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Organic ChemistryPaula Yurkanis Bruice, 5th Edition
Prepared by Merritt B. Andrus
H
H H
H
C
Methane
HH
H H
p bond
s bond
CC
Ethene
C
C
H
H
Ethyne
Chapter 1Electronic Structure and Bonding
Acids and Bases1. Atoms consist of protons (p+), neutrons
(n), and electrons Atomic number isthe number of p+; mass number is thesum of p+ and n. Isotopes have the samenumber of p+ with different numbers of n.The atomic weight of an element is theaverage weighted mass of its atoms (1.1).
2. An atomic orbital (s, p, d, f) is the volumeof space around a nucleus where anelectron is most likely to be found. Anelectron goes into the lowest energyorbital available (aufbau principle), withtwo in each orbital (Pauli exclusionprinciple). An will occupy an emptydegenerate (same energy) orbital beforeit will pair up with another (Hund’srule). Core are in filled shells; valence
are used for bonding (1.2).3. Atoms give up or accept to achieve an
outer shell of eight electrons (octet rule).Electropositive elements (on the left ofthe periodic table) lose to form cations;electronegative elements (on the right)gain to form anions. Ionic bonds areformed by electrostatic attractionbetween cations and anions.Electronegativity is a measure of anatom’s ability to attract Atoms formcovalent bonds by sharing valence Nonpolar covalent bonds are formed byatoms with the same electronegativity;polar covalent bonds are formed byatoms with different electronegativities.A polar bond has a dipole with a dipolemoment, D (debye). Electrostaticpotential maps show how charge isdistributed: red and blue (1.3).
4. Lewis structures represent compounds,showing all bonding and lone pairThe formal charge on an number of valence minus 1/2 thebonding minus the lone pair Carbocations have a positively chargedcarbon; carbanions have a negativelycharged carbon; a carbon radical has acarbon with an unpaired Kekuléstructures depict bonds as lines.Condensed structures use subscripts andfew, if any, bonds (1.4).
5. An s atomic orbital is spherical; the 2satomic orbital has a radial node. There arethree degenerate, perpendicular p orbitals;each has a node at its nucleus (1.5).
6. Bond length is the distance betweennuclei; bond dissociation energy is the energy required to break a bond. Two atomic orbitals combine to form two molecular orbitals, a bonding MO( or ) and an antibonding MO (or ). A sigma bond is 1s2p*
s*ps
e-.
e-.e-
e-
atom = thee�.
1+21-2
e-.e-.
e-
e-
e-
e�e-
e-
e-
e-
1e-2.
#cylindrically symmetrical. Two p orbitalsoverlap side-to-side to form a pibond (1.6).
7. Methane has four identical covalent bondsformed using four hybrid orbitals,which result from mixing one 2s and three2p atomic orbitals. It has tetrahedral(109.5°) bond angles. Ethane has carbons and 109.5° bond angles. Ethene(with a double bond) has carbons and120° bond angles. Ethyne (with a triplebond) has sp carbons and 180° bondangles. All single bonds are bonds; adouble bond consists of bond and bond; a triple bond consists of bondand bonds. The more s character, theshorter and stronger the bond and thelarger the bond angle. (1.6–1.9, 1.14).
2 p1 s
1 p1 ss
sp2
sp3
1sp32
1p2alcohols and waterThe equilibrium constant for
an acid-base When atoms are the same
size, the more electronegative the atomto which the hydrogen is attached, thestronger the acid. Relative electroneg-ativities: When atomsare very different in size, the strongestacid will have its hydrogen attached tothe largest atom. For example, acidstrength: Thestronger the acid, the weaker itsconjugate base. Weak bases are stablebases. A Lewis acid accepts a share in apair of a Lewis base donates a share ina pair of Curved arrows are used toshow electron flow; the arrow beginswhere the electrons originate and pointsto where they end up (1.16–1.26).
Chapter 2An Introduction to Organic
Compounds1. Hydrocarbons contain only C and H.
Alkanes are hydrocarbons with onlysingle bonds. Constitutional isomershave the same molecular formula butdiffer in the way the atoms are connected.IUPAC (systematic) and common namesare used to name compounds. methylene group. A primary (1°) carbonis bonded to one other C; a secondary (2°)carbon is bonded to 2 Cs; a tertiary (3°)carbon is bonded to 3 Cs. Substituentsare indicted as prefixes, with the parenthydrocarbon numbered in the directionthat puts the lowest number in the nameof the compound. Substituents are listedalphabetically; di, tri, tetra, are used foridentical alkyl groups, but are notalphabetized; sec and tert are also notalphabetized, but iso and cyclo are. In acycloalkane with two substituents, thefirst cited substituent gets the lowernumber (2.1–2.3).
CH2 = a
e-.e-;
HI 7 HBr 7 HCl 7 HF.
sp 7 sp27 sp3.
1product Ka2.reaction = 1reactant Ka2/
1pKa' 152.
1pKa' 102;
8. The O and N of water and ammonia arehybridized; has 104.5° bond
angles; has 107.3° bond angles. and are is (1.11, 1.12).
9. A Br�nsted acid donates a proton aBr�nsted base accepts a proton, forming aconjugate base and a conjugate acid,respectively. The acid dissociationconstant is a measure of the acidity ofa compound; the lowerthe the stronger the acid. Protonatedcarboxylic acids and protonated
acids carboxylic acids protonated weak acidsamines = very
1pKa' 52;acids = weak
1pKa 6 02;alcohols = strong
pKa,pKa = - log Ka;
(Ka)
1H+2;sp3sp2; C-C #
C+NH3
H2Osp3
CH3CHCH2
CH3an isobutyl group
CH3CH2CH
CH3a sec-butyl group
CH3C
CH3
CH3
a tert-butyl group
a secondary carbon a tertiary carbona primary carbon
2. Alkyl halides and ethers are named assubstituted alkanes; alcohols and aminesare named using a functional group suffix.Substituents on the nitrogen are precededby an N. If a parent chain has a substituent,the substituent gets the lowest number; ifit has a functional group, the functionalgroup gets the lowest number; if it hasboth a substituent and a functional group,the functional group gets the lowestnumber. Only if the functional group getsthe same number in either direction, is the
Bruice_SC_v4.qxd 11/20/06 1:28 PM Page 1
2
axial bondequatorial bond
==
C C + +Hslow
H
a carbocationintermediate
the electrophileadds to an sp2
carbon of thealkene
the nucleophileadds to thecarbocation
+C C
fastBr Br −
Br H
C C
CH3CHCH3-methyl-1-butene 3-methyl-1-butanol
CH2 CH3CHCH2CH2OH1. BH3/THF2. HO−, H2O2, H2O
CH3 CH3
chain numbered so the substituent getsthe lower number (2.4–2.7).
3. Alkyl halides and alcohols are 1°, 2°, or 3°depending on whether the X or OH is ona 1°, 2°, or 3° carbon. Amines are 1°, 2°, or3° depending on how many alkyl groupsare bonded to N (2.4, 2.6, 2.7).
4. The stronger the intramolecular forcesholding molecules together, the higherthe boiling point: hydrogen bonds arestronger than dipole-dipole interactions,which are stronger than van der Waalsforces, which increase with molecularweight and decrease with branching (2.9).
5. Polar compounds dissolve in polarsolvents; nonpolar compounds dissolvein nonpolar solvents. An oxygen can dragabout 3 carbons into water (2.9).
6. Organic compounds exist in variousconformations due to bond rotation.Newman projections depict staggered(anti and gauche) and higher energyeclipsed conformations. Cyclopropaneand cyclobutane have significant anglestrain; cyclopentane and cyclohexane arenearly strain free. Cyclohexane adopts achair conformation with an axial andequatorial bond on each carbon. Ring-flipcauses one chair conformer to convert intoanother chair conformer; bonds that areaxial in one are equatorial in the other. Asubstituent is more stable in an equatorialposition. Acis isomer has substituents onthe same side of the ring; a trans isomerhas them on opposite sides (2.10–2.14).
2. The carbons of an alkene and the fouratoms attached to them are in a plane. Cisisomers have the hydrogens on the sameside of the double bond; in trans isomersthey are on opposite sides. The E isomerhas the high priority groups (based onatomic numbers) on opposite sides of thedouble bond; the Z isomer has them onthe same side. Proceeding down asubstituent breaks a tie (3.5).
3. The double bond of an alkene is itsfunctional group (the center ofreactivity). Curved arrows show themechanism for this electrophilicaddition reaction ( is an electrophileand the bond is a nucleophile; thecarbocation is an electrophile and is anucleophile) (3.6).
Br-
p
H+
sp2 Chapter 4The Reactions of Alkenes
1. Hydrogen halides add to alkenes to formalkyl halides. Carbocations are stabilizedby hyperconjugation ( delocalizationby overlap of adjacent bond orbitalswith the empty p orbital); relativestabilities: The Hammondpostulate states that the transition state ismore similar in structure to the species towhich it is more similar in energy (4.1–4.3).
2. Electrophilic addition reactions areregioselective; the electrophile adds tothe carbon bonded to the greaternumber of hydrogens in order to form the more stable carbocation (4.4).
3. The addition of water or an alcohol to analkene requires an acid catalyst. Additionof water forms an alcohol; addition of analcohol forms an ether (4.5).
4. Acarbocation can rearrange to a morestable carbocation via a 1,2-hydride or 1,2-methyl shift, or by ring expansion (4.6).
5. Halogens ( and ) add to alkenes toform vicinal dihalides via a cyclicbromonium ion intermediate. If thereaction is carried out in water, ahalohydrin is formed with water addingto the more substituted carbon. Sincethe intermediate in these reactions is not acarbocation, carbocation rearrangementscannot occur (4.7).
6. Alkenes undergo oxymercuration-reduction and alkoxymercuration-reduction to form alcohols and ethers,respectively. Carbocations are not formedas intermediates, so carbocationrearrangements do not occur (4.8).
7. Alkenes react with peroxyacidsto form epoxides. The reaction
is concerted (it does not have anintermediate) (4.9).
