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Organic Chemistry Paula Yurkanis Bruice, 5th Edition Prepared by Merritt B. Andrus
Chapter 1 Electronic Structure and Bonding Acids and Bases
#
1. Atoms consist of protons (p+), neutrons (n), and electrons 1e -2. Atomic number is the number of p+; mass number is the sum of p+ and n. Isotopes have the same number of p+ with different numbers of n. The atomic weight of an element is the average weighted mass of its atoms (1.1). 2. An atom atomic ic orbital (s, p, d, f ) is the volume of space around a nucleus where an electron is most likely to be found. An electron goes into the lowest energy orbital available (aufbau principle ), with two e - in each orbital (Pauli exclusion principle). An e - will occupy an empty degenerate (same energy) orbital before it will pair up with another e - (Hund’s rule).. Core e - are in filled shells; valence rule) e are used for bonding (1.2). 3. Atoms give up or accep acceptt e - to achiev achievee an outer shell of eight electrons (octet rule). Electropositive elements (on the left of the periodic table) lose e - to form cations; electronegative elements (on the right) gain e - to form anions. Ionic bonds are formed by electrostatic attraction between cations and anions. Electronegativity is a measure of an atom’s ability to attract e -. Atoms form covalent bonds by sharing valence e -. Nonpolar covalent bonds are formed by atoms with the same electronegativity; polar covalent bonds are formed by atoms with different electronegativities. A polar bond bond has a dipole with a dipole moment, momen t, D (debye). Electrostatic potential maps show how charge is distributed: red 1 - 2 and blue 1 + 2 (1.3). 4. Lewis structures represent compounds, showing all bonding and lone pair e . The formal charge on an atom = the number of valence e - minus 1/2 the bonding e - minus the lone pair e -. Carbocations have a positively charged carbon; carbanions have a negatively charged carbon; a carbon radical has a carbon with an unpaired e -. Kekulé structures depict bonds as lines. Condensed structures use subscripts and few, if any, bonds (1.4). 5. An s atomic orbital is spherical; the 2s 2s atomic orbital has a radial node. There are three degenerate, perpendicular p perpendicular p orbitals; each has a node at its nucleus (1.5). 6. Bond length is the distance between nuclei; bond dissociation energy is the energy required to break a bond. Two atomic orbitals combine to form two molecular orbitals, a bonding MO (s or p) and an antibonding MO (s* or p*). A sigma 1s2 bond is
cylindrically symmetrical. Two wo p p orbitals overlap side-to-side to form a pi 1p2 bond (1.6). 7. Methane has has four identical identical covalent bonds bonds hybr brid id 1sp32 or orb bit ital als, s, formed using four hy which result from mixing one 2s 2 s and three 2 p atomic orbitals. It has tetrahedral (109.5°) bond angles. Ethane has sp 3 carbons and 109.5°bond angles. Ethene (with a double bond) has sp 2 carbons and 120° bond angles. Ethyne (with (with a triple bond) has sp carbons and and 180° bond angle an gles. s. All All singl singlee bonds bonds are are s bo bonds nds;; a double bond consists of 1 s bond and 1 p bond; a triple bond consists of 1 s bond and 2 p bonds. The more s character, the shorter and stronger the bond and the larger the bond angle. (1.6–1.9, 1.14). H
C
H
Chapter 2 An Introduction to Organic Compounds
H
H Methane p bond
H
H
C
C
H
H s bond
Ethene
H C C H
Ethyne
8. The O and N of water water and ammonia ammonia are sp3 hybridized; H 2O has 104.5° bond angles; NH3 has 107.3° bond angles. C+ and C # are sp 2; C- is sp3 (1.11, 1.12). 9. A Br nsted acid donates a proton 1H +2; a Br nst nsted ed bas base e accepts a proton, forming a conjugate base and a conjugate acid, respectively. The acid dissociation constant (Ka) is a measure of the acidity of a compound; p K a = - log Ka; the lower the pKa, the stronger the acid. Protonated carboxylic acids and protonated alcohols = strong acids 1pKa 6 02; carboxylic acids = weak acids 1pKa ' 52; protonated amines = very weak acids
1
1022; alcohols and water 1pKa ' 10 1522. The equilibrium constant for 1pKa ' 15 an acid-base reaction = 1reactant Ka2/ 1product Ka2. When atoms are the same size, the more electronegative the atom to which the hydrogen is attached, the stronger the acid. Relative electronegativities: sp 7 sp2 7 sp3. When atoms are very different in size, the strongest acid will have its hydrogen attached to the largest atom. For example, acid strength: HI 7 HBr 7 HCl 7 HF. The stronger the acid, the weaker its conjugate base. Weak bases are stable bases. A Lewis acid accepts a share in a pair of e -; a Lewis base donates a share in a pair of e -. Curved arrows are used to show electron flow; the arrow begins where the electrons originate and points to where they end up (1.16–1.26).
1. Hydrocarbons contain only C and H. Alkanes are hydrocarbons with only single bonds. Constitutional isomers have the same molecular formula but differ in the way the atoms are connected. IUPAC IUPA C (systematic) and common names are used to name compounds. CH 2 = a methylene group. A primary (1°) carbon is bonded to one other C; a secondary (2°) carbon is bonded to 2 Cs; a tertiary (3°) carbon is bonded to 3 Cs. Substituents are indicted as prefixes, with the parent hydrocarbon numbered in the direction that puts the lowest number in the name of the compound. Substituents are listed alphabetically; di, tri, tetra, are used for identical alkyl groups, but are not alphabetized; sec and tert are also not alphabetized, but iso and cyclo are. In a cycloalkane with two substituents, the first cited substituent gets the lower number (2.1–2.3). a primary carbon
a second secondary ary carbo carbon n
CH3CHCH2 CH3 an isobutyl group
a tertiar tertiary y carbon carbon CH3
CH3CH2CH CH3 a sec -butyl -butyl group
CH3C CH3 a tert -butyl -butyl group
2. Alkyl halidesand ethers are named as substituted alkanes; alcohols and amines are named using a functional group suffix. Substituents on the nitrogen are preceded by anN. an N. If a parent chain has a substituent, the substituent gets the lowest number; if it has a functional group, the functional group gets the lowest number; if it has both a substituent and a functional group, the functional group gets the lowest number.. Only if the functional group gets number the same number in either direction, is the
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3.
4.
5.
6.
chain numbered so the substituent gets the lower number (2.4–2.7). Alkyl halides and alcohols are 1°, 2°, or 3° depending on whether the X or OH is on a 1°, 2°, or 3° carbon. Amines are 1°, 2°, or 3° depending on how many alkyl groups are bonded to N (2.4, 2.6, 2.7). The stronger the intramolecular forces holding molecules together, the higher the boiling point: hydrogen bonds are stronger than dipole-dipole interactions, which are stronger than van der Waals forces, which increase with molecular weight and decrease with branching (2.9). Polar compounds dissolve in polar solvents; nonpolar compounds dissolve in nonpolar solvents. An oxygen can drag about 3 carbons into water (2.9). Organic compounds exist in various conformations due to bond rotation. Newman projections depict staggered (anti and gauche) and higher energy eclipsed conformations. Cyclopropane and cyclobutane have significant angle strain; cyclopentane and cyclohexane are nearly strain free. Cyclohexane adopts a chair conformation with an axial and equatorial bond on each carbon. Ring-flip causes one chair conformer to convert into another chair conformer; bonds that are axial in one are equatorial in the other. A substituent is more stable in an equatorial position. Acis isomer has substituents on the same side of the ring; a trans isomer has them on opposite sides (2.10–2.14).
= axial bond = equatorial bond
Chapter 3 Alkenes: An Introduction to Reactivity. Thermodynamics and Kinetic 1. Alkenes are hydrocarbons with a double bond. The total number of p bonds and rings is the degree of unsaturation. The general molecular formula for a hydrocarbon is CnH 2n + 2 minus 2 hydrogens for each degree of unsaturation. The parent hydrocabon is the longest carbon chain that contains the double bond, numbered so that the start of the double bond is given the l owest possible number. Alkadiene is used for two double bonds. Vinylic carbons are double-bonded carbons; allylic carbons are adjacent to vinylic carbons (3.1–3.2).
CH3
CH2CH3
C
+ H
Br
slow
C
C +
+
Br
−
fast
C
the electrophile adds to an sp2 carbon of the alkene
a carbocation intermediate
C
Br H
H the nucleophile adds to the carbocation
4. Energy changes are shown by a reaction coordinate diagram. A transition state has partially broken and partially formed bonds; an intermediate has fully formed bonds. The more stable the species, the lower its energy. The change in Gibbs free energy 1 ¢ G°2 is exergonic 1 - 2 when forming a more stable species, and endergonic 1 + 2 when forming a less stable species. ¢ G° is related to the equilibrium constant by - RT ln Keq. The formation of products with stronger bonds and greater freedom of movement causes ¢ G° to be negative; ¢ G° = ¢ H° - T ¢ S°. If a system at equilibrium is disturbed, it will adjust to offset the disturbance (Le Chatlelier’s principle). The free energy of activation ( ¢ G‡) is the difference between the free energy of the transition state and the free energy of the reactants. The greater ¢ G‡, the slower the reaction. The ratedetermining step has its transition state at the highest point on the reaction coordinate. The rate of a reaction is directly proportional to a rate constant, k; the smaller the rate constant, the slower the reaction. The Arrhenius equation relates the rate constant to the activati on energy 1Ea2 (3.7–3.8).
