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234 Cards in this Set
- Front
- Back
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heterocyclic cmpds
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cmpds w rings that contain >1 element
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heteroatoms
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atoms other than C
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altho chem of many sat heterocyclic cmpds is analogous to that of noncyclic counterparts
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significant number unsat heterocyclic cmpds exhibit aromatic behavior
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nomenclature of aromatic heterocycles
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heteroatom given number 1 unless isoquinoline, O & S given lower # than N
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substituent groups are given
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the lowest # consistent w the ring numbering
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resonance hybrids of furan
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bc separation of charge is present in all but the first structure, the first is more important, but others evident in comparison of dipole moments of furan & tetrahydrofuran a sat heterocyclic ether
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dipole moment of tetrahydrofuran attributable mostly to
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bond dipoles of its polar C-O sb (e in the sigma bonds are pulled toward the O bc of its electroneg)
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Same effect present in furan plus
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resonance delocalization of O unshared e into ring tends to push e away from the O into the pi-e system of the ring - two effects cancel & furan has small dipole moment
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pyridine structures of less importance reflect relative electroneg of N & C
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vinylic heteroatoms such as N of pyridine contribute
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1 pi e to the 6 pi e aromatic system just like each of C atoms in pi system
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orbital containing unshared e pair of the pyridine N
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perpendicular to the 2p orbitals of the ring and is not involved in pi bonding
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allylic heteroatoms such as N of pyrrole contribute
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2 e unshared pair to aromatic pi e system
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N adopts sp2 hybridization & trigonal planar geometry
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its unshared e pair can occupy a 2p orbital which has optimum shape & orientation to overlap w the C 2p orbitals & thus to be part of the aormatic pi-e system so H of pyrrole lies in the plane of the ring
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O of furan contributes
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1 unshared e pair to the aromatic pi e system, & other unshared e pair occupies position analogous to C-H bond of pyrrole in the ring plane perpendicular to the 2p orbitals of the ring
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empirical resonance E can be used to
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estimate the additional stability of a heterocyclic cmpd due to its aromaticity
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to the extent that resonance E is a measure of aromatic character
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furan has the least aromatic character of the heterocyclic cmpds
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pyridine & quinoline act as
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ordinary amine bases
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pyridine & quinoline are much ___ basic than aliphatic tertiary amines bc
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less, bc of sp2 hybridization of the N unshared e pairs
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pyrrole and indole are protonated
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only in strong acid & protonation occurs on C, not N
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marked contrast btwn basicities of pyridine & pyrrole can be understood by
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considering role of N unshared e pair in the aromaticity of each cmpd
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protonation of the pyrrole N would disrupt the aromatic system of 6 pi e
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by taking the N unshared pair out of circulation
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altho protonation of the C of pyrrole also disrupts the aromatic pi-e system
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the resulting cation is resonance stabilized
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protonation of the pyridine unshared e pair occurs easily bc
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this e pair is not part of the pi e system, so protonation does not disrupt pyridine's aromaticity
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how acidic are pyrrole & indol?
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weakly
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greater acidity of pyrroles and indoles over primary, secondary amines is a consequence of
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resonance stabilization of their conj base anions
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do furan, thiophene & pyrrole undergo EAS?
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Yes
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pyrrole, furan & thiophene are all much
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more reactive than benzene in EAS
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relative rates of bromination
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pyrrole > furan > thiophene > benzene
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milder rxn conditions must be used w
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more reactive cmpds - too vigorous bring about side rxns so polymerization & tar formation occur
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Less reactive acylating reagent
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used in acylation of furan than in acylation of benzene
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reactivity order of heterocycles
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is a consequence of the relative abilities of heteroatoms to stabilize pos charge in intermediate carbocations
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pyrrole & furan have heteroatoms
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from the 2nd period of the periodic table
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Bc N is better than O @ delocalizing pos charge (N is less electroneg)
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pyrrole is more reactive than furan
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S of thiphene is 3rd period element, and tho less electroneg than O
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3p orbitals overlap less efficiently w 2p orbitals of aromatic pi e system
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Reactivity order of heterocycles in aromatic sub
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parallels reactivity order of correspondingly sub benzene derivatives
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superimposed on normal activating & directing effects of substituents in aromatic sub
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is normal effect of heterocyclic atom in directing substitution to the 2-position
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-CO2H group directs the 2nd substituent into a
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meta relationship, thiophene ring tends to sub @ 2-position
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..
