyrrolidine, 2. Under basic conditions, monosaccharides
acid (malonic ester synthesis); acetoacetic
piperidine (20.1). are converted to a mixture of aldoses and
ester is alkylated, hydrolyzed, and
2. Quaternary ammonium ions react with ketoses through enolate intermediates.
decarboxylated to form a methyl ketone
hydroxide ion and heat to form alkenes Sugars are reduced to alditols with
(acetoacetic ester synthesis) (18.18–18.20).
(Hofmann elimination reaction). The NaBH 4 and are oxidized by Br2 or
malonic ester synthesis
transition state has carbanion character, Ag +/NH 3 to aldonic acids and by nitric
O O O
so the less substituted amine is the major acid to aldaric acids. Monosaccharides
C C 1. CH3CH2O− C
C2H5O CH2 OC2H5 2. RBr
R CH2 OH product (the hydrogen is removed from form osazones with excess
3. HCl, H2O, ∆
diethyl malonate
malonic ester from malonic ester the b-carbon bonded to the most phenylhydrazine (Sec. 21.5–21.7).
from the alkyl halide hydrogens). Amines react with excess 3. The Kiliani-Fischer synthesis increases
methyl iodide to form quaternary the chain by one carbon, forming C-2
Chapter 19 ammonium iodides (exhaustive epimers. The Wohl degradation decreases
More About Oxidation-Reduction methylation), which are converted by the chain by one carbon (21.8, 21.9).
Ag2O to quaternary ammonium 4. Pentoses and hexoses exist in solution as
Reactions hydroxides (20.4).
1. Reduction increases the number of C ¬ H furanoses and pyranoses, which are
3. Quaternary ammonium ions are used as hemiacetals or hemiketals. The anomers
bonds or decreases the number of phase-transfer catalysts (20.5).
C ¬ O, C ¬ N, or C ¬ X bonds are in equilibrium in solution: a (right in a
4. 3° amines are oxidized to amine oxides Fischer projection, down in a Haworth
1X = halogen2. Oxidation decreases the with peroxide, which eliminate when
number of C ¬ H bonds or increases the projection, axial in a chair conformer); b
heated to form the least substituted (left in a Fischer, up in a Haworth,
number of C ¬ O, C ¬ N, or C ¬ X bonds. alkene (Cope elimination). 2° amines are
Reducing agents are oxidized; oxidizing equatorial in a chair). The optical rotation
oxidized to hydroxylamines and 1° changes when a pure anomer is placed in
agents are reduced. There are three
mechanisms for addition of H 2: H # + H #
amines to nitro compounds (20.6). solution (mutarotation). b -D-Glucose
5. Aromatic 5-membered ring (64% at equilibrium) has all its groups in
(catalytic hydrogenation); heterocycles (pyrrole, furan,
e - + H + + e - + H + (dissolving-metal equatorial positions (21.11, 21.12).
thiophene) are more reactive than 5. Hemiacetals or hemiketals of sugars
reduction); and H - + H + (metal-hydride benzene toward electrophilic aromatic
reduction) (19.1). react with ROH + H +, forming acetals
substitution; they form 2-substituted and ketals (glycosides: furanosides and
2. Chromic acid oxidation converts 1° products. The pyridinium ion, with an
alcohols to carboxylic acids and 2° alcohols pyranosides); the new bond to OR is a
sp2 N, is more acidic 1pKa ~52 than an glycosidic bond. The mechanism
to ketones. Swern oxidation (with DMSO, alkylammonium ion. Pyridine is less
oxalyl chloride, Et3N) converts them to involves an oxocarbenium ion. The
reactive than nitrobenzene toward a-glycoside is the major product due to
aldehydes and ketones, respectively (19.2). electrophilic aromatic substitution,
3. Tollens reagent oxidizes aldehydes to favorable n-s* e - overlap (the anomeric
which occurs at the 3-position. Pyridine effect) (21.13, 21.14).