intermediate
y g r e n e
CH3CHCH2CH3 +
CH3CH
Br
CH3
6-bromo-3-chloro-4-methylcyclohexene not 3-bromo-6-chloro-5-methylcyclohexene because 4 < 5
Br−
CHCH3
HBr
−∆G˚
CH3CHCH2CH3 Br
Progress of the reaction
2
Chapter 4 The Reactions of Alkenes 1. Hydrogen halides add to alkenes to form alkyl halides. Carbocations are stabilized by hyperconjugation (e - delocalization by overlap of adjacent s bond orbitals with the empty p orbital); relative stabilities: 3° 7 2° 7 1°. The Hammond postulate states that the transition state is more similar in structure to the species to which it is more similar in energy (4.1–4.3). 2. Electrophilic addition reactions are regioselective; the electrophile adds to the sp2 carbon bonded to the greater number of hydrogens in order to form the more stable carbocation (4.4). 3. The addition of water or an alcohol to an alkene requires an acid catalyst. Addition of water forms an alcohol; addition of an alcohol forms an ether (4.5). 4. A carbocation can rearrange to a more stable carbocation via a 1,2-hydride or 1,2methyl shift, or by ring expansion (4.6). 5. Halogens (Cl2 and Br2) add to alkenes to form vicinal dihalides via a cyclic bromonium ion intermediate. If the reaction is carried out in water, a halohydrin is formed with water adding to the more substituted sp 2 carbon. Since the intermediate in these reactions is not a carbocation, carbocation rearrangements cannot occur (4.7). 6. Alkenes undergo oxymercurationreduction and alkoxymercurationreduction to form alcohols and ethers, respectively. Carbocations are not formed as intermediates, so carbocation rearrangements do not occur (4.8). 7. Alkenes react with peroxyacids 1RCO3H2 to form epoxides. The reaction is concerted (it does not have an intermediate) (4.9). 8. Hydroboration-oxidation of an alkene involves the concerted addition of borane 1BH 32 to form a trialkylborane that is treated with H 2O 2 and HO - to form an alcohol. Borane is the electrophile that adds to the less substituted sp2 carbon; H - is the nucleophile that adds to the other sp 2 carbon (4.10). CH3 CH3CHCH
CH3 CH2
3-methyl-1-butene
1. BH3/THF 2. HO−, H2O2, H2O
CH3CHCH2CH2OH 3-methyl-1-butanol
9. Alkenes undergo catalytic (Pd/C, Pt/C, Ni) hydrogenation to form alkanes. The most stable alkene has the smallest heat of hydrogenation. The greater the number of alkyl substituents attached to the sp2 carbons, the more stable the alkene (4.11).
Cl
C CH2CHCH3
2-bromo-4-ethyl-7-methyl-4-octene not 7-bromo-5-ethyl-2-methyl-4-octene because 4 < 5
C
e e r F
Br CH3CHCH2C H
2. The sp 2 carbons of an alkene and the four atoms attached to them are in a plane. Cis isomers have the hydrogens on the same side of the double bond; in trans isomers they are on opposite sides. The E isomer has the high priority groups (based on atomic numbers) on opposite sides of the double bond; the Z isomer has them on the same side. Proceeding down a substituent breaks a tie (3.5). 3. The double bond of an alkene is its functional group (the center of reactivity). Curved arrows show the mechanism for this electrophilic addition reaction (H + is an electrophile and the p bond is a nucleophile; the carbocation is an electrophile and Br - is a nucleophile) (3.6).
Chapter 5 Stereochemistry 1. Constitutional isomers differ in the way their atoms are connected. Stereoisomers (cis-trans isomers and isomers with
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asymmetric centers) differ in the way the atoms are arranged in space. Cis-trans isomers have either a double bond or a cyclic structure (5.1). 2. Amolecule is chiral if it is nonsuperimposable on its mirror image. A carbon bonded to four different substituents is an asymmetric center. A molecule with one asymmetric center is chiral; it can exist as a pair of enantiomers (nonsuperimposable mirror image molecules). Enantiomers have the same physical and chemical properties (5.2–5.6). Br CH3CH2
Br
C
H CH3
C
H
CH3
mirror
CH2CH3
the two isomers of 2-bromobutane enantiomers
3. The R,S system is used to name chiral compounds by prioritizing the four substituents attached to the asymmetric center based on at omic number. When the lowest priority substituent points to the rear, an arrow starting at the highest priority substituent and pointing at the second highest priority substituent is clockwise if the compound has the R configuration, and counterclockwise if it has the S configuration (5.7). 1
1
Br
Br
C H4 CH3CH2 CH3 2 3
(S)-2-bromobutane
4
C
H
CH3 3
CH2CH3 2
(R)-2-bromobutane
4. Chiral molecules that rotate planepolarized light to the right are dextrorotatory 1 + 2; those that rotate it to the left are levorotatory 1 - 2. A polarimeter measures observed rotation, a, from which specific rotation [a] can be calculated. A50:50 mixture of enantiomers is an optically inactive 1a = 02 racemic mixture. Enantiomeric excess is measured by dividing the observed specific rotation by the specific rotation of the pure enantiomer (5.8–5.10). 5. Stereoisomers that are not mirror images are diastereomers. Unlike enantiomers, diastereomers possess different physical and chemical properties. In compounds with two asymmetric centers, the configuration of one of the asymmetric centers is the same in both di astereomers, and the configuration of the other is not the same in both. Compounds with two or more asymmetric centers that possess a plane of symmetry are achiral (optically inactive) meso compounds (5.11–5.13). 6. Enantiomers can be separated (resolved) by chiral chromatography (5.16).
7. In a stereoselective reaction, one stereoisomer is formed in preference to another. In a stereospecific reaction, stereoisomeric (e.g., cis and trans) reactants form different stereoisomers as products. When a reactant without an asymmetric center forms a product with one asymmetric center, the product will be a racemic mixture. Electrophilic addition reactions that form carbocation intermediates involve syn and anti addition. Hydrogenation, epoxidation, and hydroboration are syn additions; halogenation is an anti addition. CISSYN-ERYTHRO or -CIS (5.18, 5.19). 8. Enzymes and receptors can distinguish between enantiomers. Enzyme-catalyzed reactions are completely stereoselective— only one stereoisomer is formed. Enzyme-catalyzed reactions are stereospecific—the enzyme reacts with only one stereoisomer (5.20, 5.21).
Chapter 6 The Reactions of Alkynes 1. Alkynes are hydrocarbons with a triple bond. A terminal alkyne has the triple bond at the end of a chain; otherwise, it is an internal alkyne. Acompound with a double and a triple bond is named as an alkenyne; the double bond has the greater priority only if there is a tie. OH and NH 2 groups have priority over double and triple bonds (6.1, 6.2). 2. Electrophiles add to the least substituted sp carbon. Addition of HCl or HBr forms a vinyl halide; with excess reagent, a geminal dihalide is formed. Addition of Cl2 or Br2 forms a dihaloalkene; excess reagent forms a tetrahaloalkane (6.5, 6.6). 3. The acid-catalyzed addition of water to an alkyne forms an enol, which tautomerizes to a ketone. HgSO4 is used with terminal alkynes (6.7). 4. Borane adds to an alkyne to form a vinyl borane, which is oxidized to an enol. An internal alkyne tautomerizes to a ketone: a terminal alkyne requires disiamylborane and forms an aldehyde (6.8). OH H2O, H2SO4 HgSO4
CH3C
CH3C
O CH2
a ketone
CH
OH 1. disiamylborane 2. HO −, H2O2, H2O
CH3CCH3
CH3C H
CH
O CH3CH2CH an aldehyde
5. Catalytic hydrogenation of an alkyne forms an alkane. With Lindlar catalyst, a cis alkene is formed; with Na 1or Li2 + NH 3, a trans alkene is formed via radical anion and vinyl radical intermediates (6.9). 6. A terminal alkyne 1pKa 252 is deprotonated with NaNH 2 to form an acetylide ion, which reacts with a 1° alkyl halide to form a longer-chain alkyne.
3
Working from product to reactants, when designing a synthesis, is called retrosynthetic analysis (6.10–6.12).
Chapter 7 Delocalized Electrons and Their Effect on Stability, Reactivity, and pKa 1. Delocalized e are shared by three or more atoms. Benzene has delocalized e -: all the C ¬ C bonds have the same length; the three pairs of p e - are shared by all six carbons. Resonance contributors use localized e - to approximate the true structure with delocalized e - (the resonance hybrid) (7.1–7.3). a. b.
c.
2. Rules for drawing resonance contributors: move only p and lone-pair e -. Move e - to a positively charged atom or to an at om with a p bond. Each resonance contributor has the same net charge. The greater the predicted stability of the resonance contributor, the more it contributes to the hybrid. Destabilizing features: incomplete octet, positively charged electronegative atom, charge separation (7.4, 7.5). 3. Delocalization (resonance) energy is the gain in stability that results from having delocalized e -. The greater the number of relatively stable resonance contributors, the greater the delocali zation energy. Relative stabilities: conjugated dienes 7 isolated dienes 7 cumulated dienes. Allylic and benzylic cations are more stable than 1° alkyl cations because of e delocalization (7.6–7.8). 4. A molecular orbital (MO) results from a linear combination of atomic orbitals (LCAO). Two e - are placed in each MO, starting from the lowest energy MO. The number of MOs equals the number of AOs; a node is added for each ascending MO. The highest occupied MO (HOMO) is the highest energy MO that contains e -; the lowest unoccupied MO (LUMO) is the lowest energy MO that does not contain e - (7.8). 5. Carboxylic acids and phenol have some e - delocalization, but their conjugate bases have more, causing carboxylic acids 1pKa ' 52 and phenol 1pKa ' 102 to be stronger acids than alcohols 1pKa ' 152, which have no e delocalization. Protonated aniline 1pKa ' 52 is more acidic than protonated alkylamines 1pKa ' 102 due to an increase in delocalization energy upon losing a proton (7.9).