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count around the C framework of the heterocyclic cmpd, not thru the heteroatom
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when directing effects of substituents & ring compete
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not unusual to observe mixtures of prod
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if both 2-positions are occupied
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3-substitution takes place
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implication of furan's small resonance E
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least aromatic character - greatest tendency to behave like a conj diene
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diff to prep monosub pyridines by EAS bc
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pyridine has low reactivity (less reactive than benzene)
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reason for pyridine low reactivity
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protonated under very acidic conditions of most EAS rxns - resulting pos charge on N makes it diff to form carbocation intermediate, which would place 2nd pos charge within same ring
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number of monosub pyridines are available from
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natural sources
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methylpyridines or picolines
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picoles & other methylated pyridines are obtained from
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coal tar
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useful monosub derivative of pyridine
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nicotinic acid (pyridine-3-CA)
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how is nicotinic acid prep
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side-chain oxidation of nicotine, an alkaloid present in tobacco
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altho EAS not very useful for intro sub into pyridine itself
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pyridine rings sub w activating groups such as methyl groups do undergo such rxns
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rxns which occur in acidic soln
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take place on very small amt of unprotonated pyridine that is in rapid equil w larger amt of conj acid
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bc reactive unprotonated heterocycle is present in very small conc
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methyl-sub pyridines are not very reactive, despite presence of activating methyl sub
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sub in pyridine generally takes place in the
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3-position
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3-sub reason
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carbocation intermed formed in sub has 3 diff resonance structures
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sub at 4-position also involves carbocation intermed w 3 resonance structures
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but one shown in red is particularly unstable & unimportant bc the N, an electroneg atom, is e-deficient
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pyrolle N is pos charged but not e-deficient bc
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it has a complete octet
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e-deficient electroneg atom is very
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unfavorable energetically
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how to obtain pyridine derivatives sub @ other positions
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for 4-sub, use pyridine-N-oxide, formed by oxidation of pyridine w 30% hydrogen peroxide
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bc N of pyridine-N-oxide has a pos charge
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cmpd is much less reactive than phenol or phenoxide but pyridine-N-oxide undergoes useful aromatic sub @ 4
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once N-oxide func no longer needed
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can be removed by cat hydrogenation (reduces nitro group)
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rxn w trivalent phosphorus cmpds such as PCl3
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removes N-oxide func w/o reducing nitro group
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pyridine ring readily undergoes
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NAS
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Chichibabin rxn
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treatment of pyridine derivative w strong base sodium amide brings about direct sub of amino group for ring hydrogen
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first step of mech
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amide ion reacts as nuc @ 2-position of ring to form tetrahedral addition intermed
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C=N linkage of the pyridine ring
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somewhat analogous to a carbonyl group (C @ 2 has some character of a carbonyl C, can react w nuc)
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C=N of pyridine is much ___ reactive than a carbonyl group
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less, bc part of aromatic system, N anion more basic than an O anion
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2nd step of mech
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LG, hydride ion, lost
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Hydride ion
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poor so unusual LG, very basic
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Rxn occurs bc
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aromatic pyridine ring reformed, aromaticity lost in formation of tetrahedral addition intermediate regained when LG departs + basic hydride prod in rxn reacts w NH2 group irreversibly to form dihydrogen & resonance stabilized conj base anion of 2-aminopyridine
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when pyridine is sub w better LG than hydride @ 2
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reacts more rapidly w nuc
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nuc sub can be related to analogous rxn of carbonyl cmpd
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acid chlorides much more reactive than 2-halopyridines
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EWG in rxns of pyridines
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pyridine N itself
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tetrahedral addition intermed
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analogous to Meisenheimer complex of NAS
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equil btwn 2-hydroxypyridine & 2-pyridone
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analogous to keto-enol equil bt keto form is amide
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ratio of hydroxy form to carbonyl
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1:910 in water, but varies w conc & solvent
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enough of each form present so that either can be involved in chem rxns, much more
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carbonyl isomer is present than in phenol
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what determines if aromatic hydroxy cmpd exists as carbonyl or hydroxy form
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whether E advantage of aromaticity (resonance stabilization of aromatic hydroxy isomer) outweights large carbonyl C=O bond E
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phenol
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resonance stabilization of benzene ring large enough that phenol isomer strongly preferred
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resonance E thus stabilization of pyridine
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considerably smaller than benzene