carboxylic acids (Tollens test). Peroxyacid is more reactive than benzene toward
oxidizes aldehydes to carboxylic acids nucleophilic aromatic substitution,
and ketones to esters (Baeyer-Villiger which occurs at the 2- and 4-positions 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. 6. Straight-chain sugars, hemiacetals, and
cleavage with periodate to form D-glyceraldehyde (a triose) has the hemiketals are reducing sugars; acetals and
aldehydes and ketones. Ozone reacts with R-configuration. Naturally occurring ketals are non-reducing sugars (21.15).
alkenes (ozonolysis); ketones and sugars are D-sugars—the bottom-most 7. Starch is composed of amylose and
aldehydes are formed when the ozonide is asymmetric center in a Fischer projection amylopectin; both are polysaccharides of
treated with Zn or 1CH 322S; ketones and has the OH group on the right. Erythrose glucose. Amylose has a-1,4¿- glycosidic
carboxylic acids are formed when it is and threose are tetroses; ribose is a linkages; amylopectin has a-1,4¿ and
treated with peroxide (19.6-19.7). pentose; glucose and fructose are a-1,6¿-linkages. Glycogen has more
7. Ozone reacts with alkynes to form hexoses. Mannose is the C-2 epimer of branches than amylopectin. Cellulose is a
carboxylic acids. Oxidation reactions and glucose; galactose is the C-4 epimer. polysaccharide of glucose with
others allow for functional group Ketoses have a keto group at C-2 b-1,4¿-linkages; chitin has N-acetyl groups
interconvertion (19.8, 19.9). (21.1–21.4). at the 2-positions of cellulose (21.17).
9
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Chapter 22 7. The primary structure of a protein is the the slow step in general-acid catalysis.
Amino Acids, Peptides, and Proteins sequence of amino acids and the location A base catalyst increases the rate by
1. Peptides and proteins are polymers of of the disulfide bridges. 2-Mercapto- removing a proton: before the slow step in
amino acids. Dipeptides have two ethanol cleaves disulfide bonds. Dilute specific-base catalysis; during the slow
amide-linked amino acids; tripeptides acid partially hydrolyzes peptides into step in general-base catalysis (23.2, 23.3).
have three and polypeptides have many; smaller fragments. Edman’s reagent 3. A nucleophilic (covalent) catalyst
proteins have 40–400. Naturally identifies the N-terminal amino acid. increases the rate by forming a new
occurring amino acids have the Peptidases, enzymes that hydrolyze covalent bond with the reactant, resulting
L-configuration (22.1, 22.2). peptide bonds, include carboxypeptidase in formation of a more reactive species
A and B (exopeptidases), which cleave (23.4).
amide bonds
the C-terminal amino acid, and 4. Metal-ion catalysis makes a group more
O O O O endopeptidases: trypsin, chymotrypsin, susceptible to nucleophilic attack, makes
C C C C and elastase. Cyanogen bromide cleaves a group a better leaving group, or makes
R CH OH NHCH NHCH NHCH O− at the C-side of Met (22.12, 22.13). water a better nucleophile by lowering its
+
NH3
a protonated
R R′ R′′
amino acids are linked together by amide bonds
8. Secondary structure describes the pKa (23.5).
A-aminocarboxylic acid repetitive conformations assumed by 5. Intramolecular reactions occur with
an amino acid
segments of the protein backbone: an faster rates compared with intermolecular
2. The pKa of the carboxylic acid group of an A-helix (right-handed coil with 3.6 amino reactions. Intramolecular catalysis occurs
amino acid is ' 2; that of the ammonium acids/turn); a B-pleated sheet (extended when the catalyst and the reaction center
group is ' 9. At physiological pH (7.3), hydrogen bonded conformation in are in the same molecule (23.6).
amino acids are zwitterions (22.3). parallel or antiparallel orientation); and 6. Enzymes (biological catalysts) bind their
a coil (loop) conformation (22.14). substrate in an active site based on
O O O molecular recognition. In the lock-and-key
a. b.