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6. Conjugated dienes form 1,2- and 1,4addition products. At low temperatures, where the reaction is not reversible, the kinetic product (the one that is formed faster) is favored. At higher temperatures, where the reaction is reversible, the thermodynamic product (the more stable product) is favored. The 1,2-product is always the kinetic product; either the 1,2or 1,4-product can be the thermodynamic product; it will depend on which is the more substituted alkene (7.10, 7.11). 7. A conjugated diene reacts with a dieneophile (an alkene with an e withdrawing group) to form a cyclohexene via a concerted Diels-Alder reaction. The diene adopts an s-cis conformation for this [4 2] cycloaddition reaction where the HOMO of one reactant interacts with the LUMO of the other. The reaction is stereospecific; e.g., a cis dienophile forms cis products. Bridged, bicyclic products favor the endo configuration when the substituent has p e - (7.12). electron-withdrawing group
nucleophile
O
4
H 3C
CH2
CH
3C
30 ºC
CH2
2C
H
CCH3
CH2
4
H
O CCH3
CH2
2C
CH2
H
1
CH2 CH
1
electrophile
a 1,4-addition reaction to 1,3-butadiene
Chapter 8 Substitution Reactions of Alkyl Halides 1. Substitution reactions involve replacement of a leaving group with a nucleophile. Alkyl halides have good leaving groups 1I -, Br -, Cl -2 (8.1). −
d+
Nu +
C
d−
X
Nu + X −
C
substitution product
a nucleophile
2. The reaction of bromomethane with HO is a bimolecular nucleophilic substitution reaction 1SN22, with a rate law dependent on [RX] and [HO -] (a second-order reaction). HO - attacks with simultaneous departure of the leaving group. Steric effects govern the relative rates with 1° alkyl halides faster than 2°, and 3° very slow. The reaction occurs with inversion of configuration because the nucleophile (HOMO) interacts with the s* (LUMO) on the backside of the carbon attached to X (8.2). the configuration of the product is inverted relative to the configuration of the reactant
CH3
+ HO− C H CH3CH2 Br (R)-2-bromobutane
CH3 H HO
C
+ Br− CH2CH3
( S)-2-butanol
3. Leaving group tendencies for RX: I - 7 Br - 7 Cl-. Strong bases are better nucleophiles, except if there is a large difference in size and they are i n a protic solvent, because of the greater polarizability of the large nucleophile and its weaker solvation (in which case I - is a better nucleophile than F - ). Aprotic polar solvents (DMSO, DMF) are used in S N2 reactions of alkyl halides with negatively charged nucleophiles because such solvents solvate only cations (8.3, 8.4). 4. The reaction of a 3° alkyl halide with H 2O is a unimolecular nucleophilic substitution reaction 1SN12, with a rate law dependent only on [RX] ( a first-order reaction). The leaving group leaves, forming a carbocation that is attacked by the nucleophile. Formation of the carbocation is the rate-limiting step, so 3° alkyl halides are the most reactive; carbocation rearrangements can occur. Products with inverted and retained configurations are obtained. Partial racemization can occur because one face of the carbocation can be partially blocked by the leaving group (8.5–8.7). 5. Benzylic and allylic halides undergo both S N1 and S N2 reactions. Vinyl and aryl halides undergo neither S N1 nor S N2 reactions (8.8). 6. High concentration of a good nucleophile favors S N2; a poor nucleophile favors S N1. If a reactant is charged, increasing the polarity of the solvent decreases the rate of the reaction; if neither of the reactants is charged, increasing the polarity of the solvent increases the rate of the reaction (8.9, 8.10). 7. Bifunctional molecules can undergo intramolecular reactions to form cyclic products. Five- and six-membered rings are favored (8.11). 8. A common cellular methylating agent is S-adenosylmethionine (SAM), a methyl sulfonium ion (8.12).
Chapter 9 Elimination Reactions of Alkyl Halides 1. An E2 reaction of an alkyl halide involves the simultaneous removal of a proton from a b -carbon and the halide ion from the a-carbon (dehydrohalogenation) to form an alkene (a B -elimination). An E1 reaction is a two-step reaction; the leaving group departs (the rate-limiting step), forming a carbocation, which loses a proton from the b -carbon. Leaving group order in both E2 and E1: I - 7 Br - 7 Cl- 7 F - (9.1, 9.3). 2. E2 and E1 reactions are regioselective: the more stable (more substituted) alkene is the major product (the hydrogen is removed from the b -carbon bonded to the fewest hydrogens; Zaitsev’s rule), because the transition state is alkene-like.
4
However, alkyl fluorides, with a poor leaving group, preferentially form the less substituted alkene, because the transition state is carbanion-like. The relative stabilities of carbanions are 1° 7 2° 7 3°, the reverse of carbocation stabilities (9.2). 3. E2 and E1 reactions are stereoselective: the alkene with the bulkiest groups on opposite sides of the double bond is favored (9.5). 4. In E2 reactions of substituted cyclohexanes, both groups that are eliminated must be in axial positions because of anti elimination (9.6). 5. Under S N1/E1 conditions: 1° alkyl halides do not react because primary carbocations are too unstable to be formed; 2° and 3° alkyl halides undergo both substitution and elimination. Under SN2/E2 conditions: 1° alkyl halides favor substitution; 2° undergo both substitution and elimination; 3° undergo only elimination (9.8). 6. Bulky, strong bases (tert- butoxide) favor E2 over S N2 due to steric hindrance. High temperatures favor E2 over S N2 due to a greater ¢ S° (9.8). 7. Ethers are formed from alkoxide ions and 1° alkyl halides (Williamson ether synthesis). Na or NaH converts an alcohol to an alkoxide ion. Geminal and vicinal dihalides react with excess -NH 2 to form alkynes (9.9, 9.10).
Chapter 10 Reactions of Alcohols, Amines, Ethers, Epoxides, and SulfurContaining Compounds 1. Alcohols and ethers have poor leaving groups due to the strong basicity of HO and RO -. If protonated, they become good leaving groups that can be replaced by halide ions. These are S N1 reactions (so carbocation rearrangements can occur) except in the case of 1° alkyl halides, which are S N2 reactions (10.1). a weakly basic leaving group
CH3
OH + HBr poor leaving group
CH3
H OH
∆
+
−
good leaving Br group
CH3
Br + H2O weak base
2. Alcohols react with PBr3, PCl3, or thionyl chloride 1SOCl 22 to form alkyl halides. Alcohols react with sulfonyl chloride to form sulfonate esters (10-2, 10-3). 3. Alcohols undergo dehydration when heated with a strong acid 1H 2SO42 to form alkenes. These are S N1 reactions, except in the case of 1° alcohols, which are S N2. POCl 3 + pyridine dehydrates alcohols without carbocation formation, so there are no rearrangements (10.4). 4. 2° alcohols are oxidized to ketones; 1° alcohols are oxidized to carboxylic acids with chromic acid 1H 2CrO42 and to aldehydes with PCC (10.5).
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5. Amines have poor leaving groups due to the very strong basicity of -NH 2. Ammonium ions are weaker acids 1pKa ~102 than hydronium ions 1pKa ~ -22, so amines are stronger bases and better nucleophiles than alcohols (10.6). 6. Ethers are cleaved with HI; the reaction is S N1 (breaking to form the more stable carbocation) unless the alkyl groups cannot form a carbocation (primary, vinyl, aryl); then it is S N2 (with iodide ion attacking the least sterically hindered carbon) (10.7). 7. Epoxides react with nucleophiles. Under acidic conditions, the ring opens to put the developing positive charge on the more substituted carbon; under basic conditions, the nucleophile attacks the less sterically hindered carbon (10. 8). O CH3CH site of nucleophilic attack under acidic conditions
CH2 site of nucleophilic attack under basic or neutral conditions
8. Arene oxides can undergo nucleophilic attack or can rearrange (via an NIH shift) to form phenols. Arene oxides that form unstable carbocations are more apt to undergo nucleophilic attack (10.9). 9. Crown ethers form inclusion compounds with metal ions based on molecular recognition. Crown ethers can be used as phase-transfer catalysts (10.10). 10. Thiols (RSH) are more acidic 1pKa ~102 than alcohols. Thiolate anions react with alkyl halides to form sulfides (RSR); sulfides react with alkyl halides to form sulfonium salts 1R3S X 2 (10.11). 11. Lithium reacts with alkyl halides to form alkyllithium compounds; magnesium reacts with alkyl halides to form Grignard reagents. These organometallic compounds are good nucleophiles; they react as if they were carbanions. For example, they react with epoxides to form (after acidification) alcohols. In the presence of H +, OH, or NH, organometallic compounds form alkanes (10.12). 12. Gilman reagents 1R 2CuLi2 are formed from alkyllithium compounds and CuI. They couple with vinyl, aryl, and alkyl halides, replacing the halogen. Catalytic palladium is used to facilitate coupling reactions with alkenes (Heck), stannanes (Stille), and organoboranes (Suzuki ) and aryl, benzyl, or vinyl halides (10.13).
Chapter 11 Radicals • Reactions of Alkanes 1. Alkanes undergo halogenation with Cl2 or Br2 and heat or light to form alkyl halides in a chain reaction that has initiation, propagtion, and termination steps. The radical formed in the initiation step is the reactant of the first propagation
step and the product of the second propagation step (11.2). 2. Radical stability: 3° 7 2° 7 1°. Relative rates for chlorination at room temp: 5: 3.8: 1 for 3°, 2°, 1°. Probability and reactivity factors are used to predict product distribution (11.3, 11.4). 3. Relative rates for bromination at 125 °C: 1600 : 82 : 1 for 1°, 2°, 3°. Abromine radical is less reactive and more selective than a chlorine radical (reactivityselectivity principle (11.5). 4. When HBr adds to alkenes in the presence of peroxide, Br # is the electrophile, so it adds to the sp2 carbon bonded to the most hydrogens—opposite to the regioselectivity of HBr addition without peroxide (11.6). 5. If a radical substitution reaction or a radical addition reaction forms an asymmetric center, the product will be a racemic mixture (11.7). 6. Allylic and benzylic halides are selectively halogenated at the allylic or benzylic positions. Bromination of allylic positions is best carried out with NBS + peroxide + ¢; if the resonance hybrid of the radical intermediate is not symmetrical, two substitution products are formed (11.8).