8. Hydroboration-oxidation of an alkeneinvolves the concerted addition of borane
to form a trialkylborane that istreated with and to form analcohol. Borane is the electrophile thatadds to the less substituted carbon;
is the nucleophile that adds to theother carbon (4.10).sp2H-
sp2
HO-H2O2
1BH32
1RCO3H2
sp2
Br2Cl2
sp2
3° 7 2° 7 1°.
s
e-
Chapter 3Alkenes: An Introduction to
Reactivity. Thermodynamics andKinetic
1. Alkenes are hydrocarbons with a doublebond. The total number of bonds andrings is the degree of unsaturation. Thegeneral molecular formula for ahydrocarbon is minus 2hydrogens for each degree ofunsaturation. The parent hydrocabon isthe longest carbon chain that contains thedouble bond, numbered so that the startof the double bond is given the lowestpossible number. Alkadiene is used fortwo double bonds. Vinylic carbons aredouble-bonded carbons; allylic carbonsare adjacent to vinylic carbons (3.1–3.2).
CnH2n+2
p
CH3CHCH2CH CCH2CHCH3
2-bromo-4-ethyl-7-methyl-4-octenenot
7-bromo-5-ethyl-2-methyl-4-octenebecause 4 < 5
CH3 CH2CH3
Br
6-bromo-3-chloro-4-methylcyclohexenenot
3-bromo-6-chloro-5-methylcyclohexenebecause 4 < 5
Br
Cl
CH3
4. Energy changes are shown by a reactioncoordinate diagram. A transition statehas partially broken and partially formedbonds; an intermediate has fully formedbonds. The more stable the species, thelower its energy. The change in Gibbs freeenergy is exergonic whenforming a more stable species, andendergonic when forming a lessstable species. is related to theequilibrium constant by The formation of products with strongerbonds and greater freedom of movementcauses to be negative;
If a system atequilibrium is disturbed, it will adjust tooffset the disturbance (Le Chatlelier’sprinciple). The free energy of activation( ‡) is the difference between the freeenergy of the transition state and the freeenergy of the reactants. The greater ‡,the slower the reaction. The rate-determining step has its transition state atthe highest point on the reactioncoordinate. The rate of a reaction isdirectly proportional to a rate constant, k;the smaller the rate constant, the slowerthe reaction. The Arrhenius equationrelates the rate constant to the activationenergy (3.7–3.8).1Ea2
¢G
¢G
¢G° = ¢H° - T¢S°.¢G°
-RT ln Keq.¢G°
1+2
1-21¢G°2
Free
en
erg
y
CH2CH3
Br
+
CH3CH
CH3CHCH2CH3
Progress of the reaction
−∆G˚
intermediate
Br−
CH3CH CHCH3
HBr
9. Alkenes undergo catalytic (Pd/C, Pt/C,Ni) hydrogenation to form alkanes. Themost stable alkene has the smallest heat ofhydrogenation. The greater the numberof alkyl substituents attached to the carbons, the more stable the alkene (4.11).
Chapter 5Stereochemistry
1. Constitutional isomers differ in the waytheir atoms are connected. Stereoisomers(cis-trans isomers and isomers with
sp2
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 2
3
a ketone
an aldehyde
H2O, H2SO4
HgSO4
CH3C CH
CH3C CH2 CH3CCH3
OH O
1. disiamylborane2. HO−, H2O2, H2O CH3CH CH CH3CH2CH
OH O
a.
b. c.
CH3CH2CH3 CH3
CH2CH3
Br
H
the two isomers of 2-bromobutaneenantiomers
mirror
Br
HC C
(S)-2-bromobutane (R)-2-bromobutane
CCH3CH2
Br
HCH3
CH
Br
CH2CH3CH3
1 1
2 23 3
4 4
asymmetric centers) differ in the way theatoms are arranged in space. Cis-transisomers have either a double bond or acyclic structure (5.1).
2. A molecule is chiral if it isnonsuperimposable on its mirror image.A carbon bonded to four differentsubstituents is an asymmetric center.A molecule with one asymmetric center ischiral; it can exist as a pair ofenantiomers (nonsuperimposable mirrorimage molecules). Enantiomers have thesame physical and chemical properties(5.2–5.6).
7. In a stereoselective reaction, onestereoisomer is formed in preference toanother. In a stereospecific reaction,stereoisomeric (e.g., cis and trans)reactants form different stereoisomers asproducts. When a reactant without anasymmetric center forms a product withone asymmetric center, the product willbe a racemic mixture. Electrophilicaddition reactions that form carbocationintermediates involve syn and antiaddition. 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 distinguishbetween enantiomers. Enzyme-catalyzedreactions are completely stereoselective—only one stereoisomer is formed.Enzyme-catalyzed reactions arestereospecific—the enzyme reacts withonly one stereoisomer (5.20, 5.21).
Chapter 6The Reactions of Alkynes
1. Alkynes are hydrocarbons with a triplebond. A terminal alkyne has the triplebond at the end of a chain; otherwise, it isan internal alkyne. A compound with adouble and a triple bond is named as analkenyne; the double bond has thegreater priority only if there is a tie. OHand groups have priority overdouble and triple bonds (6.1, 6.2).
2. Electrophiles add to the least substitutedsp carbon. Addition of HCl or HBr formsa vinyl halide; with excess reagent, ageminal dihalide is formed. Addition of
or forms a dihaloalkene; excessreagent forms a tetrahaloalkane (6.5, 6.6).
3. The acid-catalyzed addition of water toan alkyne forms an enol, whichtautomerizes to a ketone. is usedwith terminal alkynes (6.7).
4. Borane adds to an alkyne to form a vinyl-borane, which is oxidized to an enol. Aninternal alkyne tautomerizes to a ketone: aterminal alkyne requires disiamylboraneand forms an aldehyde (6.8).
HgSO4
Br2Cl2
NH2
Working from product to reactants, whendesigning a synthesis, is calledretrosynthetic analysis (6.10–6.12).
Chapter 7Delocalized Electrons and Their
Effect on Stability, Reactivity, and 1. Delocalized are shared by three or
more atoms. Benzene has delocalized all the bonds have the same length;the three pairs of are shared by allsix carbons. Resonance contributors uselocalized to approximate the truestructure with delocalized (theresonance hybrid) (7.1–7.3).
e-
e-
p e-
C ¬ Ce-:
e�pKa
3. The R,S system is used to name chiralcompounds by prioritizing the foursubstituents attached to the asymmetriccenter based on atomic number. When thelowest priority substituent points to therear, an arrow starting at the highestpriority substituent and pointing at thesecond highest priority substituent isclockwise if the compound has the Rconfiguration, and counterclockwise if ithas the S configuration (5.7).
4. Chiral molecules that rotate plane-polarized light to the right aredextrorotatory those that rotate it tothe left are levorotatoryA polarimeter measures observedrotation, from which specific rotation
can be calculated. A 50:50 mixture ofenantiomers is an optically inactive
racemic mixture. Enantiomericexcess is measured by dividing theobserved specific rotation by the specificrotation of the pure enantiomer (5.8–5.10).
5. Stereoisomers that are not mirror imagesare diastereomers. Unlike enantiomers,diastereomers possess different physicaland chemical properties. In compoundswith two asymmetric centers, theconfiguration of one of the asymmetriccenters is the same in both diastereomers,and the configuration of the other is notthe same in both. Compounds with two ormore asymmetric centers that possess aplane of symmetry are achiral (opticallyinactive) meso compounds (5.11–5.13).
6. Enantiomers can be separated (resolved)by chiral chromatography (5.16).
1a = 02
[a]a,
1-2.1+2;
5. Catalytic hydrogenation of an alkyneforms an alkane. With Lindlar catalyst, a cis alkene is formed; with
a trans alkene isformed via radical anion and vinylradical intermediates (6.9).
6. A terminal alkyne isdeprotonated with to form anacetylide ion, which reacts with a 1° alkylhalide to form a longer-chain alkyne.
NaNH2
1pKa 252
Na 1or Li2 + NH3,
2. Rules for drawing resonance contributors:move only and lone-pair Move toa positively charged atom or to an atomwith a bond. Each resonancecontributor has the same net charge. Thegreater the predicted stability of theresonance contributor, the more itcontributes to the hybrid. Destabilizingfeatures: incomplete octet, positivelycharged electronegative atom, chargeseparation (7.4, 7.5).
3. Delocalization (resonance) energy is thegain in stability that results from havingdelocalized The greater the number ofrelatively stable resonance contributors,the greater the delocalization energy.Relative stabilities:
Allylic and benzylic cations are morestable than 1° alkyl cations because of delocalization (7.6–7.8).
4. A molecular orbital (MO) results from alinear combination of atomic orbitals(LCAO). Two are placed in each MO,starting from the lowest energy MO. Thenumber of MOs equals the number ofAOs; a node is added for each ascendingMO. The highest occupied MO (HOMO)is the highest energy MO that contains the lowest unoccupied MO (LUMO) isthe lowest energy MO that does notcontain (7.8).
5. Carboxylic acids and phenol have somedelocalization, but their conjugate
bases have more, causing carboxylicacids and phenol to be stronger acids than alcohols
which have no delocalization. Protonated aniline
is more acidic than protonatedalkylamines due to anincrease in delocalization energy uponlosing a proton (7.9).
1pKa ' 1021pKa ' 52
e-1pKa ' 152,
1pKa ' 1021pKa ' 52
e-
e-
e-;
e-
e-
cumulated dienes.isolated dienes 7
conjugated dienes 7
e-.
p
e-e-.p
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 3
4
+Nu NuC X + X−d+ d−−C
substitutionproduct
a nucleophile
CH3 HBr+ H2O+
Br− weak base
∆H CH3 H CH3 Br
a weakly basic leaving group
poor leavinggroup
good leavinggroup
OO +H
6. Conjugated dienes form 1,2- and 1,4-addition products. At low temperatures,where the reaction is not reversible, thekinetic product (the one that is formedfaster) is favored. At higher temperatures,where the reaction is reversible, thethermodynamic product (the more stableproduct) is favored. The 1,2-product isalways the kinetic product; either the 1,2-or 1,4-product can be the thermodynamicproduct; it will depend on which is themore substituted alkene (7.10, 7.11).