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resonance interaction of amide N w carbonyl group
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further stabilizes 2-pyridone
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resulting resonance structure
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aromatic
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nuc sub rxns @ 2/4 positions of pyridine ring
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particularly common - neg charge in addition intermediate delocalized onto electroneg pyridine N
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sub at C 2
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sub at C 4
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3 sub pyridines not reactive in nuc sub bc
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neg charge in addition intermed cannot be delocalized onto electroneg N
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N-alkylpyridinium salts are activated toward nuc rxns @ 2, 4 positions of the ring more than pyridines bc
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pos charged N is more electroneg, so better e acceptor, than neutral N of a pyridine
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When nuc in displacement rxns are anions
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charge is neutralized
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benzylic H of 2 / 4 alkylpyridinium salts are much more acidic than those of analogous pyridines
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bc conj base anion is actually a neutral cmpd
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conj base of a pyridinium salt is used as the enolate component in a variation of the Claisen-Schmidt condensation
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benzylic H of 2/4 alkylpyridinium salts acidic enough that conj base anions
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can be formed in useful conc by aq. NaOH or amines
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many side-chain rxns of pyridines
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analogous to those of corresponding benzene derivatives
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N of pyridine ring can serve as
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acceptor of e, particularly enhanced in pyridinium ions
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pyridinium ion strongly activated toward
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rxns w nuc (e flow onto pos charged N)
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pos charged N of the pyridinium ion serves to
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stabilize the attached carbanion by resonance
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Pyridinium ion of NAD+ serves as
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an e acceptor in biochem rxns
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important pyridine derivative
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pyridoxal phosphate - one of several forms of vitamin B6
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pyridoxal phosphate
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essential coenzyme in several important biochem transformations
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utilized for prod of bio important amines i.e. neurotransmitters serotonin & dopamine in human brain & vasoconstrictor histamine
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important source of single C units for bio processes that involve single C transfer
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In bio systems
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each rxn catalyzed by pyridoxal phosphate & appropriate enzyme
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pyridoxal phosphate exists in the bio world as
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imine derivatives in which it is covalently attached to various enzymes
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in the first step of all pyridoxal-cat rxns of a-amino acids
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amino group acting as nuc in its unprotonated form, forms an imine w pyridoxal phosphate (exactly like imine formation from an amine & aldehyde except rxn of the amino group is w C=N bond of imine rather than w C=O bond of an aldehyde
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decarboxylation yields
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carbanion intermediate
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most carbanions- such strong bases that they cannot exist under phys conditions but this carbanion much weaker B bc
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stabilized by resonance
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pyridinium ion stabilizes negative charge by
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accepting e
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carbanion not really carbanion at all
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neutral mlc
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same type of carbanion involved in
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all pyridoxal-cat transformations
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protonation of anion & hydrolysis of resulting imine gives
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pyridoxal phosphate
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typical pKa of pyridinium ions
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5 yet rxns promoted by pyridoxal phosphate take place at phys pH values ~ 7.4
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If pyridinium ion in pyridoxal phosphate had pKa near 5
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most would exist in conj B pyridine form at pH 7.4 - less than 1% would exist in conj A pyridinium ion form
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mlclr architecture of pyridoxal phosphate
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ensures much higher conc of crucial pyridinium ion form
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key element in structure
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OH group in the 3 position & ortho relationship to aldehyde
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Ortho relationship makes
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phenolic OH group of pyridoxal phosphate unusually acidic
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Ionization of the phenolic OH group
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raises the pKa of the pyridinium ion bc neg charge of the phenolate stabilizes the pos charge of the pyridinium ion & vice versa => predominant form of pyridoxal phosphate at phs pH is form in which phneol is ionized & pyridine is protonated
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when pyridoxal phosphate is bound to the enzymes that cat its rxns
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the pyridinium form is further stabilized
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this stabilization is the result of
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an ionized carboxylate group that interacts directly w pos charged N
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ribonucleoside
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cmpd formed btwn furanose form of D-ribose & heterocyclic cmpd
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heterocyclic group
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base
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ribose
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sugar
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stereochem of bond btwn base & ribose most commonly
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B
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deoxyribonucleoside
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similar derivative of D-2-deoxyribose & a heterocyclic base
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prefix deoxy
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w/o oxygen
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sugar ring & heterocyclic ring
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numbered separately