Chapter 12 Mass Spectrometry, IR Spectroscopy, and UV/Vis Spectroscopy
1. An e - beam removes an e - to form a molecular ion (a radical cation), which then fragments. Amagnetic field focuses cations toward a detector, giving a mass spectrum, which plots abundance versus mass-to-charge (m/z) (12.1). 2. The molecular ion corresponds to the nominal molecular mass. The base peak is the highest abundance ion. M + 1 peaks can be used to determine the number of carbons. For a chlorine-containing compound, the M + 2 peak is 1/3 the M peak; for a compound that contains bromine, the M + 2 peak is equal to the M peak. High resolution MS can determine the exact molecular mass. The e - beam is most likely to dislodge a lone-pair e -. A bond between carbon and a more electronegative atom breaks heterolytically; a bond between carbon and an atom of similar electronegativity breaks homolytically. a-cleavage (cleavage of the bond a to the heteroatom) occurs because the positive charge is then shared by two atoms (12.2–12.5). 3. Spectroscopy uses electromagnetic radiation to probe molecular structure. Frequency 1n2 is directly proportional to energy 1E = hn2; wavelength 1l2 is inversely proportional to energy (E = hc/l; c = speed of light). IR spectroscopy uses wavenumbers (the number of waves in 1 cm), which are directly proportional to energy and have units of cm-1 (12.6).
5
Frequency (n) in Hz
high frequency 1019 Cosmic rays
1017
g-rays
−6
10
X-rays
−4
10
short wavelength
1015
1010
1013
Ultraviolet Visible light light
Infrared radiation
−1
Microwaves
102
10 0.4 0.8 Wavelength (l) in µm
low frequency
105 Radio waves NMR
10 6
1010 long wavelength
4. Stretching vibrations involve changes in bond length and occur at a higher energy than bending vibrations, which involve changes in bond angles. Absorption bands indicate the kind of bonds present in a compound. Those in the functional group region 14000–1400 cm-12 detect functional groups; those in the fingerprint region 11400–600 cm-12 are characteristic of the molecule as a whole (12.7, 12.8). Wavelength (µm) 2.5 2.6 2.7 2.8 2.9 3
100
3.5
4.5
O
e c n a t t i m s n a r T %
5
5.5
6
7
8
9
10
OH
CH3CCH2CCH3 CH3
O 0
4
H
4000 3800 3600 3400 3200 3000 2800 2600 2400 2200
C O 2000
1800
1600
1400
1200
1000
Wavenumber (cm −1)
5. The greater the change in dipole moment when a bond vibrates, the more intense the absorption. The energy required to stretch a bond depends on the bond strength and the masses of the bonded atoms; stronger bonds and lighter atoms absorb at higher frequencies (Hook’s law); triple bonds are stronger than double bonds, which are stronger than single bonds. Electron delocalization can affect bond order. C-H stretch frequency depends on the hybridization of C 1sp 7 sp 2 7 sp32. Alkene substitution patterns can be identified in the fingerprint region (12.9–12.11). 6. O ¬ H (of RCOOH and ROH) and N ¬ H show absorption bands at the same frequency, but their shapes are different. The absence of bands can rule out functional groups. Stretches with no net change in dipole moment are IR inactive (12.12–12.14). 7. UV/Vis spectroscopy involves excitation of an e - to a higher energy state: n p* and p p* transitions; the latter are lower in energy and have greater molar absorptivities 1e2. The greater the lmax, the lower the energy: UV radiation (180–400 nm) is of higher energy than visible light (400–780 nm). A chromophore is the group in the molecule that causes the absorption. Absorbance depends on the concentration of the sample, the length of the light path, and the e of the compound (Beer-Lambert Law) (12.15–12.17). 8. The more conjugated double bonds, the greater the lmax (due to raised energy of the HOMO and lowered energy of the :
:
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 6
LUMO) and the greater the e. Colored compounds absorb visible light. Auxochromes (OH and NH 2) attached to chromophores increase both lmax and e (12.18, 12.19).
5. Integration indicates the relative number of protons responsible for each signal. Asignal has a multiplicity 1 rule, where N is according to the N the number of neighboring equivalent protons bonded to adjacent carbons. Splitting occurs as a result of the proton(s) that give rise to the signal being coupled to adjacent nonequivalent protons whose nuclear spins can align either with or against the applied magnetic field (13.9, 13.10).
Chapter 13 NMR Spectroscopy 1. Nuclear magnetic resonance (NMR) establishes atom connectivity. When NMR active nuclei 11H, 13C, 15N, 19F, 31P2 are subjected to an applied magnetic field, they align either with the field 1A-spin state2 or against the field 1 B -spin state2. The energy difference between the spin states depends on the strength of the magnetic field 1B o2 and the gyromagnetic ratio (13.1). 2. Nuclei resonate at different frequencies due to shielding by nearby electrons that induce a local magnetic field that opposes the applied magnetic field, thereby changing the effective magnetic field 1Beffective = Bapplied - Blocal2. Protons in e - rich environments are shielded and resonate at lower frequencies (upfield); those in e - poor environments are deshielded and resonate at higher frequencies (downfield) (13.3, 13.6).
these protons sense a larger effective magnetic field, so come into resonance at a higher frequency y t i s n e t n I
these protons sense a smaller effective magnetic field, so come into resonance at a lower frequency
deshielded nuclei
"downfield"
shielded nuclei
"upfield"
Frequency
3. Chemically equivalent protons resonate at the same frequency; nonequivalent sets of protons resonate at different frequencies. The chemical shift 1 D2 is independent of spectrometer frequency; d = distance of the signal in Hz from TMS divided by spectrometer frequency in MHz. Low frequency (shielded) signals have small d values (13.4, 13.5). 4. In a similar environment, a signal for CH 3 is at a lower frequency than a signal for CH 2, which is at a lower frequency than a signal for CH. Induced ring currents cause sp2-bound protons (aryl and vinyl) and sp-bound protons to experience diamagnetic anisotropy and resonate at 7–5 ppm and 2.4 ppm, respectively (13.7, 13.8). O C
H H
C
O C
Z
H C
vinylic
OH
C
O
H
C
C
C
C
a
b
2
2
2 3.7
8
7
3.6
3.5 PPM
6
3.4
C
C
C
3.3
5
3.2 PPM
9.0
8.0
6.5
4.5 d (ppm)
2.5
H
C
0
2.2
2.1 PPM
1
C C C
200
150
100 d (ppm)
6
C
C
C
O
N Cl Br 3 sp
50
Chapter 14 # Reactions of Benzene
1. Aromatic compounds have large delocalization energies: benzene is 36 kcal/mol more stable than hypothetical ‘cyclohexatriene.’ To be aromatic, a compound must have an uninterrupted cloud of p electrons (that is, it must be cyclic, planar, and every ring atom must have a p orbital), and the p cloud must contain an odd number of pairs of p e (Hückel’s 4n 2 rule) (14.1, 14.2). 2. Cyclobutadiene and cyclooctatetraene, with an even number of pairs of p e -, are not aromatic. The cyclopentadienyl anion and the cyloheptatrienyl cation, each with three pairs of p e -, are aromatic. Pyridine, pyrrole, furan, and thiophene (heterocyclic compounds) are aromatic (14.1, 14.2).
0
O
saturated
1.5
2
C
allylic
12
2 .3
4 3 d (ppm) frequency
6. The coupling constant ( J ) is the distance (in Hz) between adjacent peaks in a signal. The coupling constant for H a being split by H b is denoted by Jab. The signals of coupled protons have the same coupling constant. The number of observed peaks in a signal can be explained by a splitting diagram. When the coupling constants of two sets of nonequivalent adjacent protons are similar, the signal multiplicity is the same as if the adjacent sets were equivalent (13.12, 13.13). 7. Two hydrogens bonded to a carbon that is bonded to two different groups are called enantiotopic hydrogens; one is a pro-Shydrogen, the other a pro-R-hydrogen, and the carbon is prochiral. Enantiotopic hydrogens are equivalent. If the compound has an asymmetric center, the two hydrogens are diastereotopic hydrogens; they are not equivalent, so they produce different signals (13.14). 8. NMR spectra show an average of various conformers at room temperature. Hydrogens involved in proton exchange (OH, NH 2) are not split and do not split; they appear as broadened singlets (13.15, 13.16). 9. 13C NMR determines the types of carbons present in a compound (0–200 ppm). The signals cannot be integrated and are not split unless the spectrum is run in a proton-coupled mode. The multiplicity is determined by the N + 1 rule, where N is the number of hydrogens bonded to the carbon that produces the signal (13.19).
C H
H
Z = O, N, halogen
c
ClCH2CH2CH2I
Aromaticity
carbon
0
N
N H
O
S
pyridine
pyrrole
furan
thiophene
3. The pKa of cyclopentadiene is unusually low (15) due to its aromatic conjugate base. Cycloheptatrienyl bromide ionizes readily due to its aromatic cation. Antiaromatic compounds, with an uninterrupted cloud of p electrons that contains an even number of pairs of p e -, are less stable than analogous compounds with localized e -. Frost circle diagrams are used to assign relative energies to the MOs of cyclic compounds (14.5–14.7). 4. Some monosubstituted benzenes have names that incorporate the substituent (toluene, phenol, aniline, benzenesulfonic acid, anisole, styrene, benzaldehyde, benzoic acid, benzonitrile). A benzene substituent is a phenyl group (Ph-); a phenyl methyl substituent is a benzyl group 1PhCH2-2 (14.8). 5. Aromatic compounds undergo electrophilic aromatic substitution reactions, which replace a hydrogen with an electrophile. Halogenation employs Br2 + FeBr3 or Cl2 + FeCl3 (14.9–14.11). +
+
+ −
Br Br
F eB r3
H
Br B
Br
+ HB+
−
+ FeBr4
6. Nitration employs nitric acid and sulfuric acid; the nitronium ion 1+NO22 is the electrophile. Sulfonation uses sulfuric acid; the sulfonium ion 1+SO3H2 is the electrophile. This reaction is reversible at 100 °C (14.12, 14.13). 7. Friedel-Crafts acylation employs an acyl chloride or an acid anhydride + AlCl3 (the acylium ion is the electrophile) and forms a phenyl ketone. Friedel-Crafts alkylation
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 7
employs an alkyl halide + AlCl3 (a carbocation is the electrophile); an alkylbenzene is the product. Acarbocation generated from an alkene or an alcohol can also be used. Carbocations can rearrange; therefore, a benzene ring with a straightchain alkyl group is synthesized by Friedel-Crafts acylation, followed by reduction with H 2, Pd/C, or Zn1Hg2 + HCl + ¢ (Clemmensen), or H 2NNH 2 + NaOH + ¢ (WolffKishner). Alkylbenzenes with straightchain alkyl groups can also be prepared by Stille and Suzuki reactions (14.13–14.18). 8. Bromination of an alkylbenzene at the benzylic position allows subsequent substitution and elimination reactions. Oxidation with KMnO4 or Na 2Cr2O7/H + converts alkyl groups to COOH groups. Mild oxidation of a 1° or 2° benzyl alcohol with MnO2 produces benzaldehyde or a phenyl ketone, respectively. Nitrobenzenes are reduced to anilines with Sn + HCl followed by HO - or with H 2, Pd/C (14.19).