7. Aconjugated diene reacts with adieneophile (an alkene with an withdrawing group) to form a cyclohexenevia a concerted Diels-Alder reaction. Thediene adopts an s-cis conformation for this
cycloaddition reaction where theHOMO of one reactant interacts with theLUMO of the other. The reaction isstereospecific; e.g., a cis dienophile formscis products. Bridged, bicyclic productsfavor the endo configuration when thesubstituent has (7.12).p e-
[4 � 2]
e�
3. Leaving group tendencies for RX:Strong bases are better
nucleophiles, except if there is a largedifference in size and they are in a proticsolvent, because of the greaterpolarizability of the large nucleophile andits weaker solvation (in which case is abetter nucleophile than ). Aprotic polarsolvents (DMSO, DMF) are used in reactions of alkyl halides with negativelycharged nucleophiles because suchsolvents solvate only cations (8.3, 8.4).
4. The reaction of a 3° alkyl halide with is a unimolecular nucleophilicsubstitution reaction with a ratelaw dependent only on [RX] (a first-orderreaction). The leaving group leaves,forming a carbocation that is attacked bythe nucleophile. Formation of thecarbocation is the rate-limiting step, so 3°alkyl halides are the most reactive;carbocation rearrangements can occur.Products with inverted and retainedconfigurations are obtained. Partialracemization can occur because one faceof the carbocation can be partiallyblocked by the leaving group (8.5–8.7).
5. Benzylic and allylic halides undergo bothand reactions. Vinyl and aryl
halides undergo neither nor reactions (8.8).
6. High concentration of a good nucleophilefavors a poor nucleophile favors
If a reactant is charged, increasingthe polarity of the solvent decreases therate of the reaction; if neither of thereactants is charged, increasing thepolarity of the solvent increases the rateof the reaction (8.9, 8.10).
7. Bifunctional molecules can undergointramolecular reactions to form cyclicproducts. Five- and six-membered ringsare favored (8.11).
8. A common cellular methylating agent isS-adenosylmethionine (SAM), a methylsulfonium ion (8.12).
Chapter 9Elimination Reactions of Alkyl
Halides1. An E2 reaction of an alkyl halide involves
the simultaneous removal of a protonfrom a and the halide ion fromthe (dehydrohalogenation) toform an alkene (a ). An E1reaction is a two-step reaction; theleaving group departs (the rate-limitingstep), forming a carbocation, which losesa proton from the Leavinggroup order in both E2 and E1:
(9.1, 9.3).2. E2 and E1 reactions are regioselective: the
more stable (more substituted) alkene isthe major product (the hydrogen isremoved from the bonded to thefewest hydrogens; Zaitsev’s rule), becausethe transition state is alkene-like.
b-carbon
I-7 Br-
7 Cl-7 F-
b-carbon.
B-eliminationa-carbonb-carbon
SN1.SN2;
SN2SN1SN2SN1
1SN12,
H2O
SN2F-
I-
I-7 Br-
7 Cl-.However, alkyl fluorides, with a poorleaving group, preferentially form the lesssubstituted alkene, because the transitionstate is carbanion-like. The relativestabilities of carbanions are the reverse of carbocation stabilities (9.2).
3. E2 and E1 reactions are stereoselective:the alkene with the bulkiest groups onopposite sides of the double bond isfavored (9.5).
4. In E2 reactions of substitutedcyclohexanes, both groups that areeliminated must be in axial positionsbecause of anti elimination (9.6).
5. Under conditions: 1° alkylhalides do not react because primarycarbocations are too unstable to beformed; 2° and 3° alkyl halides undergoboth substitution and elimination. Under
conditions: 1° alkyl halides favorsubstitution; 2° undergo bothsubstitution and elimination; 3° undergoonly elimination (9.8).
6. Bulky, strong bases (tert-butoxide) favorE2 over due to steric hindrance. Hightemperatures favor E2 over due to agreater (9.8).
7. Ethers are formed from alkoxide ions and1° alkyl halides (Williamson ethersynthesis). Na or NaH converts analcohol to an alkoxide ion. Geminal andvicinal dihalides react with excess to form alkynes (9.9, 9.10).
Chapter 10Reactions of Alcohols, Amines,Ethers, Epoxides, and Sulfur-
Containing Compounds1. Alcohols and ethers have poor leaving
groups due to the strong basicity of and If protonated, they becomegood leaving groups that can be replacedby halide ions. These are reactions(so carbocation rearrangements canoccur) except in the case of 1° alkylhalides, which are reactions (10.1).SN2
SN1
RO-.HO-
-NH2
¢S°SN2
SN2
SN2/E2
SN1/E1
1° 7 2° 7 3°,
a 1,4-addition reaction to 1,3-butadiene
C CHH
CH2
CH2
HC
30 ºC CCH3
O
CH
CH2
CCH3
O
CH2
CH CH2
HC
CH2
electron-withdrawing groupnucleophile
electrophile
4
3
2
1
4
3
2
1
Chapter 8Substitution Reactions of Alkyl
Halides1. Substitution reactions involve
replacement of a leaving group with anucleophile. Alkyl halides have goodleaving groups (8.1).1I-, Br-, Cl-2
2. The reaction of bromomethane with is a bimolecular nucleophilicsubstitution reaction with a ratelaw dependent on [RX] and (asecond-order reaction). attacks withsimultaneous departure of the leavinggroup. Steric effects govern the relativerates with 1° alkyl halides faster than 2°,and 3° very slow. The reaction occurs withinversion of configuration because thenucleophile (HOMO) interacts with the
(LUMO) on the backside of the carbonattached to X (8.2).s*
HO-
[HO-]1SN22,
HO-
the configuration of theproduct is inverted relativeto the configuration ofthe reactant
Br−HO−+ +CCH3CH2 CH2CH3
CH3
H HHOBr
C
CH3
(R)-2-bromobutane (S)-2-butanol
2. Alcohols react with or thionylchloride to form alkyl halides.Alcohols react with sulfonyl chloride toform sulfonate esters (10-2, 10-3).
3. Alcohols undergo dehydration whenheated with a strong acid toform alkenes. These are reactions,except in the case of 1° alcohols, which are
dehydratesalcohols without carbocation formation,so there are no rearrangements (10.4).
4. 2° alcohols are oxidized to ketones; 1°alcohols are oxidized to carboxylic acidswith chromic acid and toaldehydes with PCC (10.5).
1H2CrO42
POCl3 + pyridineSN2.
SN11H2SO42
1SOCl22PBr3, PCl3,
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 4
5
site of nucleophilic attackunder acidic conditions
site of nucleophilic attack underbasic or neutral conditions
CH3CH CH2
O 2.5 2.6 2.7 2.8 2.9 3 3.5 4 5 5.5 6 7Wavelength (µm)
8 9 104.5
2200 2000 1800 1600 1400 1200 1000240026002800300032003400360038004000
Wavenumber (cm−1)
CH3CCH2CCH3
CH3
O OH
O H
% T
rans
mitt
ance
OC0
100
1019
10−6 10−4
Frequency (n) in Hz
g-rays
1017 1013 1010 105
X-rays Microwaves
10−1 0.4 0.8 106 1010102
Wavelength (l) in µm
1015
Radio wavesNMR
Ultravioletlight
Cosmicrays
Infraredradiation
Visiblelight
highfrequency
shortwavelength
lowfrequency
longwavelength
5. Amines have poor leaving groups due tothe very strong basicity of Ammonium ions are weaker acids
than hydronium ions so amines are stronger bases and betternucleophiles than alcohols (10.6).
6. Ethers are cleaved with HI; the reaction is(breaking to form the more stable
carbocation) unless the alkyl groupscannot form a carbocation (primary,vinyl, aryl); then it is (with iodide ionattacking the least sterically hinderedcarbon) (10.7).
7. Epoxides react with nucleophiles. Underacidic conditions, the ring opens to putthe developing positive charge on themore substituted carbon; under basicconditions, the nucleophile attacks theless sterically hindered carbon (10. 8).
SN2
SN1
1pKa ~ -22,1pKa ~102
-NH2.step and the product of the secondpropagation step (11.2).
2. Radical stability: Relativerates for chlorination at room temp: 5: 3.8:1 for 3°, 2°, 1°. Probability and reactivityfactors are used to predict productdistribution (11.3, 11.4).
3. Relative rates for bromination at 125 °C:1600 : 82 : 1 for 1°, 2°, 3°. A bromineradical is less reactive and more selectivethan a chlorine radical (reactivity-selectivity principle (11.5).
4. When HBr adds to alkenes in thepresence of peroxide, is theelectrophile, so it adds to the carbonbonded to the most hydrogens—oppositeto the regioselectivity of HBr additionwithout peroxide (11.6).
5. If a radical substitution reaction or aradical addition reaction forms anasymmetric center, the product will be aracemic mixture (11.7).
6. Allylic and benzylic halides areselectively halogenated at the allylic orbenzylic positions. Bromination of allylicpositions is best carried out with
if the resonancehybrid of the radical intermediate is notsymmetrical, two substitution productsare formed (11.8).
Chapter 12Mass Spectrometry, IR Spectroscopy,
and UV/Vis Spectroscopy1. An beam removes an to form a
molecular ion (a radical cation), whichthen fragments. A magnetic field focusescations toward a detector, giving a massspectrum, which plots abundance versusmass-to-charge (m/z) (12.1).
2. The molecular ion corresponds to thenominal molecular mass. The base peak isthe highest abundance ion. peaks canbe used to determine the number ofcarbons. For a chlorine-containing com-pound, the peak is 1/3 the M peak;for a compound that contains bromine, the
peak is equal to the M peak. Highresolution MS can determine the exactmolecular mass. The beam is most likelyto dislodge a lone-pair Abond betweencarbon and a more electronegative atombreaks heterolytically; a bond betweencarbon and an atom of similar electroneg-ativity breaks homolytically. (cleavage of the bond to the heteroatom)occurs because the positive charge is thenshared by two atoms (12.2–12.5).
3. Spectroscopy uses electromagneticradiation to probe molecular structure.Frequency is directly proportional toenergy wavelength isinversely proportional to energy( of light). IR spectroscopy uses wavenumbers (thenumber of waves in 1 cm), which aredirectly proportional to energy and haveunits of (12.6).cm-1
c = speedE = hc/l;
1l21E = hn2;1n2
a
a-cleavage
e-.e-
M+2
M+2
M+1
e-e-
NBS + peroxide + ¢;
sp2Br #
3° 7 2° 7 1°.