C C C
model, the substrate fits into the active
R CH OH R CH O− R CH O− site like a key fits into a lock; in the
+
NH3 +
NH3 + H+ NH2 + H+ induced-fit model, the enzyme changes its
pH = 0 a zwitterion
pH = 7
pH = 11
conformation to become complementary
to the shape of the substrate after binding
hydrogen
3. The isoelectric point (pI), the pH at which bond it. The catalytic ability of an enzyme
the amino acid has no net charge, is found results from bringing reacting and
by averaging the pKa’s for neutral side catalytic groups together. A pH-activity
chain amino acids, and by averaging the profile can be used to assess participation
like charge pKa’s for amino acids with of ionizable groups (23.8, 23.9).
ionizable side chains (except Cys and
Tyr). Electrophoresis separates amino
Chapter 24
acids based on pI values; paper and thin-
layer chromatography separates them 9. Tertiary structure, the 3D structure of the The Organic Mechanisms of the
based on polarity. Ion-exchange protein, is maintained by disulfide bonds, Coenzymes
chromatography separates and quantifies hydrogen bonds, hydrophobic 1. Cofactors are metal ions or organic
amino acids based on charge and polarity. interactions, and electrostatic attractions. molecules (coenzymes) that some
Ninhydrin reacts with amino acids to Quaternary structure describes the enzymes need to catalyze a reaction. An
form a colored product (22.4, 22.5). arrangement of protein subunits. enzyme with its cofactor is a holoenzyme;
4. Amino acids are synthesized from Denaturation by pH change, urea, without its cofactor it is an apoenzyme.
carboxylic acids by a-bromination detergent, solvents, or by heat or agitation All the water-soluble vitamins (except
followed by reaction with NH 3; by forms a random coil (22.15–22.17). vitamin C) and water-insoluble vitamin K
reductive amination of a-keto acids; by are precursors for coenzymes (24.1).
the N-phthalimidomalonic ester Chapter 23 2. Vitamin B3 (niacin) is a precursor for
synthesis; or by the acetamidomalonic NAD # and NADP # that are oxidizing
Catalysis agents and for NADH and NADPH that
ester synthesis. A racemic mixture of
1. A catalyst increases the rate of a reaction are reducing agents (24.2).
amino acids can be separated via a kinetic
(without being consumed) by decreasing
resolution with an enzyme (22.6, 22.7).
the free energy of activation ( ¢G‡) (23.1). a basic group of an
5. Peptide bonds have double bond character amino acid side chain
due to electron delocalization. In writing O H B

an amino acid sequence, the N-terminal ‡


∆Gcatalyzed ‡
∆Guncatalyzed
O H B– C
C R R
amino acid is on the left, the C-terminal is O O
a one-step H
on the right. Disulfide bonds are formed mechanism 4 oxidation of substrate
H H
3 CNH2 CNH2
between cysteine side chains (22.8). 5 reduction of coenzyme
Free energy

a two-step
mechanism 6 2
1
N+ N
O R a-carbon O− R
R R
C CH C +
CH
CH N CH N 3. Vitamin B2 (riboflavin) is a precursor for
a-carbon R H
resonance contributors
R H FAD and FMN that catalyze oxidation
reactions. FAD catalyzes the oxidation of
6. t-BOC protects amino groups; DCC Progress of the reaction
thiols to disulfides and amines to imines;
activates carboxyl groups. Automated FADH2 is a reducing agent (24.3).
solid-phase peptide synthesis 2. An acid catalyst increases the rate of a 4. Vitamin B1 is the precursor to thiamine
synthesizes polypeptides from the reaction by donating a proton: before the pyrophosphate (TPP) that catalyzes the
C-terminal end (22.10, 22.11). slow step in specific-acid catalysis; during transfer of a two-carbon unit (24.4).