Chapter 15 Reactions of Substituted Benzenes 1. Disubstituted benzenes can be named using ortho (1,2), meta (1,3), and para (1,4) designations. Substituents are listed alphabetically, or one of the substituents is incorporated into the parent name. In polysubstituted benzenes, the substituents are numbered in the direction that results in the lowest possible numbers (15.1).
NH2 Cl
OH CH2CH3
CH3 NO2 2-chlorotoluene 4-nitroaniline 2-ethylphenol ortho-chlorotoluene para-nitroaniline ortho-ethylphenol not not not ortho-chloromethylbenzene para-aminonitrobenzene ortho-ethylhydroxybenzene
2. Groups that donate e - either by resonance or by hyperconjugation activate a benzene ring toward electrophilic aromatic substitution; groups that withdraw e either by resonance or by inductive electron withdrawal deactivate it. The position to which a substituent directs an incoming substituent depends on which of the three possible carbocation intermediates is the most stable. Activating groups and the mildly deactivating halogens are ortho-para directors; all groups more deactivating than the halogens are meta directors. All ortho-para directors (except alkyl, aryl, RCH “ CHR) have a lone pair on the atom attached to the ring; all meta directors have a positive or partial positive charge on the atom attached to the ring (15.2, 15.3).
3. Deactivating substituents stabilize the conjugate bases of phenols, carboxylic acids, and anilinium ions, making the acids more acidic (lowering their pK a ); activating substituents make the compounds less acidic (15.4). 4. The relative amounts of ortho and para products depend on the size of the directing and incoming substituents. Benzene rings with highly activating substituents are monohalogenated without a catalyst and polyhalogenated with it. A benzene ring with a meta-directing substituent cannot undergo a FriedelCrafts reaction. Anilines form ammonium ions (strongly deactivating meta directors) with Lewis acids (15.5, 15.6). 5. When a disubstitued benzene ring undergoes an electrophilic aromatic substitution reaction, a strongly activating substituent wins out over a weakly activating or deactivating substituent (15.8). 6. Arenediazonium salts 1ArN2 +2, produced from aniline using nitrous acid 1NaNO2 + HCl2 undergo substitution with CuCl, CuBr, CuCN (Sandmeyer reaction), KI, HBF4 (Schiemann reaction), and form phenols with Cu 2O, Cu1NO322, H 2O. The diazonium group can be replaced by an H with H 3PO2. ArN2 + reacts with strongly activated benzene rings via electrophilic aromatic substitution to form colored azo compounds. Diazonium ion formation results from reaction of a 1° aniline (or amine) with a nitrosonium ion 1+N = O2; 2° anilines form Nnitrosoamines; with 3° anilines, the nitrosonium ion is an electrophile that replaces an H of benzene (15.9–15.11). 7. Aryl halides with strongly electronwithdrawing substituents in the ortho and/or para positions undergo nucleophilic aromatic substitution reactions 1SNAr2 with good nucleophiles (HO -, RO -, amines). Halobenzenes react with NaNH 2 to form anilines via a benzyne intermediate (15.12, 15.13). 8. Polycyclic benzenoid hydrocarbons with fused rings (naphthalene, anthracene, phenanthrene, etc.) undergo reactions similar to the ones that benzene undergoes (15.14).
Chapter 16 Carbonyl Compounds I 1. Carbonyl compounds have a carbonyl group 1C = O2. Carboxylic acid derivatives have an acyl group 1RC = O2 bonded to OH, Cl, OC1 = O2 R, OR, NH2, NHR, NR 2; these groups can be substituted by another group. Acyl groups bonded to H or R do not posses a group that can be substituted by another group. The parent name for carboxylic acid is alkanoic acid. The positions adjacent to the carbonyl carbon are a, b , g, d, e in common nomenclature (16.1).
7
O
O
C CH3CH2CH2CH2
C OH
CH3CH2CH2CH2CH2
pentanoic acid valeric acid
hexanoic acid caproic acid
O
O
C
C CH2
CH
OH
OH
OH
propenoic acid acrylic acid
benzenecarboxylic acid benzoic acid
2. Nomenclature: an acyl halide is an alkanoyl halide, an acid anhydride is a alkanoic anhydride, an ester is an alkyl alkanoate (where the alkyl prefix refers to the group bonded to the carboxyl oxygen), a lactone (a cyclic ester) is a 2-oxacycloalkanone, an amide is an alkanamide with N -alkyl as a prefix , if necessary; a lactam (a cyclic amide) is a 2-azacycloalkanone, a nitrile is an alkanenitrile (16.1). 3. The carbonyl carbon and carbonyl oxygen are sp2 hybridized; carboxylic acids, esters, and amides are stabilized by e - delocalization. Elevated boiling points of carboxylic acids and amides are due to hydrogen bonds and dipole-dipole interactions (16.2, 16.3). 4. Carboxylic acid derivatives undergo nucleophilic acyl substitution reactions via a tetrahedral intermediate that expels the weakest base. The order of reactivity: acyl chloride 7 acid anhydride 7 ester ' acid 7 amide. More reactive carboxylic acid derivatives are converted to less reactive ones (16.5–16.7). a group is expelled
O sp2 C R
sp3 O
+ Z
−
Y
nucleophile attacks the carbonyl carbon
k 1 k −1
R
C
−
O sp2 Y
k 2 k −2
Z
C R
+ Y
−
Z
a tetrahedral intermediate
5. Acyl halides react with carboxylate ions to form acid anhydrides, with alcohols to form esters, with water to form carboxylic acids, and with excess amine to form amides. Acid anhydrides react with alcohols to form esters, with water to form carboxylic acids, and with excess amine to form amides. The reaction of esters with excess water to form carboxylic acids or with excess alcohol to form a new ester requires a catalyst; H + (Fischer esterification) or HO - for hydrolysis, and H + or RO - for transesterification. Esters undergo aminolysis with amines to form amides (16.8–16.12). 6. Hydrolysis of an ester with a 3° alkyl group occurs via a carbocation (16.11). 7. Triesters of glycerol (fats and oils) are hydrolyzed under basic conditions (saponification) to form sodium
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 8
carboxylates (soaps), which form micelles in water ordered by hydrophobic interactions (16.14). 8. Reactions of carboxylic acids with amines form ammonium carboxylate salts. Amides react with water and alcohols under acidic conditions to form carboxylic acids and esters, respectively. Dehydrating reagents 1P2O5, POCl32 convert amides without a substituent on the N to nitriles (16.15–16.17). 9. Alkyl halides are converted to 1°amines using the reaction of phthalimide anion with an alkyl halide to form an N-substituted imide, which is hydrolyzed (Gabriel synthesis). Nitriles, formed by an S N2 reaction of an alkyl halide with cyanide ion, are hydrolyzed with acid and heat to produce carboxylic acids. Catalytic hydrogenation of a nitrile forms a 1° amine (16.18, 16.19). 10. Carboxylic acids are activated in the lab with SOCl2, PCl3, or PBr3, which converts them to acyl halides. Carboxylic acids are activated in the cell with ATP to form acyl phosphates, acyl pyrophosphates, or acyl adenylates, or by being converted to thioesters. Diacids include oxalic, malonic, succinic, glutaric, adipic, and phthalic acids (16.20–16.23).
Chapter 17 Carbonyl Compounds II 1. An aldehyde is named as an alkanal, and a ketone as an alkanone (17.1). 2. Aldehydes and ketones undergo nucleophilic addition reactions. Steric effects and crowding in the tetrahedral intermediate cause aldehydes to be more reactive than ketones (17.2, 17.3). a nucleophile that is a strong base
O−
O R
+
C R'
Z
−
R
C
OH R'
HB+ B
Z
R
C
R'
reduced to 1° alcohols and amides are reduced to amines. Diisobutylaluminum hydride reduces esters to aldehydes at -78 °C (17.6). 5. Ketones and aldehydes add cyanide ion to form cyanohydrins. Aldehydes and ketones react with 1° amines to form imines (Schiff base) and with 2°amines to form enamines (a, b -unsaturated tertiary amines). Imines and enamines can be hydrolyzed to carbonyl compounds and amines under acidic conditions. Hydroxylamine forms oximes; hydrazine forms hydrazones. Imines and enamines are reduced to amines with H 2, Pd/C, or with sodium triacetoxyborohydride (reductive amination) (17.7, 17.8).
C
C C
O
+
R
C
NH2
N
+
H2O
R an aldehyde or a ketone
a primary amine
an imine a Schiff base
a, b-position
H R
C O
C
C NH
+
R C
N
an aldehyde or a ketone
+
H2O
R
R a secondary amine
an enamine
6. As a result of steric and electronic effects, ketones form less hydrate than do aldehydes. Aldehydes react with alcohols + + H to form acetals via a hemiacetal intermediate; ketones form ketals. Acetals and ketals are hydrolyzed (with H + ) back to aldehydes and ketones. 1,2-Diols and 1,3-diols 1 + acid2 form cyclic acetals that can be used as a protecting group. Thioketals are formed from thiols, which are reduced with H 2 and Raney Ni to alkanes (17.9–17.12).