4. Stretching vibrations involve changes inbond length and occur at a higher energythan bending vibrations, which involvechanges in bond angles. Absorptionbands indicate the kind of bonds presentin a compound. Those in the functionalgroup region detectfunctional groups; those in the fingerprintregion are characteristicof the molecule as a whole (12.7, 12.8).
11400–600 cm-12
14000–1400 cm-12
8. Arene oxides can undergo nucleophilicattack or can rearrange (via an NIH shift)to form phenols. Arene oxides that formunstable carbocations are more apt toundergo nucleophilic attack (10.9).
9. Crown ethers form inclusion compoundswith metal ions based on molecularrecognition. Crown ethers can be used asphase-transfer catalysts (10.10).
10. Thiols (RSH) are more acidic than alcohols. Thiolate anions react withalkyl halides to form sulfides (RSR);sulfides react with alkyl halides to formsulfonium salts (10.11).
11. Lithium reacts with alkyl halides to formalkyllithium compounds; magnesiumreacts with alkyl halides to form Grignardreagents. These organometalliccompounds are good nucleophiles; theyreact as if they were carbanions. Forexample, they react with epoxides to form(after acidification) alcohols. In thepresence of OH, or NH, organometalliccompounds form alkanes (10.12).
12. Gilman reagents are formedfrom alkyllithium compounds and CuI.They couple with vinyl, aryl, and alkylhalides, replacing the halogen. Catalyticpalladium is used to facilitate couplingreactions with alkenes (Heck), stannanes(Stille), and organoboranes (Suzuki) andaryl, benzyl, or vinyl halides (10.13).
Chapter 11Radicals • Reactions of Alkanes
1. Alkanes undergo halogenation with or and heat or light to form alkylhalides in a chain reaction that hasinitiation, propagtion, and terminationsteps. The radical formed in the initiationstep is the reactant of the first propagation
Br2
Cl2
1R2CuLi2
H+,
1R3S� X�2
1pKa ~102
5. The greater the change in dipole momentwhen a bond vibrates, the more intensethe absorption. The energy required tostretch a bond depends on the bondstrength and the masses of the bondedatoms; stronger bonds and lighter atomsabsorb at higher frequencies (Hook’slaw); triple bonds are stronger thandouble bonds, which are stronger thansingle bonds. Electron delocalization canaffect bond order. C-H stretch frequencydepends on the hybridization of C
Alkene substitutionpatterns can be identified in thefingerprint region (12.9–12.11).
6. (of RCOOH and ROH) and show absorption bands at the samefrequency, but their shapes are different.The absence of bands can rule outfunctional groups. Stretches with no netchange in dipole moment are IR inactive(12.12–12.14).
7. UV/Vis spectroscopy involves excitationof an to a higher energy state: and transitions; the latter arelower in energy and have greater molarabsorptivities The greater the the lower the energy: UV radiation(180–400 nm) is of higher energy thanvisible light (400–780 nm). A chromophoreis the group in the molecule that causes theabsorption. Absorbance depends on theconcentration of the sample, the length ofthe light path, and the of the compound(Beer-Lambert Law) (12.15–12.17).
8. The more conjugated double bonds, thegreater the (due to raised energy ofthe HOMO and lowered energy of the
lmax
e
lmax,1e2.
p: p*n : p*e-
N ¬ HO ¬ H
1sp 7 sp27 sp32.
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 5
6
C CH
C H
OC
C
O
CC
H
C
H
C
9.012 8.0 6.5 4.5 2.5 1.5 0
H
Z
C OH
O
H
vinylicZ = O, N, halogen
CC H
saturated
allylic
d (ppm)200 150 100 50 0
C OC C
C O
C NC ClC Br
sp3 carbon
C C
d (ppm)
Br
++ HB+
+ FeBr4
B
+ H
BrBr Br FeBr3+ −
−
N
pyrroleH
pyridine
N
furan
O
thiophene
S
LUMO) and the greater the Coloredcompounds absorb visible light.Auxochromes (OH and ) attached tochromophores increase both and (12.18, 12.19).
Chapter 13NMR Spectroscopy
1. Nuclear magnetic resonance (NMR)establishes atom connectivity. WhenNMR active nuclei are subjected to an applied magneticfield, they align either with the field
or against the fieldThe energy difference
between the spin states depends on thestrength of the magnetic field andthe gyromagnetic ratio (13.1).
2. Nuclei resonate at different frequenciesdue to shielding by nearby electrons thatinduce a local magnetic field that opposesthe applied magnetic field, therebychanging the effective magnetic field
Protons inrich environments are shielded and
resonate at lower frequencies (upfield);those in poor environments aredeshielded and resonate at higherfrequencies (downfield) (13.3, 13.6).
e-
e-
1Beffective = Bapplied - Blocal2.
1Bo2
1B-spin state2.1A-spin state2
11H, 13C, 15N, 19F, 31P2
elmax
NH2
e. 5. Integration indicates the relative number of protons responsible for eachsignal. A signal has a multiplicityaccording to the where N isthe number of neighboring equivalentprotons bonded to adjacent carbons.Splitting occurs as a result of theproton(s) that give rise to the signal beingcoupled to adjacent nonequivalentprotons whose nuclear spins can aligneither with or against the appliedmagnetic field (13.9, 13.10).
N � 1 rule,
Chapter 14Aromaticity Reactions of Benzene1. Aromatic compounds have large
delocalization energies: benzene is 36kcal/mol more stable than hypothetical‘cyclohexatriene.’ To be aromatic, acompound must have an uninterruptedcloud of electrons (that is, it must becyclic, planar, and every ring atom musthave a p orbital), and the cloud mustcontain an odd number of pairs of (Hückel’s ) (14.1, 14.2).
2. Cyclobutadiene and cyclooctatetraene,with an even number of pairs of arenot aromatic. The cyclopentadienyl anionand the cyloheptatrienyl cation, eachwith three pairs of are aromatic.Pyridine, pyrrole, furan, and thiophene(heterocyclic compounds) are aromatic(14.1, 14.2).
p e-,
p e-,
4n � 2 rulep e-
p
p
#
Frequency
Inte
nsi
ty
"downfield" "upfield"
deshielded nuclei shielded nuclei
these protons sense alarger effective magneticfield, so come into resonanceat a higher frequency
these protons sense asmaller effective magneticfield, so come into resonanceat a lower frequency
3. Chemically equivalent protons resonateat the same frequency; nonequivalent setsof protons resonate at differentfrequencies. The chemical shift isindependent of spectrometer frequency;
of the signal in Hz from TMSdivided by spectrometer frequency inMHz. Low frequency (shielded) signalshave small values (13.4, 13.5).
4. In a similar environment, a signal for is at a lower frequency than a signal for
which is at a lower frequency than asignal for CH. Induced ring currentscause protons (aryl and vinyl)and sp-bound protons to experiencediamagnetic anisotropy and resonate at7–5 ppm and 2.4 ppm, respectively (13.7,13.8).
sp2-bound
CH2,
CH3
d
d = distance
1D2
ClCH2CH2CH2Iac b
8 7 6 5 3
2
2
2
2 1 04d (ppm)
frequency
3.7 3.6 3.5 PPM 3.4 3.3 3.2 PPM 2.3 2.2 2.1 PPM
6. The coupling constant (J) is the distance(in Hz) between adjacent peaks in a signal.The coupling constant for being splitby is denoted by The signals ofcoupled protons have the same couplingconstant. The number of observed peaksin a signal can be explained by a splittingdiagram. When the coupling constants oftwo sets of nonequivalent adjacentprotons are similar, the signal multiplicityis the same as if the adjacent sets wereequivalent (13.12, 13.13).
7. Two hydrogens bonded to a carbon that isbonded to two different groups are calledenantiotopic hydrogens; one is a pro-S-hydrogen, the other a pro-R-hydrogen,and the carbon is prochiral. Enantiotopichydrogens are equivalent. If thecompound has an asymmetric center, thetwo hydrogens are diastereotopichydrogens; they are not equivalent, sothey produce different signals (13.14).
8. NMR spectra show an average of variousconformers at room temperature.Hydrogens involved in proton exchange(OH, ) are not split and do not split;they appear as broadened singlets (13.15, 13.16).
9. determines the types ofcarbons present in a compound (0–200ppm). The signals cannot be integratedand are not split unless the spectrum isrun in a proton-coupled mode. Themultiplicity is determined by the rule, where N is the number ofhydrogens bonded to the carbon thatproduces the signal (13.19).
N+1
13C NMR
NH2
Jab.Hb
Ha
3. The of cyclopentadiene is unusuallylow (15) due to its aromatic conjugatebase. Cycloheptatrienyl bromide ionizesreadily due to its aromatic cation.Antiaromatic compounds, with anuninterrupted cloud of electrons thatcontains an even number of pairs of are less stable than analogous compoundswith localized Frost circle diagramsare used to assign relative energies to theMOs of cyclic compounds (14.5–14.7).
4. Some monosubstituted benzenes havenames that incorporate the substituent(toluene, phenol, aniline, benzenesulfonicacid, anisole, styrene, benzaldehyde,benzoic acid, benzonitrile). A benzenesubstituent is a phenyl group (Ph-); aphenyl methyl substituent is a benzylgroup (14.8).
5. Aromatic compounds undergoelectrophilic aromatic substitutionreactions, which replace a hydrogen withan electrophile. Halogenation employs
or (14.9–14.11).Cl2 + FeCl3Br2 + FeBr3
1PhCH2-2
e-.
p e-,p
pKa
6. Nitration employs nitric acid and sulfuricacid; the nitronium ion is theelectrophile. Sulfonation uses sulfuricacid; the sulfonium ion is theelectrophile. This reaction is reversible at100 °C (14.12, 14.13).