10
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5. Biotin, from vitamin H, catalyzes the 7. The citric acid cycle is series of 8 Chapter 27
carboxylation of the a-carbon of pyruvate reactions that convert acetyl-CoA to 2 Nucleosides, Nucleotides, and
and acetyl-CoA (24.5). CO2 and CoASH. Each round forms 3 Nucleic Acids
6. Pyridoxal phosphate (PLP), from vitamin NADH, 1 FADH 2, and 1 ATP (25.10). 1. Deoxyribonucleic acid (DNA) and
B6, catalyzes amino acid transformations 8. In the fourth stage of catabolism ribonucleic acid (RNA) are nucleic
including decarboxylation, (oxidative phosphorylation), each acids—phosphodiesters with purine
transamination, racemization, and NADH is oxidized to NAD + and 3 ATP; and pyrimidine bases. The bases in
Ca —Cb bond cleavage (24.6). each FADH 2 is oxidized to FAD and 2 DNA are adenine, guanine, cytosine,
7. Coenzyme B12, from vitamin B12, is a ATP (25.11). and thymine; RNA has uracil instead
cobalt-coordinated porphyrin compound 9. Anabolism is the reverse of catabolism: of thymine. Nucleosides =
that catalyzes certain isomerization acetyl-CoA, pyruvate, and other base + ribose;
reactions (24.7). intermediates are converted into fatty nucleotides = base + ribose +
8. A substituted tetrahyrofolate (THF), from acids, monosaccharides, and amino phosphate . The primary structure
folic acid, transfers a one-carbon unit acids (25.12). of a nucleic acid is the sequence of its
(methyl, methylene, formyl) to its bases. DNA is double stranded (the
substrate. 5-Fluorouracil is a suicide double helix) with major and minor
inhibitor. Methotrexate and wafarin are Chapter 26
grooves. Stacking interactions between
competitive inhibitors (24.8, 24.9). Lipids
the bases add stability. The 2¿-OH
9. Vitamin KH2, from vitamin K, carboxy- 1. Lipids, biological compounds soluble in
group of RNA causes it to be easily
lates the g-carbon of glutamate (24.9). nonpolar solvents, include fatty acids
cleaved (27.1–27.4).
(saturated and unsaturated), waxes (long
chain esters), and fats and oils
Chapter 25 (triacylglycerols) (26.1–26.3).
a. c.
The Chemistry of Metabolism 2. Membranes are composed of
1. Metabolism consists of catabolic phosphoacylglycerols (phospholipids), b.
reactions that break down compounds to which form lipid bilayers. Cholesterol
release energy and anabolic reactions decreases fluidity. Vitamin E is an
that require energy to synthesize antioxidant (Sec. 26.4).
compounds. Catabolism has four stages: 3. Prostaglandins regulate physiological
stage 1 involves the hydrolysis of fats, responses, such as inflammation and
carbohydrates, and proteins; in stage 2 pain. They are synthesized from
the products of the first stage are arachidonic acid and contain a
converted to pyruvate, acetyl-CoA, or cyclopentane ring with a 7-carbon
citric acid cycle intermediates; stage 3 is carboxylic acid side chain and an 2. DNA is synthesized in the 5¿ : 3¿
the citric acid cycle; ATP is synthesized in adjacent (trans) 8-cabon hydrocarbon direction by complementary base
stage 4 (25.1). side chain (26.5). pairing dictated by hydrogen bonds:
2. ATP is used in phosphoryl transfer 4. Terpenes contain multiples of 5 carbons A pairs with T; G pairs with C.
reactions. ATP hydrolysis is favored due to linked head-to-tail (isoprene rule). One strand of DNA is made continuously
electrostatic repulsion, enhanced solvation, Monoterpenes have 10 carbons; and the other is made in pieces
and e - delocalization. ATP, because of its sesquiterpenes have 15. Squalene is a (semiconservative replication). The
negative charges, is not reactive unless triterpene (30 carbons) and is the template strand of DNA is read in the
bound to an enzyme (25.2–25.5). precursor of cholesterol, which is the 3¿ : 5¿ direction to make RNA in the
3. Fatty acids are converted to acetyl-CoA precursor of all steroids. The carotenoids 5¿ : 3¿ direction (transcription); thus,
by a repeating 4-step pathway (lycopene and carotene) are tetraterpenes. RNA has the same base sequence as
1B-oxidation2: oxidation by FAD, Vitamin A is a diterpene that plays an the sense strand of DNA, with Us in
addition of water, oxidation by NAD +, important role in vision (26.6, 26.7). place of Ts. Messenger RNA is the
and cleavage with CoASH (25.6). template for protein synthesis
4. Glucose is converted to pyruvate via a 10- (translation); a codon (a 3 base sequence
head head
reaction pathway (glycolysis), including of RNA) determines the amino acid
a reverse aldol addition that forms brought in. Ribosomal RNA forms
dihydroxyacetone phosphate and ribosomes, on which protein synthesis
glyceraldehyde-3-phosphate (25.7). tail tail
A-farnesene
a sesquiterpene found in the takes place. Each transfer RNA carries an
5. Under aerobic conditions, oxygen oxidizes
waxy coating on apple skins
amino acid (27.5–27.8).