R
C
OH H
+ CH3OH
R
C
H
OCH3 an aldehyde
3. Grignard reagents react with formaldehyde to form 1° alcohols (following protonation of the alkoxide ion); aldehydes form 2° alcohols, ketones form 3° alcohols, and reaction with carbon dioxide forms a carboxylic acid. Acyl chlorides and esters add two equivalents of Grignard reagent to form 3° alcohols. Acetylide ions also form nucleophilic addition products with aldehydes and ketones (17.4, 17.5). 4. Aldehydes and ketones react withNaBH 4 to form 1°and 2° alcohols, respectively. Acyl chlorides add two equivalents of hydride ion to form 1°alcohols. Esters, carboxylic acids, and amides are too unreactive to be reduced by NaBH 4; LiAlH 4 must be used. Two equivalents of hydride ion add to these compounds: esters and carboxylic acids are
HCl
a hemiacetal
CH3OH, HCl
OCH3 R
C
H + H2O
OCH3 an acetal
7. Phosphonium ylides react with aldehydes and ketones to form alkenes (Wittig reaction). A prochiral carbonyl carbon, with Re and Si faces, reacts with achiral nucleophiles to form R and S products. Retrosynthetic analysis allows for multistep planning by disconnection and synthons, and synthetic equivalent identification (17.13–17.15). 8. A ,B -Unsaturated carbonyl compounds undergo conjugate addition with weakly basic nucleophiles (cyanide ion, thiols, amines, Gilman reagents); with strongly basic nucleophiles (Grignard reagents and hydride ion), reactive carbonyl groups undergo direct addition, and less reactive carbonyl groups undergo conjugate addition (17.16–17.18).
8
−
O
O
O
C
C
C
RCH
R
RCH −
H
R
RCH
O C R
E+
+ H2O
RCH
R
E A-substituted product
enolate ion
−
H
Z product of nucleophilic addition
1. Aldehydes, ketones, and esters have acidic a-hydrogens, because the electrons left behind when the proton is removed are delocalized onto oxygen, forming an enolate. Aldehydes and ketones (pKa 1620) are more acidic than esters (pKa 25). b -Dicarbonyl compounds ( B -keto esters, B -diketones) have enhanced acidity (pKa 6-10). Keto and enol tautomers are in equilibrium. Enolization can be catalyzed by acid or by base (18.1–18.4).
HO
H
O the reaction is irreversible because Z is too basic to be expelled
Chapter 18 Carbonyl Compounds III
2. Ketones and aldehydes react with halogens under acidic conditions to form a-halo carbonyl compounds; under basic conditions multihalogenation occurs. Methyl ketones react with HO - and I2 to form carboxylate ions and iodoform (haloform reaction) (18.5). 3. Carboxylic acids react with P + Br2 and water to form a-bromocarboxylic acids (Hell-Volhard-Zelinski reaction) (18.6). 4. LDA removes an a-hydrogen to form an enolate, which undergoes alkylation with 1° alkyl halides. The a -carbon can also be alkylated (or acylated) via an enamine (18.8–18.10). 5. a, b -Unsaturated carbonyl compounds undergo conjugate addition with b -dicarbonyl anions (Michael reaction) or with enamines (Stork enamine reaction) (18.11). 6. Aldehydes and ketones react with HO - to form b -hydroxyaldehydes and b -hydroxyketones (aldol addition), as a result of the addition of an enolate of one molecule to the carbonyl carbon of another. Heating with acid or base causes loss of water (aldol condensation). Enolates formed with LDAreact with aldehydes and ketones (added slowly), forming aldol products (mixed aldol addition) (18.12–18.14). O
O
O LDA
−
1. CH3CH2CH2CH add slowly 2. H2O
O
OH CHCH 2CH2CH3
7. An ester with two ␣-hydrogens reacts with RO - (corresponding to its alkoxy group) to form a b -keto ester (Claisen condensation) after acidification. A mixed Claisen condensation leads to primarily one product if an ester with a-hydrogens is added slowly to an ester without a-hydrogens. An intramolecular Claisen condensation (Dieckmann condensation) forms cyclic b -keto esters; 5- and 6-membered rings are favored. Intramolecular aldol additions also favor
Bruice_SC_v4.qxd 11/20/06 1:29 PM Page 9
5- and 6-membered ring products. A Michael addition combined with an intramolecular aldol condensation forms a compound with a 2-cyclohexenone ring (Robinson annulation) (18.15–18.17). 8. 3-Oxocarboxylic acids lose CO 2 (decarboxylate) when heated. Malonic ester is alkylated, hydrolyzed with acid, and decarboxylated to form a carboxylic acid (malonic ester synthesis); acetoacetic ester is alkylated, hydrolyzed, and decarboxylated to form a methyl ketone (acetoacetic ester synthesis) (18.18–18.20). malonic ester synthesis
C2H5O
O
O
C
C
CH2
O OC2H5
diethyl malonate malonic ester
1. CH 3CH2O− 2. RBr 3. HCl, H2O, ∆
R
CH2
C
OH
from malonic ester from the alkyl halide
Chapter 19 More About Oxidation-Reduction Reactions 1. Reduction increases the number of C ¬ H bonds or decreases the number of C ¬ O, C ¬ N, or C ¬ X bonds 1X = halogen2. Oxidation decreases the number of C ¬ H bonds or increases the number of C ¬ O, C ¬ N, or C ¬ X bonds. Reducing agents are oxidized; oxidizing agents are reduced. There are three mechanisms for addition of H 2: H # + H # (catalytic hydrogenation); e - + H + + e - + H + (dissolving-metal reduction); and H - + H + (metal-hydride reduction) (19.1). 2. Chromic acid oxidation converts 1° alcohols to carboxylic acids and 2° alcohols to ketones. Swern oxidation (with DMSO, oxalyl chloride, Et3N ) converts them to aldehydes and ketones, respectively (19.2). 3. Tollens reagent oxidizes aldehydes to carboxylic acids (Tollens test). Peroxyacid oxidizes aldehydes to carboxylic acids and ketones to esters (Baeyer-Villiger oxidation). Migration tendencies: H 7 tert-alkyl 7 sec-alkyl = phenyl 7 primary alkyl 7 methyl (19.3). 4. Enantioselective reactions (which form more of one enantiomer than another ) use enzymes or enantiomerically pure catalysts (19.4). 5. Alkenes react with basic, cold KMnO4 or with OsO4 to form vicinal diols. Cyclic alkenes form cis-1,2-diols via syn addition (19.5). 6. Vincinal diols undergo oxidative cleavage with periodate to form aldehydes and ketones. Ozone reacts with alkenes (ozonolysis); ketones and aldehydes are formed when the ozonide is treated with Zn or 1CH 322S; ketones and carboxylic acids are formed when it is treated with peroxide (19.6-19.7). 7. Ozone reacts with alkynes to form carboxylic acids. Oxidation reactions and others allow for functional group interconvertion (19.8, 19.9).
Chapter 20 More About Amines # Heterocyclic Compounds 1. Amines are bases and nucleophiles. Heterocyclic compounds possess one or more heteroatoms (N, O, S) in a ring. Cyclic amines are named as azacycloalkanes or use common names: aziridine, azetidine, pyrrolidine, piperidine (20.1). 2. Quaternary ammonium ions react with hydroxide ion and heat to form alkenes (Hofmann elimination reaction). The transition state has carbanion character, so the less substituted amine is the major product (the hydrogen is removed from the b -carbon bonded to the most hydrogens). Amines react with excess methyl iodide to form quaternary ammonium iodides (exhaustive methylation), which are converted by Ag 2O to quaternary ammonium hydroxides (20.4). 3. Quaternary ammonium ions are used as phase-transfer catalysts (20.5). 4. 3° amines are oxidized to amine oxides with peroxide, which eliminate when heated to form the least substituted alkene (Cope elimination). 2° amines are oxidized to hydroxylamines and 1° amines to nitro compounds (20.6). 5. Aromatic 5-membered ring heterocycles (pyrrole, furan, thiophene) are more reactive than benzene to ward elec trophil ic aromat ic substitution; they form 2-substituted products. The pyridinium ion, with an sp 2 N, is more acidic 1pKa ~52 than an alkylammonium ion. Pyridine is less reactive than nitrobenzene toward electrophilic aromatic substitution, which occurs at the 3-position. Pyridine is more reactive than benzene toward nucleophilic aromatic substitution, which occurs at the 2- and 4-positions (20.8, 20.9).
HC
O
HC H
CH2OH
O OH
C
OH
HO
C
H
H
C
OH
H
OH
H C
OH
H
H
C
OH
H
OH
H C
OH
H
HO
H
C
O
HO C
H
CH2OH
CH2OH
Fischer projection
wedge-and-dash structure
O H OH OH
CH2OH
CH2OH
Fischer projection
wedge-and-dash structure
D-fructose
a polyhydroxy aldehyde
a polyhydroxy ketone
2. Under basic conditions, monosaccharides are converted to a mixture of aldoses and ketoses through enolate intermediates. Sugars are reduced to alditols with NaBH 4 and are oxidized by Br2 or Ag +/NH 3 to aldonic acids and by nitric acid to aldaric acids. Monosaccharides form osazones with excess phenylhydrazine (Sec. 21.5–21.7). 3. The Kiliani-Fischer synthesis increases the chain by one carbon, forming C-2 epimers. The Wohl degradation decreases the chain by one carbon (21.8, 21.9). 4. Pentoses and hexoses exist in solution as furanoses and pyranoses, which are hemiacetals or hemiketals. The anomers are in equilibrium in solution: a (right in a Fischer projection, down in a Haworth projection, axial in a chair conformer); b (left in a Fischer, up in a Haworth, equatorial in a chair). The optical rotation changes when a pure anomer is placed in solution (mutarotation). b -D-Glucose (64% at equilibrium) has all it s groups in equatorial positions (21.11, 21.12). 5. Hemiacetals or hemiketals of sugars react with ROH + H +, forming acetals and ketals (glycosides: furanosides and pyranosides); the new bond to OR is a glycosidic bond. The mechanism involves an oxocarbenium ion. The a-glycoside is the major product due to favorable n-s* e - overlap (the anomeric effect) (21.13, 21.14). CH2OH HO HO
CH2OH
O OH
CH3CH2OH HCl
HO HO
a glycosidic bond
O OCH2CH3
OH
H
-D-glucose -D-glucopyranose
H
ethyl -D-glucoside ethyl -D-glucopyranoside
Chapter 21 Carbohydrates
9
C HO
D-glucose
OH
1. Carbohydrates are polyhydroxy aldehydes (aldoses) or polyhydroxy ketones (ketoses). Monosaccharides have one sugar unit, disaccharides have two, oligosaccharides have 3–10, and polysaccharides have many. D-glyceraldehyde (a triose) has the R-configuration. Naturally occurring sugars are D-sugars—the bottom-most asymmetric center in a Fischer projection has the OH group on the right. Erythrose and threose are tetroses; ribose is a pentose; glucose and fructose are hexoses. Mannose is the C-2 epimer of glucose; galactose is t he C-4 epimer. Ketoses have a keto group at C-2 (21.1–21.4).