7. Friedel-Crafts acylation employs an acylchloride or an acid (theacylium ion is the electrophile) and forms aphenyl ketone. Friedel-Crafts alkylation
anhydride + AlCl3
1+SO3H2
1+NO22
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 6
7
Cl
CH3
NO2
NH2 OH
2-chlorotolueneortho-chlorotoluene
notortho-chloromethylbenzene
CH2CH3
4-nitroanilinepara-nitroaniline
notpara-aminonitrobenzene
2-ethylphenolortho-ethylphenol
notortho-ethylhydroxybenzene
COH
O
CHCH2
propenoic acidacrylic acid
COH
O
benzenecarboxylic acidbenzoic acid
COHCH3CH2CH2CH2
O
pentanoic acidvaleric acid
COHCH3CH2CH2CH2CH2
O
hexanoic acidcaproic acid
nucleophile attacksthe carbonyl carbon
a group isexpelled
ZC
YZ+ −
sp2sp2 sp3
R RC Y+ −
O
C
Za tetrahedral intermediate
YRk2
k−2
−O Ok1
k−1
employs an alkyl (acarbocation is the electrophile); analkylbenzene is the product. Acarbocationgenerated from an alkene or an alcohol canalso be used. Carbocations can rearrange;therefore, a benzene ring with a straight-chain alkyl group is synthesized byFriedel-Crafts acylation, followed byreduction with Pd/C, or
(Clemmensen), or(Wolff-
Kishner). Alkylbenzenes with straight-chain alkyl groups can also be prepared byStille and Suzuki reactions (14.13–14.18).
8. Bromination of an alkylbenzene at thebenzylic position allows subsequentsubstitution and elimination reactions.Oxidation with or converts alkyl groups to COOH groups.Mild oxidation of a 1° or 2° benzyl alcoholwith produces benzaldehyde or aphenyl ketone, respectively.Nitrobenzenes are reduced to anilineswith followed by or with
Pd/C (14.19).
Chapter 15Reactions of Substituted Benzenes1. Disubstituted benzenes can be named
using ortho (1,2), meta (1,3), and para(1,4) designations. Substituents are listedalphabetically, or one of the substituentsis incorporated into the parent name. Inpolysubstituted benzenes, thesubstituents are numbered in thedirection that results in the lowestpossible numbers (15.1).
H2,HO-Sn + HCl
MnO2
Na2Cr2O7/H+KMnO4
H2NNH2 + NaOH + ¢
Zn1Hg2 + HCl + ¢
H2,
halide + AlCl3 3. Deactivating substituents stabilize theconjugate bases of phenols, carboxylicacids, and anilinium ions, making theacids more acidic (lowering their );activating substituents make thecompounds less acidic (15.4).
4. The relative amounts of ortho and paraproducts depend on the size of thedirecting and incoming substituents.Benzene rings with highly activatingsubstituents are monohalogenated with-out a catalyst and polyhalogenated withit. A benzene ring with a meta-directingsubstituent cannot undergo a Friedel-Crafts reaction. Anilines form ammoniumions (strongly deactivating metadirectors) with Lewis acids (15.5, 15.6).
5. When a disubstitued benzene ringundergoes an electrophilic aromaticsubstitution reaction, a strongly activatingsubstituent wins out over a weakly acti-vating or deactivating substituent (15.8).
6. Arenediazonium saltsproduced from aniline using nitrous acid
undergo substitutionwith CuCl, CuBr, CuCN (Sandmeyerreaction), KI, (Schiemannreaction), and form phenols with
The diazoniumgroup can be replaced by an H with
reacts with stronglyactivated benzene rings via electrophilicaromatic substitution to form colored azocompounds. Diazonium ion formationresults from reaction of a 1° aniline (oramine) with a nitrosonium ion
anilines form N-nitrosoamines; with 3° anilines, thenitrosonium ion is an electrophile thatreplaces an H of benzene (15.9–15.11).
7. Aryl halides with strongly electron-withdrawing substituents in the orthoand/or para positions undergonucleophilic aromatic substitutionreactions with good nucleophiles( amines). Halobenzenes reactwith to form anilines via abenzyne intermediate (15.12, 15.13).
8. Polycyclic benzenoid hydrocarbons withfused rings (naphthalene, anthracene,phenanthrene, etc.) undergo reactionssimilar to the ones that benzeneundergoes (15.14).
Chapter 16Carbonyl Compounds I
1. Carbonyl compounds have a carbonylgroup Carboxylic acidderivatives have an acyl groupbonded to OH, Cl, OC R, OR, NH2,NHR, these groups can be substi-tuted by another group. Acyl groupsbonded to H or R do not posses a groupthat can be substituted by another group.The parent name for carboxylic acid isalkanoic acid. The positions adjacent tothe carbonyl carbon are incommon nomenclature (16.1).
a, b, g, d, e
NR2;1=O2
1RC=O21C=O2.
NaNH2
HO-, RO-,1SNAr2
1+N=O2; 2°
ArN2
+H3PO2.
Cu2O, Cu1NO322, H2O.
HBF4
1NaNO2 + HCl2
1ArN2
+2,
pKa
2. Nomenclature: an acyl halide is analkanoyl halide, an acid anhydride is aalkanoic anhydride, an ester is an alkylalkanoate (where the alkyl prefix refers tothe group bonded to the carboxyl oxygen),a lactone (a cyclic ester) is a 2-oxacycloalkanone, an amide is analkanamide with N-alkyl as a prefix , ifnecessary; a lactam (a cyclic amide) is a 2-azacycloalkanone, a nitrile is analkanenitrile (16.1).
3. The carbonyl carbon and carbonyloxygen are hybridized; carboxylicacids, esters, and amides are stabilized by
delocalization. Elevated boiling pointsof carboxylic acids and amides are due tohydrogen bonds and dipole-dipoleinteractions (16.2, 16.3).
4. Carboxylic acid derivatives undergonucleophilic acyl substitution reactionsvia a tetrahedral intermediate that expelsthe weakest base. The order of reactivity:acyl chloride acid anhydride ester acid amide. More reactivecarboxylic acid derivatives are convertedto less reactive ones (16.5–16.7).
7'
77
e-
sp2
2. Groups that donate either by resonanceor by hyperconjugation activate a benzenering toward electrophilic aromaticsubstitution; groups that withdraw either by resonance or by inductiveelectron withdrawal deactivate it. Theposition to which a substituent directs anincoming substituent depends on whichof the three possible carbocationintermediates is the most stable.Activating groups and the mildlydeactivating halogens are ortho-paradirectors; all groups more deactivatingthan the halogens are meta directors. Allortho-para directors (except alkyl, aryl,
) have a lone pair on theatom attached to the ring; all metadirectors have a positive or partialpositive charge on the atom attached tothe ring (15.2, 15.3).
RCH “ CHR
e-
e- 5. Acyl halides react with carboxylate ions toform acid anhydrides, with alcohols toform esters, with water to form carboxylicacids, and with excess amine to formamides. Acid anhydrides react withalcohols to form esters, with water to formcarboxylic acids, and with excess amine toform amides. The reaction of esters withexcess water to form carboxylic acids orwith excess alcohol to form a new esterrequires a catalyst; (Fischeresterification) or for hydrolysis, and
or for transesterification. Estersundergo aminolysis with amines to formamides (16.8–16.12).
6. Hydrolysis of an ester with a 3° alkylgroup occurs via a carbocation (16.11).
7. Triesters of glycerol (fats and oils) arehydrolyzed under basic conditions(saponification) to form sodium
RO-H+
HO-
H+
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 7
8
C
C
O + +R
H
R
NH2 H2O
an aldehyde ora ketone
a primary amine an imine a Schiff base
C
C
H
N
an aldehyde a hemiacetal an acetal
CH3OH, HClHCl+ CH3OH + H2OHC
OH
HC
OCH3
OCH3OCH3
H
O
RR RC
LDA1. CH3CH2CH2CH add slowly
O
2. H2O
O O OOH
CHCH2CH2CH3−
a, -positionb
C
O + +
R
H
R R
R
NH H2O
an aldehyde ora ketone
a secondary amine an enamine
C
C
NC
O−
H
HO−E+
A-substituted productenolate ionH2O+
−RCH
O
RRCH
E
RCHC
RRCHC
O
RC
O
RC
carboxylates (soaps), which formmicelles in water ordered byhydrophobic interactions (16.14).
8. Reactions of carboxylic acids with aminesform ammonium carboxylate salts.Amides react with water and alcoholsunder acidic conditions to formcarboxylic acids and esters, respectively.Dehydrating reagents convert amides without a substituent onthe N to nitriles (16.15–16.17).
9. Alkyl halides are converted to 1° aminesusing the reaction of phthalimide anionwith an alkyl halide to form an N-substituted imide, which is hydrolyzed(Gabriel synthesis). Nitriles, formed byan reaction of an alkyl halide withcyanide ion, are hydrolyzed with acidand heat to produce carboxylic acids.Catalytic hydrogenation of a nitrile formsa 1° amine (16.18, 16.19).
10. Carboxylic acids are activated in the labwith or which convertsthem to acyl halides. Carboxylic acids areactivated in the cell with ATP to form acylphosphates, acyl pyrophosphates, or acyladenylates, or by being converted tothioesters. Diacids include oxalic,malonic, succinic, glutaric, adipic, andphthalic acids (16.20–16.23).
Chapter 17Carbonyl Compounds II
1. An aldehyde is named as an alkanal, anda ketone as an alkanone (17.1).
2. Aldehydes and ketones undergonucleophilic addition reactions. Stericeffects and crowding in the tetrahedralintermediate cause aldehydes to be morereactive than ketones (17.2, 17.3).
PBr3,SOCl2, PCl3,
SN2
1P2O5, POCl32
reduced to 1° alcohols and amides arereduced to amines. Diisobutylaluminumhydride reduces esters to aldehydes at -78 °C (17.6).
5. Ketones and aldehydes add cyanide ionto form cyanohydrins. Aldehydes andketones react with 1° amines to formimines (Schiff base) and with 2° aminesto form enamines (tertiary amines). Imines and enaminescan be hydrolyzed to carbonylcompounds and amines under acidicconditions. Hydroxylamine formsoximes; hydrazine forms hydrazones.Imines and enamines are reduced toamines with Pd/C, or with sodiumtriacetoxyborohydride (reductiveamination) (17.7, 17.8).