NADH to NAD +: under anaerobic
conditions, pyruvate oxidizes NADH to 5. Acetyl-CoA and malonyl-CoA are
NAD + and forms lactate. Pyruvate is converted to isopentenyl pyrophosphate
converted to acetyl-CoA by the pyruvate for the synthesis of terpenes.
dehydrogenase system. In yeast, pyruvate Isomerization forms dimethylallyl
is converted to ethanol (25.8). pyrophosphate, from which isopentenyl H H
6. Amino acids, each following a different pyrophosphate displaces pyrophosphate CH3 O H N N N H O N

route, are converted to acetyl-CoA, to form a 10-carbon compound; additional N H N N N H N N


N N
pyruvate, and citric acid cycle reactions with isopentenyl pyrophosphate sugar
N
O
sugar
sugar
N
O H N
sugar

intermediates, depending on the amino make larger terpenes (26.8). thymine adenine cytosine
H
guanine

acid. For example, phenylalanine is 6. Steroids are hormones with 4 fused rings
converted to tyrosine, which is and angular methyl groups.
transaminated to p-hydroxyphenyl- B-Substituents are on the same side as the 3. Synthetic oligonucleotides can be made
pyruvate, which is converted to angular methyl groups; a-substituents are using phosphoramidite monomers or H-
fumarate and acetyl-CoA (25.9). on the opposite side (26.9). phosphonate monomers (27.13).
11
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Chapter 28 cyclic compound. Sigmatropic Chapter 30


Synthetic Polymers rearrangements are intramolecular: a s The Organic Chemistry of Drugs
1. A polymer is made from monomers via bond breaks, a new s bond forms, and the 1. A brand name can be used only by the
polymerization. Chain-growth p bonds rearrange. A thermal reaction holder of the patent; a generic name can
(addition) polymers are made by occurs without the absorption of light; a be used by anyone. Natural products are
attaching monomers to a radical, cation, photochemical reaction occurs with the traditional sources for lead compounds
or anion propagating site (28.1). absorption of light. The conservation of (30.1, 30.2).
orbital theory (in-phase orbitals overlap)
repeating unit explains the relationship between the
CH2 CH CH2 CH CH2 CH CH2 CH CH2 CH CH2 CH structure and configuration of the
H 3C O OCH3
reactant, the conditions, and the H 3C
N
styrene polystyrene
n
configuration of the product (29.1-29-2). O N O
a chain-growth polymer
2. Electrocyclic reactions: For a reactant H 3C
O O
with an even number of conjugated
2. Chain-growth polymerization includes cocaine improved lead compound
double bonds ring closure is conrotatory lead compound
initiation, propagation, and termination
under thermal conditions and disrotatory
steps. Head-to-tail addition is favored
under photochemical conditions (TE-AC). 2. Related compounds with improved
due to steric and electronic factors. The
With an odd number of conjugated properties are formed by molecular
mechanism of polymerization depends on
double bonds, ring closure is disrotatory modification (30.3).
the initiator and the stability of the
under thermal conditions and 3. A random screen is the search for a drug
propagating site: radical initiators have
conrotatory under photochemical
bonds that break homolytically; H + is the without structural information. Many
conditions (29.3). drugs have been discovered
initiator in cationic polymerization;
organolithium compounds initiate accidentally (nitroglycerin, Librium,
anionic polymerization. Hydrogen atom Viagra) (30.5).