CH2OH
H
+ CH2OH HO
O H
HO OH
OCH2CH3
ethyl -D-glucoside ethyl -D-glucopyranoside
6. Straight-chain sugars, hemiacetals, and hemiketals are reducing sugars; acetals and ketals are non-reducing sugars (21.15). 7. Starchis composed of amylose and amylopectin; both are polysaccharides of glucose. Amylose has a-1,4 ¿ - glycosidic linkages; amylopectin has a-1,4 ¿ and a-1,6 ¿ -linkages. Glycogen has more branches than amylopectin. Cellulose is a polysaccharide of glucose with b -1,4 ¿ -linkages; chitin has N -acetyl groups at the 2-positions of cellulose (21.17).
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Chapter 22 Amino Acids, Peptides, and Proteins 1. Peptides and proteins are polymers of amino acids. Dipeptides have two amide-linked amino acids; tripeptides have three and polypeptides have many; proteins have 40–400. Naturally occurring amino acids have the L-configuration (22.1, 22.2). amide bonds
O
O R +
C
C
CH
O
NHCH
OH
NH3
C NHCH
C
O−
NHCH
R′
R
a protonated
O
R′′
amino acids are linked together by amide bonds
A-aminocarboxylic acid
an amino acid
2. The pKa of the carboxylic acid group of an amino acid is ' 2; that of the ammonium group is ' 9. At physiological pH (7.3), amino acids are zwitterions (22.3). O
O
C R
CH +
C OH
R
CH +
NH3 pH = 0
O O−
a.
C R
NH3 + H+
CH
3.
4.
5.
6.
b.
O−
CH
NH2 + H+
a zwitterion pH = 7
pH = 11
3. The isoelectric point (pI), the pH at which the amino acid has no net charge, is found by averaging the pKa’s for neutral side chain amino acids, and by averaging t he like charge pKa’s for amino acids with ionizable side chains (except Cys and Tyr). Electrophoresis separates amino acids based on pI values; paper and thinlayer chromatography separates them based on polarity. Ion-exchange chromatography separates and quantifies amino acids based on charge and polarity. Ninhydrin reacts with amino acids to form a colored product (22.4, 22.5). 4. Amino acids are synthesized from carboxylic acids by a-bromination followed by reaction with NH 3; by reductive amination of a-keto acids; by the N -phthalimidomalonic ester synthesis; or by the acetamidomalonic ester synthesis. Aracemic mixture of amino acids can be separated via a kinetic resolution with an enzyme (22.6, 22.7). 5. Peptide bonds have double bond character due to electron delocalization. In writing an amino acid sequence, the N-terminal amino acid is on the left, the C-terminal is on the right. Disulfide bonds are formed between cysteine side chains (22.8).
a-carbon R
7. The primary structure of a protein is the sequence of amino acids and the location of the disulfide bridges. 2-Mercaptoethanol cleaves disulfide bonds. Dilute acid partially hydrolyzes peptides into smaller fragments. Edman’s reagent identifies the N-terminal amino acid. Peptidases, enzymes that hydrolyze peptide bonds, include carboxypeptidase A and B (exopeptidases), which cleave the C-terminal amino acid, and endopeptidases: trypsin, chymotrypsin, and elastase. Cyanogen bromide cleaves at the C-side of Met (22.12, 22.13). 8. Secondary structure describes the repetitive conformations assumed by segments of the protein backbone: an A-helix (right-handed coil with 3.6 amino acids/turn); a B -pleated sheet (extended hydrogen bonded conformation in parallel or antiparallel orientation); and a coil (loop) conformation (22.14).
O
R a-carbon
O−
C
CH
C
R +
N
CH
N
H
R
H
hydrogen bond
9. Tertiary structure, the 3D structure of the protein, is maintained by disulfide bonds, hydrogen bonds, hydrophobic interactions, and electrostatic attractions. Quaternary structure describes the arrangement of protein subunits. Denaturation by pH change, urea, detergent, solvents, or by heat or agitati on forms a random coil (22.15–22.17).
Chapter 23 Catalysis 1. A catalyst increases the rate of a reaction (without being consumed) by decreasing the free energy of activation ( ¢ G‡) (23.1). ‡ ∆G catalyzed
‡ ∆G uncatalyzed
a two-step mechanism
1. Cofactors are metal ions or organic molecules (coenzymes) that some enzymes need to catalyze a reaction. An enzyme with its cofactor is a holoenzyme; without its cofactor it is an apoenzyme. All the water-soluble vitamins (except vitamin C) and water-insoluble vitamin K are precursors for coenzymes (24.1). 2. Vitamin B3 (niacin) is a precursor for NAD and NADP that are oxidizing agents and for NADH and NADPH that are reducing agents (24.2). a basic group of an amino acid side chain
O C
H
B –
O
4
5 6
H
B
C R
R O
H 3
CNH2
oxidation of substrate reduction of coenzyme
H
H
O CNH2
2 1
e e r F
N+
N
R
R
CH
resonance contributors
6. t-BOC protects amino groups; DCC activates carboxyl groups. Automated solid-phase peptide synthesis synthesizes polypeptides from the C-terminal end (22.10, 22.11).
Chapter 24 The Organic Mechanisms of the Coenzymes
a one-step mechanism y g r e n e
the slow step in general-acidcatalysis. A base catalyst increases the rate by removing a proton: before the slow step in specific-base catalysis; during the slow step in general-base catalysis (23.2, 23.3). A nucleophilic (covalent) catalyst increases the rate by forming a new covalent bond with the reactant, resulting in formation of a more reactive species (23.4). Metal-ion catalysis makes a group more susceptible to nucleophilic attack, makes a group a better leaving group, or makes water a better nucleophile by lowering its pKa (23.5). Intramolecular reactions occur with faster rates compared with intermolecular reactions. Intramolecular catalysis occurs when the catalyst and the reaction center are in the same molecule (23.6). Enzymes (biological catalysts) bind their substrate in an active site based on molecular recognition. In the lock-and-key model, the substrate fits into the active site like a key fits into a lock; in the induced-fit model, the enzyme changes its conformation to become complementary to the shape of the substrate after binding it. The catalytic ability of an enzyme results from bringing reacting and catalytic groups together. A pH-activity profile can be used to assess participation of ionizable groups (23.8, 23.9).
Progress of the reaction
2. An acid catalyst increases the rate of a reaction by donating a proton: before the slow step in specific-acid catalysis; during
10
3. Vitamin B2 (riboflavin) is a precursor for FAD and FMN that catalyze oxidation reactions. FAD catalyzes the oxidation of thiols to disulfides and amines to i mines; FADH2 is a reducing agent (24.3). 4. Vitamin B1 is the precursor to thiamine pyrophosphate (TPP) that catalyzes the transfer of a two-carbon unit (24.4).
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5. Biotin, from vitamin H, catalyzes the carboxylation of the a-carbon of pyruvate and acetyl-CoA(24.5). 6. Pyridoxal phosphate (PLP), from vitamin B6, catalyzes amino acid transformations including decarboxylation, transamination, racemization, and Ca — Cb bond cleavage (24.6). 7. Coenzyme B12, from vitamin B12, is a cobalt-coordinated porphyrin compound that catalyzes certain isomerization reactions (24.7). 8. Asubstituted tetrahyrofolate (THF), from folic acid, transfers a one-carbon unit (methyl, methylene, formyl) to its substrate. 5-Fluorouracil is a suicide inhibitor. Methotrexate and wafarin are competitive inhibitors (24.8, 24.9). 9. Vitamin KH2, from vitamin K, carboxylates the g-carbon of glutamate (24.9).
Chapter 25 The Chemistry of Metabolism 1. Metabolism consists of catabolic reactions that break down compounds to release energy and anabolic reactions that require energy to synthesize compounds. Catabolism has four stages: stage 1 involves the hydrolysis of fats, carbohydrates, and proteins; in stage 2 the products of the first stage are converted to pyruvate, acetyl-CoA, or citric acid cycle intermediates; stage 3 is the citric acid cycle; ATPis synthesized in stage 4 (25.1). 2. ATPis used in phosphoryl transfer reactions. ATP hydrolysis is favored due to electrostatic repulsion, enhanced solvation, and e - delocalization. ATP, because of its negative charges, is not reactive unless bound to an enzyme (25.2–25.5). 3. Fatty acids are converted to acetyl-CoA by a repeating 4-step pathway 1 B -oxidation2: oxidation by FAD, addition of water, oxidation by NAD +, and cleavage with CoASH (25.6). 4. Glucose is converted to pyruvate via a 10reaction pathway (glycolysis), including a reverse aldol addition that forms dihydroxyacetone phosphate and glyceraldehyde-3-phosphate (25.7). 5. Under aerobic conditions, oxygen oxidizes NADH to NAD +: under anaerobic conditions, pyruvate oxidizes NADH to NAD + and forms lactate. Pyruvate is converted to acetyl-CoAby the pyruvate dehydrogenase system. In yeast, pyruvate is converted to ethanol (25.8). 6. Amino acids, each following a different route, are converted to acetyl-CoA, pyruvate, and citric acid cycle intermediates, depending on the amino acid. For example, phenylalanine is converted to tyrosine, which is transaminated to p-hydroxyphenylpyruvate, which is converted to fumarate and acetyl-CoA(25.9).