H2,
a,b-unsaturated
Chapter 18Carbonyl Compounds III
1. Aldehydes, ketones, and esters haveacidic because the electronsleft behind when the proton is removedare delocalized onto oxygen, forming anenolate. Aldehydes and ketones ( 16-20) are more acidic than esters ( 25).
compounds( ) haveenhanced acidity ( 6-10). Keto andenol tautomers are in equilibrium.Enolization can be catalyzed by acid or bybase (18.1–18.4).
pKa
B-keto esters, B-diketonesb-Dicarbonyl
pKa
pKa
a-hydrogens,
C
O
C R'
O−
+R
RR'
Z Z
product of nucleophilicaddition
C R'
OH
RHB+
BZ −
the reaction is irreversiblebecause Z is too basic tobe expelled
a nucleophile that is a strong base
3. Grignard reagents react withformaldehyde to form 1° alcohols(following protonation of the alkoxideion); aldehydes form 2° alcohols, ketonesform 3° alcohols, and reaction with carbondioxide forms a carboxylic acid. Acylchlorides and esters add two equivalentsof Grignard reagent to form 3° alcohols.Acetylide ions also form nucleophilicaddition products with aldehydes andketones (17.4, 17.5).
4. Aldehydes and ketones react with to form 1° and 2° alcohols, respectively. Acylchlorides add two equivalents of hydrideion to form 1° alcohols. Esters, carboxylicacids, and amides are too unreactive to bereduced by must be used.Two equivalents of hydride ion add to thesecompounds: esters and carboxylic acids are
NaBH4; LiAlH4
NaBH4
6. As a result of steric and electronic effects,ketones form less hydrate than doaldehydes. Aldehydes react with alcohols
to form acetals via a hemiacetalintermediate; ketones form ketals. Acetalsand ketals are hydrolyzed (with ) backto aldehydes and ketones. 1,2-Diols and 1,3-diols formcyclic acetals that can be used as aprotecting group. Thioketals are formedfrom thiols, which are reduced with and Raney Ni to alkanes (17.9–17.12).
H2
1+acid2
H+
+H+
7. Phosphonium ylides react withaldehydes and ketones to form alkenes(Wittig reaction). A prochiral carbonylcarbon, with Re and Si faces, reacts withachiral nucleophiles to form R and Sproducts. Retrosynthetic analysis allowsfor multistep planning by disconnectionand synthons, and synthetic equivalentidentification (17.13–17.15).
8. compoundsundergo conjugate addition with weaklybasic nucleophiles (cyanide ion, thiols,amines, Gilman reagents); with stronglybasic nucleophiles (Grignard reagents andhydride ion), reactive carbonyl groupsundergo direct addition, and less reactivecarbonyl groups undergo conjugateaddition (17.16–17.18).
A,B-Unsaturated carbonyl
2. Ketones and aldehydes react withhalogens under acidic conditions to form
under basicconditions multihalogenation occurs.Methyl ketones react with toform carboxylate ions and iodoform(haloform reaction) (18.5).
3. Carboxylic acids react with andwater to form acids(Hell-Volhard-Zelinski reaction) (18.6).
4. LDA removes an -hydrogen to form anenolate, which undergoes alkylation with1° alkyl halides. The -carbon can also bealkylated (or acylated) via an enamine(18.8–18.10).
5. carbonyl compoundsundergo conjugate addition with
anions (Michael reaction)or with enamines (Stork enaminereaction) (18.11).
6. Aldehydes and ketones react with toform and
(aldol addition), as aresult of the addition of an enolate of onemolecule to the carbonyl carbon ofanother. Heating with acid or base causesloss of water (aldol condensation).Enolates formed with LDA react withaldehydes and ketones (added slowly),forming aldol products (mixed aldoladdition) (18.12–18.14).
b-hydroxyketonesb-hydroxyaldehydes
HO-
b-dicarbonyl
a,b-Unsaturated
a
a
a-bromocarboxylicP + Br2
HO- and I2
a-halo carbonyl compounds;
7. An ester with two �-hydrogens reactswith (corresponding to its alkoxygroup) to form a ester (Claisencondensation) after acidification. A mixed Claisen condensation leads toprimarily one product if an ester with
is added slowly to an esterwithout An intramolecularClaisen condensation (Dieckmanncondensation) forms cyclic esters;5- and 6-membered rings are favored.Intramolecular aldol additions also favor
b-keto
a-hydrogens.a-hydrogens
b-ketoRO-
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 8
9
1. CH3CH2O−
2. RBr3. HCl, H2O, ∆
R
diethyl malonatemalonic ester from malonic ester
from the alkyl halide
malonic ester synthesis
C
O
C2H5O CH2C
O
OC2H5 CH2C
O
OH
CH2OH
CH2OH
HO H
H OH
H OH
a polyhydroxy ketone
CH2OH
CH2OH
HO C H
H C OH
H C OH
C O C O
HO
H
H
H
a polyhydroxy aldehyde
wedge-and-dashstructure
D-glucose
Fischer projectionCH2OH
C H
C OH
C OH
HC O
C OH
wedge-and-dashstructure
HC
CH2OH
O
HO H
H OH
H OH
H OH
Fischer projection
D-fructose
OH
H
CH2OH
HOHO
OH
O CH3CH2OHHCl
+
-D-glucose -D-glucopyranose
OCH2CH3
CH2OH
HOHO
OH
O
H
ethyl -D-glucosideethyl -D-glucopyranoside
a glycosidic bond
OCH2CH3
CH2OH
HOHO
OH
O
Hethyl -D-glucoside
ethyl -D-glucopyranoside
5- and 6-membered ring products. A Michael addition combined with anintramolecular aldol condensation formsa compound with a 2-cyclohexenone ring(Robinson annulation) (18.15–18.17).
8. 3-Oxocarboxylic acids lose (decarboxylate) when heated. Malonicester is alkylated, hydrolyzed with acid,and decarboxylated to form a carboxylicacid (malonic ester synthesis); acetoaceticester is alkylated, hydrolyzed, anddecarboxylated to form a methyl ketone(acetoacetic ester synthesis) (18.18–18.20).
CO2
Chapter 20More About Amines Heterocyclic
Compounds1. Amines are bases and nucleophiles.
Heterocyclic compounds possess one ormore heteroatoms (N, O, S) in a ring.Cyclic amines are named asazacycloalkanes or use common names:aziridine, azetidine, pyrrolidine,piperidine (20.1).
2. Quaternary ammonium ions react withhydroxide ion and heat to form alkenes(Hofmann elimination reaction). Thetransition state has carbanion character,so the less substituted amine is the majorproduct (the hydrogen is removed fromthe bonded to the mosthydrogens). Amines react with excessmethyl iodide to form quaternaryammonium iodides (exhaustivemethylation), which are converted by
to quaternary ammoniumhydroxides (20.4).
3. Quaternary ammonium ions are used asphase-transfer catalysts (20.5).
4. 3° amines are oxidized to amine oxideswith peroxide, which eliminate whenheated to form the least substitutedalkene (Cope elimination). 2° amines areoxidized to hydroxylamines and 1°amines to nitro compounds (20.6).
5. Aromatic 5-membered ringheterocycles (pyrrole, furan,thiophene) are more reactive thanbenzene toward electrophilic aromaticsubstitution; they form 2-substitutedproducts. The pyridinium ion, with an
N, is more acidic than analkylammonium ion. Pyridine is lessreactive than nitrobenzene towardelectrophilic aromatic substitution,which occurs at the 3-position. Pyridineis more reactive than benzene towardnucleophilic aromatic substitution,which occurs at the 2- and 4-positions(20.8, 20.9).
Chapter 21Carbohydrates
1. Carbohydrates are polyhydroxyaldehydes (aldoses) or polyhydroxyketones (ketoses). Monosaccharideshave one sugar unit, disaccharides havetwo, oligosaccharides have 3–10, andpolysaccharides have many. D-glyceraldehyde (a triose) has the R-configuration. Naturally occurringsugars are D-sugars—the bottom-mostasymmetric center in a Fischer projectionhas the OH group on the right. Erythroseand threose are tetroses; ribose is apentose; glucose and fructose arehexoses. Mannose is the C-2 epimer ofglucose; galactose is the C-4 epimer.Ketoses have a keto group at C-2(21.1–21.4).
1pKa ~52sp2
Ag2O
b-carbon
#
Chapter 19More About Oxidation-Reduction
Reactions1. Reduction increases the number of
bonds or decreases the number ofor bondsOxidation decreases the
number of bonds or increases thenumber of or bonds.Reducing agents are oxidized; oxidizingagents are reduced. There are threemechanisms for addition of (catalytic hydrogenation);
(dissolving-metalreduction); and (metal-hydridereduction) (19.1).
2. Chromic acid oxidation converts 1°alcohols to carboxylic acids and 2° alcoholsto ketones. Swern oxidation (with DMSO,oxalyl chloride, ) converts them toaldehydes and ketones, respectively (19.2).
3. Tollens reagent oxidizes aldehydes tocarboxylic acids (Tollens test). Peroxyacidoxidizes aldehydes to carboxylic acidsand ketones to esters (Baeyer-Villigeroxidation). Migration tendencies:
(19.3).4. Enantioselective reactions (which form
more of one enantiomer than another) useenzymes or enantiomerically purecatalysts (19.4).
5. Alkenes react with basic, cold orwith to form vicinal diols. Cyclicalkenes form cis-1,2-diols via syn addition(19.5).
6. Vincinal diols undergo oxidativecleavage with periodate to formaldehydes and ketones. Ozone reacts withalkenes (ozonolysis); ketones andaldehydes are formed when the ozonide istreated with Zn or ketones andcarboxylic acids are formed when it istreated with peroxide (19.6-19.7).
7. Ozone reacts with alkynes to formcarboxylic acids. Oxidation reactions andothers allow for functional groupinterconvertion (19.8, 19.9).
1CH322S;
OsO4
KMnO4
phenyl 7 primary alkyl 7 methylH 7 tert-alkyl 7 sec-alkyl =
Et3N
H-+ H+
e-+ H+
+ e-+ H+
H2: H #+ H #
C ¬ XC ¬ O, C ¬ N,C ¬ H
1X = halogen2.C ¬ XC ¬ O, C ¬ N,
C ¬ H
2. Under basic conditions, monosaccharidesare converted to a mixture of aldoses andketoses through enolate intermediates.Sugars are reduced to alditols with
and are oxidized by orto aldonic acids and by nitric
acid to aldaric acids. Monosaccharidesform osazones with excessphenylhydrazine (Sec. 21.5–21.7).