removal from the main chain causes 4. Drugs bind to specific receptors by
disrotatory H 3C CH3
branching. Living polymers contain ring closure hydrogen bonding, electrostatic
reactive ends that can continue H3C HH CH3 H H interactions, and hydrophobic
polymerization. Alkoxides or acids are (2E,4Z,6E)-octatriene cis-5,6-dimethyl-1,3-cyclohexadiene
interactions (30.6).
used to initiate ring-opening 5. Drugs can inhibit enzymes through
polymerization with epoxides and covalent modification (suicide
3. Cycloaddition reactions: If the sum of the
oxacyclobutanes (28.2). inhibitor). Two drugs can have
reacting p bonds is even, bond formation
3. An isotactic polymer has groups on the synergistic (additive) or antagonistic
is antarafacial under thermal conditions
same side; a syndiotactic polymer has effects; two drugs can be used to
and suprafacial under photochemical
alternating groups. The groups in an overcome drug resistance. Therapeutic
conditions (TE-AC); if the sum is odd,
atactic polymer are random. index, the ratio of toxic dose to
bond formation is suprafacial under
Ziegler-Natta catalysts (aluminum- therapeutic dose, is a measure of drug
thermal conditions and antarafacial under
titantium complexes) control the safety (30.7, 30.8).
photochemical conditions. Cycloaddition
structure of the polymer (28.3). 6. In rational drug design, the chemical or
reactions that form 4-, 5-, or 6-
4. Butadienes polymerize to form rubber physical property of a series of drugs is
memberered rings must occur by
and neoprene. Heating with sulfur causes correlated with biological activity
suprafacial bond formation (29.4).
cross-linking. Two or more different (QSAR). Molecular modeling allows for
4. Sigmatropic rearrangements: If the sum
monomers produce copolymers evaluation of the fit of a potential drug
of the pairs of electrons in the reacting
(alternating, block, graft, or random) with its receptor (30.9, 30.10).
system is even, rearrangement is
(28.4, 28.5). 7. Combinatorial synthesis uses libraries of
antarafacial under thermal conditions and
5. Step-growth (condensation) polymers, compounds for the synthesis of analogs
suprafacial under photochemical
formed by condensation of bifunctional (13.11).
conditions ((TE-AC); if the sum is odd,
compounds, include polyamides and 8. Nucleoside analogs are important
rearrangement is suprafacial under
aramides, polyesters, and antiviral drugs (30.12).
thermal conditions and antarafacial under
polyurethanes that form when a photochemical conditions. Migration on
diisocyanate reacts with a diol. Epoxy the same p-face is suprafacial and to the
resins involve a prepolymer and a opposite face is antarafacial. Sigmatropic
hardener (28.6). rearrangements that form 4-, 5-, or 6- © 2007 Pearson Education, Inc.,
memberered transition states must be Upper Saddle River, NJ.
O O O O
+ ∆ suprafacial. In suprafacial rearrangement, All rights reserved. This material
H3N(CH2)5CO− NH(CH2)5C NH(CH2)5C NH(CH2)5C
−H2O n carbon migrates using one of its p lobes is protected under all copyright
6-aminohexanoic acid 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
Chapter 29 configuration) if it is antisymmetric (29.5). any form or by any means. without permission
Pericyclic Reactions 5. UV light promotes [2 + 2] cycloaddition of in writing from the publisher.
1. The three types of pericyclic reactions two adjacent thymine bases in DNA
involve concerted cyclic reorganization of leading to mutations. Luminescence
e -. Electrocyclic reactions are results from a retro [2+2] cycloaddition
intramolecular with a s bond formed reaction. Vitamin D is produced from
between the ends of a conjugated system. ergosterol, which undergoes a light-
In cycloaddition reactions, two p bond- mediated electrocyclic reaction, followed
containing compounds react to form a by [1,7] sigmatropic rearrangement (29.6).

12