7. The citric acid cycle is series of 8 reactions that convert acetyl-CoAto 2 CO2 and CoASH. Each round forms 3 NADH, 1 FADH2, and 1 ATP(25.10). 8. In the fourth stage of catabolism (oxidative phosphorylation), each NADH is oxidized to NAD + and 3 ATP; each FADH2 is oxidized to FAD and 2 ATP(25.11). 9. Anabolism is the reverse of catabolism: acetyl-CoA, pyruvate, and other intermediates are converted into fatty acids, monosaccharides, and amino acids (25.12).
Chapter 26 Lipids 1. Lipids, biological compounds soluble in nonpolar solvents, include fatty acids (saturated and unsaturated), waxes (long chain esters), and fats and oils (triacylglycerols) (26.1–26.3). 2. Membranes are composed of phosphoacylglycerols (phospholipids), which form lipid bilayers. Cholesterol decreases fluidity. Vitamin E is an antioxidant (Sec. 26.4). 3. Prostaglandins regulate physiological responses, such as inflammation and pain. They are synthesized from arachidonic acid and contain a cyclopentane ring with a 7-carbon carboxylic acid side chain and an adjacent (trans) 8-cabon hydrocarbon side chain (26.5). 4. Terpenes contain multiples of 5 carbons linked head-to-tail (isoprene rule). Monoterpenes have 10 carbons; sesquiterpenes have 15. Squalene is a triterpene (30 carbons) and is the precursor of cholesterol, which is the precursor of all steroids. The carotenoids (lycopene and carotene) are tetraterpenes. Vitamin A is a diterpene that plays an important role in vision (26.6, 26.7). head
tail
head
A -farnesene a sesquiterpene found in the waxy coating on apple skins
tail
5. Acetyl-CoAand malonyl-CoAare converted to isopentenyl pyrophosphate for the synthesis of terpenes. Isomerization forms dimethylallyl pyrophosphate, from which isopentenyl pyrophosphate displaces pyrophosphate to form a 10-carbon compound; additional reactions with isopentenyl pyrophosphate make larger terpenes (26.8). 6. Steroids are hormones with 4 fused rings and angular methyl groups. B -Substituents are on the same side as the angular methyl groups; a-substituents are on the opposite side (26.9).
11
Chapter 27 Nucleosides, Nucleotides, and Nucleic Acids 1. Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are nucleic acids—phosphodiesters with purine and pyrimidine bases. The bases in DNA are adenine, guanine, cytosine, and thymine; RNAhas uracil instead of thymine. Nucleosides = base + ribose; nucleotides = base + ribose + phosphate . The primary structure of a nucleic acid is the sequence of its bases. DNA is double str anded (the double helix) with major and minor grooves. Stacking interactions between the bases add stability. The 2 ¿ -OH group of RNAcauses it to be easily cleaved (27.1–27.4).
a.
c. b.
2. DNAis synthesized in the 5 ¿ 3¿ direction by complementary base pairing dictated by hydrogen bonds: A pairs with T; G pairs with C. One strand of DNAis made continuously and the other is made in pieces (semiconservative replication). The template strand of DNAi s read in the 3¿ 5 ¿ direction to make RNAin the 5¿ 3 ¿ direction (transcription); thus, RNA has the same base sequence as the sense strand of DNA, with Us in place of Ts. Messenger RNA is the template for protein synthesis (translation); a codon (a 3 base sequence of RNA) determines the amino acid brought in. Ribosomal RNA forms ribosomes, on which protein synthesis takes place. Each transfer RNA carries an amino acid (27.5–27.8). :
: :
H CH3
O N
H
N N
N N
N sugar
H N
H N
O
thymine
N
N
O
N
H N N
N
sugar sugar
adenine
H
O
cytosine
H
N H
sugar
guanine
3. Synthetic oligonucleotides can be made using phosphoramidite monomers or Hphosphonate monomers (27.13).
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Chapter 28 Synthetic Polymers 1. A polymer is made from monomers via polymerization. Chain-growth (addition) polymers are made by attaching monomers to a radical, cation, or anion propagating site (28.1). repeating unit
CH2
CH
CH2
CH
CH2
CH
CH2
C H C H2
C H C H2
CH
n
styrene
polystyrene a chain-growth polymer
2. Chain-growth polymerization includes initiation, propagation, and termination steps. Head-to-tail addition is favored due to steric and electronic factors. The mechanism of polymerization depends on the initiator and the stability of the propagating site: radical initiators have bonds that break homolytically; H + is the initiator in cationic polymerization; organolithium compounds initiate anionic polymerization. Hydrogen atom removal from the main chain causes branching. Living polymers contain reactive ends that can continue polymerization. Alkoxides or acids are used to initiate ring-opening polymerization with epoxides and oxacyclobutanes (28.2). 3. An isotactic polymer has groups on the same side; a syndiotactic polymer has alternating groups. The groups in an atactic polymer are random. Ziegler-Natta catalysts (aluminumtitantium complexes) control the structure of the polymer (28.3). 4. Butadienes polymerize to form rubber and neoprene. Heating with sulfur causes cross-linking. Two or more different monomers produce copolymers (alternating, block, graft, or random) (28.4, 28.5). 5. Step-growth (condensation) polymers, formed by condensation of bifunctional compounds, include polyamides and aramides, polyesters, and polyurethanes that form when a diisocyanate reacts with a diol. Epoxy resins involve a prepolymer and a hardener (28.6). O +
H3N(CH2)5CO− 6-aminohexanoic acid
∆ −H2O
O
O
NH(CH2)5C
NH(CH2)5C
O n
NH(CH2)5C
nylon 6 a polyamide
Chapter 29 Pericyclic Reactions 1. The three types of pericyclic reactions involve concerted cyclic reorganization of e -. Electrocyclic reactions are intramolecular with a s bond formed between the ends of a conjugated system. In cycloaddition reactions, two p bondcontaining compounds react to form a
cyclic compound. Sigmatropic rearrangements are intramolecular: a s bond breaks, a new s bond forms, and the p bonds rearrange. A thermal reaction occurs without the absorption of light; a photochemical reaction occurs with the absorption of light. The conservation of orbital theory (in-phase orbitals overlap) explains the relationship between the structure and configuration of the reactant, the conditions, and the configuration of the product (29.1-29-2). 2. Electrocyclic reactions: For a reactant with an even number of conjugated double bonds ring closure is conrotatory under thermal conditions and disrotatory under photochemical conditions (TE-AC). With an odd number of conjugated double bonds, ring closure is disrotatory under thermal conditions and conrotatory under photochemical conditions (29.3).
disrotatory ring closure
H3C
HH
CH3
H3C H
(2E ,4 Z ,6E )-octatriene
CH3 H
cis-5,6-dimethyl-1,3-cyclohexadiene
3. Cycloaddition reactions: If the sum of the reacting p bonds is even, bond formation is antarafacial under thermal conditions and suprafacial under photochemical conditions (TE-AC); if the sum is odd, bond formation is suprafacial under thermal conditions and antarafacial under photochemical conditions. Cycloaddition reactions that form 4-, 5-, or 6memberered rings must occur by suprafacial bond formation (29.4). 4. Sigmatropic rearrangements: If the sum of the pairs of electrons in the reacting system is even, rearrangement is antarafacial under thermal conditions and suprafacial under photochemical conditions ((TE-AC); if the sum is odd, rearrangement is suprafacial under thermal conditions and antarafacial under photochemical conditions. Migration on the same p-face is suprafacial and to the opposite face is antarafacial. Sigmatropic rearrangements that form 4-, 5-, or 6memberered transition states must be suprafacial. In suprafacial rearrangement, carbon migrates using one of its p lobes (retained configuration) if the HOMO is symmetric and both p lobes (inversion of configuration) if it is antisymmetric (29.5). 5. UV light promotes [2 + 2] cycloaddition of two adjacent thymine bases in DNA leading to mutations. Luminescence results from a retro [2+2] cycloaddition reaction. Vitamin D is produced from ergosterol, which undergoes a lightmediated electrocyclic reaction, followed by [1,7] sigmatropic rearrangement (29.6).
12
Chapter 30 The Organic Chemistry of Drugs 1. A brand name can be used only by the holder of the patent; a generic name can be used by anyone. Natural products are traditional sources for lead compounds (30.1, 30.2).
O
H3C
OCH3 H3C
N
N
O O cocaine lead compound
H3C
O O
improved lead compound
2. Related compounds with improved properties are formed by molecular modification (30.3). 3. A random screen is the search for a drug without structural information. Many drugs have been discovered accidentally (nitroglycerin, Librium, Viagra) (30.5). 4. Drugs bind to specific receptors by hydrogen bonding, electrostatic interactions, and hydrophobic interactions (30.6). 5. Drugs can inhibit enzymes through covalent modification (suicide inhibitor). Two drugs can have synergistic (additive) or antagonistic effects; two drugs can be used to overcome drug resistance. Therapeutic index, the ratio of toxic dose to therapeutic dose, is a measure of drug safety (30.7, 30.8). 6. In rational drug design, the chemical or physical property of a series of drugs is correlated with biological activity (QSAR). Molecular modeling allows for evaluation of the fit of a potential drug with its receptor (30.9, 30.10). 7. Combinatorial synthesis uses libraries of compounds for the synthesis of analogs (13.11). 8. Nucleoside analogs are important antiviral drugs (30.12).
© 2007 Pearson Education, Inc., Upper Saddle River, NJ. All rights reserved. This material is protected under all copyright laws as they currently exist. No portion of this material may be reproduced, in any form or by any means. without permission in writing from the publisher.