3. The Kiliani-Fischer synthesis increasesthe chain by one carbon, forming C-2epimers. The Wohl degradation decreasesthe chain by one carbon (21.8, 21.9).
4. Pentoses and hexoses exist in solution asfuranoses and pyranoses, which arehemiacetals or hemiketals. The anomersare in equilibrium in solution: (right in aFischer projection, down in a Haworthprojection, axial in a chair conformer); (left in a Fischer, up in a Haworth,equatorial in a chair). The optical rotationchanges when a pure anomer is placed insolution (mutarotation). -D-Glucose(64% at equilibrium) has all its groups inequatorial positions (21.11, 21.12).
5. Hemiacetals or hemiketals of sugarsreact with forming acetalsand ketals (glycosides: furanosides andpyranosides); the new bond to OR is aglycosidic bond. The mechanisminvolves an oxocarbenium ion. The
is the major product due tofavorable overlap (the anomericeffect) (21.13, 21.14).
n-s* e-
a-glycoside
ROH + H+,
b
b
a
Ag+/NH3
Br2NaBH4
6. Straight-chain sugars, hemiacetals, andhemiketals are reducing sugars; acetals andketals are non-reducing sugars (21.15).
7. Starch is composed of amylose andamylopectin; both are polysaccharides ofglucose. Amylose has glycosidiclinkages; amylopectin has and
Glycogen has morebranches than amylopectin. Cellulose is apolysaccharide of glucose with
chitin has N-acetyl groupsat the 2-positions of cellulose (21.17).b-1,4¿-linkages;
a-1,6¿-linkages.a-1,4¿
a-1,4¿-
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 9
10
CH NC
R H
R
CH
O
CH N+C
R H
R
CH
O−
resonance contributors
a-carbon
a-carbon
a one-stepmechanism
a two-stepmechanism
Free
en
erg
y
Progress of the reaction
∆G‡uncatalyzed∆G‡
catalyzed
a.
hydrogenbond
b.
Chapter 22Amino Acids, Peptides, and Proteins1. Peptides and proteins are polymers of
amino acids. Dipeptides have twoamide-linked amino acids; tripeptideshave three and polypeptides have many;proteins have 40–400. Naturallyoccurring amino acids have the L-configuration (22.1, 22.2).
7. The primary structure of a protein is thesequence of amino acids and the locationof the disulfide bridges. 2-Mercapto-ethanol cleaves disulfide bonds. Diluteacid partially hydrolyzes peptides intosmaller fragments. Edman’s reagentidentifies the N-terminal amino acid.Peptidases, enzymes that hydrolyzepeptide bonds, include carboxypeptidaseA and B (exopeptidases), which cleavethe C-terminal amino acid, andendopeptidases: trypsin, chymotrypsin,and elastase. Cyanogen bromide cleavesat the C-side of Met (22.12, 22.13).
8. Secondary structure describes therepetitive conformations assumed bysegments of the protein backbone: an
(right-handed coil with 3.6 aminoacids/turn); a (extendedhydrogen bonded conformation inparallel or antiparallel orientation); anda coil (loop) conformation (22.14).
B-pleated sheetA-helix
the slow step in general-acid catalysis.A base catalyst increases the rate byremoving a proton: before the slow step inspecific-base catalysis; during the slowstep in general-base catalysis (23.2, 23.3).
3. Anucleophilic (covalent) catalystincreases the rate by forming a newcovalent bond with the reactant, resultingin formation of a more reactive species(23.4).
4. Metal-ion catalysis makes a group moresusceptible to nucleophilic attack, makesa group a better leaving group, or makeswater a better nucleophile by lowering its
(23.5).5. Intramolecular reactions occur with
faster rates compared with intermolecularreactions. Intramolecular catalysis occurswhen the catalyst and the reaction centerare in the same molecule (23.6).
6. Enzymes (biological catalysts) bind theirsubstrate in an active site based onmolecular recognition. In the lock-and-keymodel, the substrate fits into the activesite like a key fits into a lock; in theinduced-fit model, the enzyme changes itsconformation to become complementaryto the shape of the substrate after bindingit. The catalytic ability of an enzymeresults from bringing reacting andcatalytic groups together. A pH-activityprofile can be used to assess participationof ionizable groups (23.8, 23.9).
Chapter 24The Organic Mechanisms of the
Coenzymes1. Cofactors are metal ions or organic
molecules (coenzymes) that someenzymes need to catalyze a reaction. Anenzyme with its cofactor is a holoenzyme;without its cofactor it is an apoenzyme.All the water-soluble vitamins (exceptvitamin C) and water-insoluble vitamin Kare precursors for coenzymes (24.1).
2. Vitamin (niacin) is a precursor forand that are oxidizing
agents and for NADH and NADPH thatare reducing agents (24.2).
NADP�NAD�B3
pKa
CH
a protonatedA-aminocarboxylic acid
an amino acid
R
R R′ R′′amino acids are linked together by amide bonds
amide bonds
+NH3
COH
O
NHCHC
O
NHCHC
O
NHCHC
O−
O
H++
R CH R
a zwitterionpH = 7
H++
R
NH2pH = 0 pH = 11
+NH3+NH3
CHC
O−
O
CHC
O−
O
COH
O
2. The of the carboxylic acid group of anamino acid is that of the ammoniumgroup is At physiological pH (7.3),amino acids are zwitterions (22.3).
'9.'2;
pKa
3. The isoelectric point (pI), the pH at whichthe amino acid has no net charge, is foundby averaging the for neutral sidechain amino acids, and by averaging thelike charge for amino acids withionizable side chains (except Cys andTyr). Electrophoresis separates aminoacids based on pI values; paper and thin-layer chromatography separates thembased on polarity. Ion-exchangechromatography separates and quantifiesamino acids based on charge and polarity.Ninhydrin reacts with amino acids toform a colored product (22.4, 22.5).
4. Amino acids are synthesized fromcarboxylic acids by followed by reaction with byreductive amination of acids; bythe N-phthalimidomalonic estersynthesis; or by the acetamidomalonicester synthesis. A racemic mixture ofamino acids can be separated via a kineticresolution with an enzyme (22.6, 22.7).
5. Peptide bonds have double bond characterdue to electron delocalization. In writingan amino acid sequence, the N-terminalamino acid is on the left, the C-terminal ison the right. Disulfide bonds are formedbetween cysteine side chains (22.8).
a-ketoNH3;
a-bromination
pKa’s
pKa’s
9. Tertiary structure, the 3D structure of theprotein, is maintained by disulfide bonds,hydrogen bonds, hydrophobicinteractions, and electrostatic attractions.Quaternary structure describes thearrangement of protein subunits.Denaturation by pH change, urea,detergent, solvents, or by heat or agitationforms a random coil (22.15–22.17).
Chapter 23Catalysis
1. A catalyst increases the rate of a reaction(without being consumed) by decreasingthe free energy of activation ( ‡) (23.1).¢G
3. Vitamin (riboflavin) is a precursor forFAD and FMN that catalyze oxidationreactions. FAD catalyzes the oxidation ofthiols to disulfides and amines to imines;
is a reducing agent (24.3).4. Vitamin is the precursor to thiamine
pyrophosphate (TPP) that catalyzes thetransfer of a two-carbon unit (24.4).
B1
FADH2
B2
O
N+
oxidation of substratereduction of coenzyme
CNH2
O
O H B
N
CNH2
RR
H H
R
C
H
O H B–
R
43
26
5
1
C
a basic group of anamino acid side chain
6. t-BOC protects amino groups; DCCactivates carboxyl groups. Automatedsolid-phase peptide synthesissynthesizes polypeptides from the C-terminal end (22.10, 22.11).
2. An acid catalyst increases the rate of areaction by donating a proton: before theslow step in specific-acid catalysis; during
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 10
11
a.
b.
c.
A-farnesenea sesquiterpene found in thewaxy coating on apple skins
head
tail
head
tail
5. Biotin, from vitamin H, catalyzes thecarboxylation of the of pyruvateand acetyl-CoA (24.5).
6. Pyridoxal phosphate (PLP), from vitamincatalyzes amino acid transformations
including decarboxylation,transamination, racemization, and
bond cleavage (24.6).7. Coenzyme from vitamin , is a
cobalt-coordinated porphyrin compoundthat catalyzes certain isomerizationreactions (24.7).
8. A substituted tetrahyrofolate (THF), fromfolic acid, transfers a one-carbon unit(methyl, methylene, formyl) to itssubstrate. 5-Fluorouracil is a suicideinhibitor. Methotrexate and wafarin arecompetitive inhibitors (24.8, 24.9).
9. Vitamin , from vitamin K, carboxy-lates the of glutamate (24.9).
Chapter 25The Chemistry of Metabolism
1. Metabolism consists of catabolicreactions that break down compounds torelease energy and anabolic reactionsthat require energy to synthesizecompounds. Catabolism has four stages:stage 1 involves the hydrolysis of fats,carbohydrates, and proteins; in stage 2the products of the first stage areconverted to pyruvate, acetyl-CoA, orcitric acid cycle intermediates; stage 3 isthe citric acid cycle; ATP is synthesized instage 4 (25.1).
2. ATP is used in phosphoryl transferreactions. ATP hydrolysis is favored due toelectrostatic repulsion, enhanced solvation,and delocalization. ATP, because of itsnegative charges, is not reactive unlessbound to an enzyme (25.2–25.5).
3. Fatty acids are converted to acetyl-CoAby a repeating 4-step pathway
oxidation by FAD,addition of water, oxidation by and cleavage with CoASH (25.6).
4. Glucose is converted to pyruvate via a 10-reaction pathway (glycolysis), includinga reverse aldol addition that formsdihydroxyacetone phosphate andglyceraldehyde-3-phosphate (25.7).
5. Under aerobic conditions, oxygen oxidizesNADH to under anaerobicconditions, pyruvate oxidizes NADH to
and forms lactate. Pyruvate isconverted to acetyl-CoA by the pyruvatedehydrogenase system. In yeast, pyruvateis converted to ethanol (25.8).