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how to differentiate the 2 sets of #s
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primes used in referring to atoms of the sugar
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2' C of adenosine
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C-2 of the sugar ring
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bases that occur most frequently in nucleosides
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derived from 2 heterocyclic ring systems: pyrimidine & purine
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base attached to the sugar @
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N-9 of purines & N-1 of pyrimidines
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in living systems, 5' OH group of ribose in a nucleoside
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usually found esterified to a phosphate group
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nucleotide
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5' phosphorylated nucleoside
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ribonucleotide
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derived from the monosaccharide ribose
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deoxyribonucleotide
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derived from 2-deoxyribose
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nucleotides either contain
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single phosphate group or 2/3 phosphate groups condensed in phosphoric anhydride linkages
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altho ionization state of phosphate groups depends on pH
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groups written conventionally in ionized form
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to name corresponding 2' deoxy derivatives from ribonucleosides & ribonucleotides
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prefix 2'-deoxy appended to names of corresponding ribose derivatives
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AMP
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adenosine monophosphate
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dTMP
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2'-deoxythymidylic acid
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NAD+ & coenzyme A
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ribonucleotides
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ATP
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anhydride of phosphoric acid
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hydrolysis of anhydrides
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very favorable rxn
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overall process for muscle contraction
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nucleic acids
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polymers of nucleotides
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deoxyribonucleic acid
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polymer of deoxyribonucleotides - storehouse of genetic info thu all nature
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residues
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monomeric units of DNA polymer
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nucleotide residues in DNA
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interconnected by phosphate groups that are esterified both to the 3' OH group of one ribose & 5' OH of another
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DNA polymer incorporates
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adenine, thymine, guanine, cytoside as nucleotide bases
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typical strand of DNA
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thousands of mill nucleotides long
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Each residue in a polynucleotide differentiated by
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identity of its base & sequence of bases encodes genetic info in DNA
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DNA polymer
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backbone of alternating phosphates & 2'-deoxyribose groups to which are connected bases that differ from residue to residue
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Ends of DNA polymer
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labeled 3' or 5' corresponding to deoxyribose C to which terminal hydroxy group attached
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ribonucleic acid
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polymers conceptually much like DNA polymers except ribose rather than 2'-deoxyribose is sugar
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fourth base in RNA
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uracil instead of thymine - some rare bases found in certain types of RNA
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Chargaff's first parity rule
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ratios of adenine to thymine & guanosine to cytosine are 1.0
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Watson & Crick
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proposed DNA structure based on x-ray diffraction patterns of DNA fibers
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structure of DNA
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2 right handed helical polynuc chains run opp directions coiled around common axis - double helix
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the helix makes a complete turn every
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10 nucleotide residues
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sugars & phosphates (rich in OH groups & charges)
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outside of helix, interact w solvent water or other hydrophilic cmpds
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Bases
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hydrophobic, buried in interior of the double helix away from h2o
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Chains held together by
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H bonds btwn bases
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Each A bonds to
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T
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Each G bonds to
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C
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Every purine in one chain H bonded to
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a pyrimidine in the other
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A is
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complementary to T
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Watson-Crick base pairs
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H bonded AT & GC pairs
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Planes of successive complementary base pairs
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stacked one on top of the other & perpendicular to axis of helix
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Distance btwn each successive base pair plane
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3.4 A
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Distance along helix per complete turn
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10 x 3.4 = 34 A
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Double helical structure of DNA results in
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two grooves, wrap around double helix along periphery
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Larger groove
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Major groove
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Smaller groove
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Minor groove
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Grooves, particularly major
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Sites at which other macromlcs such as proteins are found to interact w DNA
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Is there an intrinsic restriction on the sequence of bases in a polynucleotide?