6. Amino acids, each following a differentroute, are converted to acetyl-CoA,pyruvate, and citric acid cycleintermediates, depending on the aminoacid. For example, phenylalanine isconverted to tyrosine, which istransaminated to p-hydroxyphenyl-pyruvate, which is converted tofumarate and acetyl-CoA (25.9).
NAD+
NAD+:
NAD+,1B-oxidation2:
e-
g-carbonKH2
B12B12,Ca—Cb
B6,
a-carbon7. The citric acid cycle is series of 8
reactions that convert acetyl-CoA to 2and CoASH. Each round forms 3
NADH, 1 and 1 ATP (25.10).8. In the fourth stage of catabolism
(oxidative phosphorylation), eachNADH is oxidized to and 3 ATP;each is oxidized to FAD and 2ATP (25.11).
9. Anabolism is the reverse of catabolism:acetyl-CoA, pyruvate, and otherintermediates are converted into fattyacids, monosaccharides, and aminoacids (25.12).
Chapter 26Lipids
1. Lipids, biological compounds soluble innonpolar solvents, include fatty acids(saturated and unsaturated), waxes (longchain esters), and fats and oils(triacylglycerols) (26.1–26.3).
2. Membranes are composed ofphosphoacylglycerols (phospholipids),which form lipid bilayers. Cholesteroldecreases fluidity. Vitamin E is anantioxidant (Sec. 26.4).
3. Prostaglandins regulate physiologicalresponses, such as inflammation andpain. They are synthesized fromarachidonic acid and contain acyclopentane ring with a 7-carboncarboxylic acid side chain and anadjacent (trans) 8-cabon hydrocarbonside chain (26.5).
4. Terpenes contain multiples of 5 carbonslinked head-to-tail (isoprene rule).Monoterpenes have 10 carbons;sesquiterpenes have 15. Squalene is atriterpene (30 carbons) and is theprecursor of cholesterol, which is theprecursor of all steroids. The carotenoids(lycopene and carotene) are tetraterpenes.Vitamin A is a diterpene that plays animportant role in vision (26.6, 26.7).
FADH2
NAD+
FADH2,CO2
Chapter 27Nucleosides, Nucleotides, and
Nucleic Acids1. Deoxyribonucleic acid (DNA) and
ribonucleic acid (RNA) are nucleicacids—phosphodiesters with purineand pyrimidine bases. The bases in DNA are adenine, guanine, cytosine, and thymine; RNA has uracil instead of thymine.
The primary structureof a nucleic acid is the sequence of itsbases. DNA is double stranded (thedouble helix) with major and minorgrooves. Stacking interactions betweenthe bases add stability. The group of RNA causes it to be easilycleaved (27.1–27.4).
2¿-OH
phosphate .nucleotides = base + ribose +
base + ribose;Nucleosides =
2. DNA is synthesized in the direction by complementary base pairing dictated by hydrogen bonds: A pairs with T; G pairs with C. One strand of DNA is made continuouslyand the other is made in pieces(semiconservative replication). Thetemplate strand of DNA is read in the
direction to make RNA in thedirection (transcription); thus,
RNA has the same base sequence as the sense strand of DNA, with Us in place of Ts. Messenger RNA is thetemplate for protein synthesis(translation); a codon (a 3 base sequenceof RNA) determines the amino acidbrought in. Ribosomal RNA formsribosomes, on which protein synthesistakes place. Each transfer RNA carries anamino acid (27.5–27.8).
5¿ : 3¿
3¿ : 5¿
5¿ : 3¿
5. Acetyl-CoA and malonyl-CoA areconverted to isopentenyl pyrophosphatefor the synthesis of terpenes.Isomerization forms dimethylallylpyrophosphate, from which isopentenylpyrophosphate displaces pyrophosphateto form a 10-carbon compound; additionalreactions with isopentenyl pyrophosphatemake larger terpenes (26.8).
6. Steroids are hormones with 4 fused ringsand angular methyl groups.
are on the same side as theangular methyl groups; areon the opposite side (26.9).
a-substituentsSubstituentsB-
thymine adenine
sugar
sugar
cytosine guanine
sugar
sugar
O
H
N
H
NHNN
N
NH
H
O
N
NNH
CH3 N
N
H
H
NN
O
O
N
N
3. Synthetic oligonucleotides can be madeusing phosphoramidite monomers or H-phosphonate monomers (27.13).
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 11
2. Related compounds with improvedproperties are formed by molecularmodification (30.3).
3. A random screen is the search for a drugwithout structural information. Manydrugs have been discoveredaccidentally (nitroglycerin, Librium,Viagra) (30.5).
4. Drugs bind to specific receptors byhydrogen bonding, electrostaticinteractions, and hydrophobicinteractions (30.6).
5. Drugs can inhibit enzymes throughcovalent modification (suicideinhibitor). Two drugs can havesynergistic (additive) or antagonisticeffects; two drugs can be used toovercome drug resistance. Therapeuticindex, the ratio of toxic dose totherapeutic dose, is a measure of drugsafety (30.7, 30.8).
6. In rational drug design, the chemical orphysical property of a series of drugs iscorrelated with biological activity(QSAR). Molecular modeling allows forevaluation of the fit of a potential drugwith its receptor (30.9, 30.10).
7. Combinatorial synthesis uses libraries ofcompounds for the synthesis of analogs(13.11).
8. Nucleoside analogs are importantantiviral drugs (30.12).
Chapter 30The Organic Chemistry of Drugs
1. A brand name can be used only by theholder of the patent; a generic name canbe used by anyone. Natural products aretraditional sources for lead compounds(30.1, 30.2).
12
disrotatoryring closure
(2E,4Z,6E)-octatriene cis-5,6-dimethyl-1,3-cyclohexadiene
H3C
H3C
CH3
CH3
H HH H
cyclic compound. Sigmatropicrearrangements are intramolecular: a bond breaks, a new bond forms, and the
bonds rearrange. A thermal reactionoccurs without the absorption of light; aphotochemical reaction occurs with theabsorption of light. The conservation oforbital theory (in-phase orbitals overlap)explains the relationship between thestructure and configuration of thereactant, the conditions, and theconfiguration of the product (29.1-29-2).
2. Electrocyclic reactions: For a reactantwith an even number of conjugateddouble bonds ring closure is conrotatoryunder thermal conditions and disrotatoryunder photochemical conditions (TE-AC).With an odd number of conjugateddouble bonds, ring closure is disrotatoryunder thermal conditions andconrotatory under photochemicalconditions (29.3).
p
s
s
O O
H3N(CH2)5CO− NH(CH2)5C
O
NH(CH2)5C
O
NH(CH2)5C−H2O
nylon 6a polyamide
n
+
6-aminohexanoic acid
∆
Chapter 28Synthetic Polymers
1. A polymer is made from monomers viapolymerization. Chain-growth(addition) polymers are made byattaching monomers to a radical, cation,or anion propagating site (28.1).
Chapter 29Pericyclic Reactions
1. The three types of pericyclic reactionsinvolve concerted cyclic reorganization of
Electrocyclic reactions areintramolecular with a bond formedbetween the ends of a conjugated system.In cycloaddition reactions, two bond-containing compounds react to form a
p
s
e-.
3. Cycloaddition reactions: If the sum of thereacting bonds is even, bond formationis antarafacial under thermal conditionsand suprafacial under photochemicalconditions (TE-AC); if the sum is odd,bond formation is suprafacial underthermal conditions and antarafacial underphotochemical conditions. Cycloadditionreactions that form 4-, 5-, or 6-memberered rings must occur bysuprafacial bond formation (29.4).
4. Sigmatropic rearrangements: If the sumof the pairs of electrons in the reactingsystem is even, rearrangement isantarafacial under thermal conditions andsuprafacial under photochemicalconditions ((TE-AC); if the sum is odd,rearrangement is suprafacial underthermal conditions and antarafacial underphotochemical conditions. Migration onthe same is suprafacial and to theopposite face is antarafacial. Sigmatropicrearrangements that form 4-, 5-, or 6-memberered transition states must besuprafacial. In suprafacial rearrangement,carbon migrates using one of its p lobes(retained configuration) if the HOMO issymmetric and both p lobes (inversion ofconfiguration) if it is antisymmetric (29.5).
5. UV light promotes [2 + 2] cycloaddition oftwo adjacent thymine bases in DNAleading to mutations. Luminescenceresults from a retro [2+2] cycloadditionreaction. Vitamin D is produced fromergosterol, which undergoes a light-mediated electrocyclic reaction, followedby [1,7] sigmatropic rearrangement (29.6).
p-face
p
© 2007 Pearson Education, Inc.,Upper Saddle River, NJ.All rights reserved. This materialis protected under all copyrightlaws as they currently exist. No
portion of this material may be reproduced, inany form or by any means. without permissionin writing from the publisher.
N
H3CH3C
H3C
improved lead compoundcocainelead compound
OCH3O
O
O
NO
O
repeating unit
styrene polystyrenea chain-growth polymer
CH2 CH CH2 CH CH2 CH CH2 CH CH2 CH CH2 CH
n
2. Chain-growth polymerization includesinitiation, propagation, and terminationsteps. Head-to-tail addition is favoreddue to steric and electronic factors. Themechanism of polymerization depends onthe initiator and the stability of thepropagating site: radical initiators havebonds that break homolytically; is theinitiator in cationic polymerization;organolithium compounds initiateanionic polymerization. Hydrogen atomremoval from the main chain causesbranching. Living polymers containreactive ends that can continuepolymerization. Alkoxides or acids areused to initiate ring-openingpolymerization with epoxides andoxacyclobutanes (28.2).
3. An isotactic polymer has groups on thesame side; a syndiotactic polymer hasalternating groups. The groups in anatactic polymer are random. Ziegler-Natta catalysts (aluminum-titantium complexes) control thestructure of the polymer (28.3).
4. Butadienes polymerize to form rubberand neoprene. Heating with sulfur causescross-linking. Two or more differentmonomers produce copolymers(alternating, block, graft, or random)(28.4, 28.5).
5. Step-growth (condensation) polymers,formed by condensation of bifunctionalcompounds, include polyamides andaramides, polyesters, andpolyurethanes that form when adiisocyanate reacts with a diol. Epoxyresins involve a prepolymer and ahardener (28.6).
H+
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