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No, but bc of base pairing, sequence of one polynucleotide strand (Watson) in double helix complementary to that in the other (Crick) so everywhere there is A, T in other, where G, C in other
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Chargaff parity rule accounted for by
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H bonding complementarity in DNA
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How does structure suggest a reasonable mech for the duplication of DNA during cell division
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two strands come apart & new strand grown as a complement of each original strand
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Proper sequence of each new DNA strand during cell reprod ensured by
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H bonding complementarity
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DNA sequencing
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development of methods for rapidly determining the sequential arrangement of individual bases in DNA
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DNA sequences of human genes provide
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codes that living orgs use for biosynth of messenger RNAs whose sequences serve as codes for biosynth of proteins
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Sequence data beginning to
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unlock genetic bases of diseases & genetic variations that occur among individuals
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If H bonding btwn pyrimidine & purine base disrupted
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Watson-Crick base pairing complementarity can also be disrupted & bio processes that rely on it
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Alkylating agents
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type of chem damage to DNA - react w DNA by alkylating 1+ nucleotide bases
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Carcinogens
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cancer causing cmpds (include alkylating agents: methyl methanesulfonate, dimethyl sulfate)
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When alkylating agents react w DNA
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alkylated guanosines are among products
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Major product
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alkylated on N-7 of guanine base, but important minor prod: alkylated on oxygen @ C-6 (O-6 position)
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alkylation @ O-6 prevents
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N-1 nitrogen from acting as a H-bond donor in Watson-Crick base pair bc H lost from N as a result of alkylation
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N-7 alkylation
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does not affect any atoms involved in H-bonding complementarity
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Alkylating agents that are most potent carcinogens also yield
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greatest amt guanines alkylated @ O-6 & thymes alkylated @ O-4
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Epoxides have been shown to react w
|
DNA, prod include guanosine residue alkylated on N @ C-2 of the guanine base
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N also involved in
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H-bonding interaction of G w C
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May be that alkylation by aromatic hydrocarbon epoxides
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triggers onset of cancer by interfering w base-pairing complementarity
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Ultraviolet light promotes
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cycloaddition of 2 pyrimidines when occur in adjacent positions on a strand of DNA
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Most ppl have bio repair system that
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effects removal of modified pyrimidines & repairs DNA
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Xeroderma pigmentosum
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genetic deficiency in enzyme that initiates repair - most contract skin cancer, die @ early age
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Do N heterocycles occur widely in nature?
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Yes - alkaloids, many contain heterocyclic ring systems
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Naturally occurring amino acids proline, histidine, tryptophan contain
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pyrrolidine, imidazole & indole ring
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Number of vitamins are
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heterocyclic cmpds w/o with many important metabolic processes could not take place
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Porphyrin
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Iron complex of heme, a heterocycle composed of pyrrole units
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Heme
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Fe(II) complex of an aromatic heterocycle found in red blood cells tightly bound to a protein called globin
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Iron, held in position by coordination w N of heme & imidazole of globin
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complexes reversibly w O
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Hemoglobin
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O carrier of blood - oxygenated hemoglobin responsible for red color of blood
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Carbon monoxide & cyanide
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well-known respiratory poisons complex w iron in hemoglobin & w iron in heme groups of other respiratory proteins
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chlorophyll
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class of cmpds closely related to porphyrins, causes green color of plants
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Absorption of sunlight by chlorophylls
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first step in conversion of sunlight into usable energy by plants
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