Chapter 25:Chapter 25:
HeterocyclesHeterocycles
HeterocylesHeterocyles – Cyclic molecules that– Cyclic molecules that
contain at least 1 heteroatom (O, N, S)contain at le...
Aromatics:Aromatics:
1.1. Intramolecular SIntramolecular SNN2 reaction2 reaction
XX
::
CHCH22−− LL
(CH(CH22))nn
2.2. Special reaction for oxacy...
Three- and four-membered rings open:Three- and four-membered rings open:
ReactionsReactions
Usual conditionsUsual conditio...
For ringsFor rings larger than fourlarger than four, ring strain driving force is, ring strain driving force is absentabse...
For azaheterocycloalkanes: Acid just protonates theFor azaheterocycloalkanes: Acid just protonates the
nitrogen to ammoniu...
Heterocyclopentadienes:Heterocyclopentadienes:
Pyrrole, Furan, and ThiophenePyrrole, Furan, and Thiophene
The lone pairs p...
ResonanceResonance
OrbitalsOrbitals
Relative to benzene: Electron richRelative to benzene: Electron rich
N
H
:
N
H
:
δδ--
δδ--
mm//zz = 67 (= 67 (MM ++
))
N
H
:
MM ++
- CN/HCN/HCNH- CN/HCN/HCNH
ννN-HN-H
~~
Paal-Knorr synthesis of pyrroles andPaal-Knorr synthesis of pyrroles and
its variationsits variations
Synthesis of Heteroc...
O
O
:
H
: :H
O
O
:
H
: :
-H+ H+
O
O
:
H
:
H
:
O
H
:
OH
-H+ H+
O
:
OH2
:
:
-H2O
O
::
H
-H+
O
::
Mechanism:Mechanism:
Goes via thioketone and then enethiolGoes via thioketone and then enethiol
O
O
:
: :
P
S
S
P
S
S
S
:
::
S
O
:
: :H
S
O
:
H...
N
O
(H3C)2HC
: :
:
H
Mechanism:Mechanism:
Goes via enamineGoes via enamine
1.1. Electrophilic Aromatic Substitution:Electrophilic Aromatic Substitution: Activated!Activated!
Attack atAttack at C2C2...
Examples:Examples:
Relative reactivityRelative reactivity: B: Benzene << thiophene < furan < pyrrole
MixtureMixture
Recall:Recall:
2.2. BasicityBasicity of pyrrole (and otherof pyrrole (and other
heterocyclopentadienes)heterocyclopentadie...
3. Pyrrole is quite3. Pyrrole is quite acidicacidic
Reason isReason is spsp22
-hybridization of attached carbons-hybridiza...
4. Ring opening4. Ring opening
Mechanism is the reverse of synthesis:Mechanism is the reverse of synthesis:
General for al...
ReductiveReductive desulfurizationdesulfurization: Unique for: Unique for thiophenesthiophenes
O
O
:
::
O
O
:
H
::
-H+
O
O...
5. Diels-Alder5. Diels-Alder cycloadditionscycloadditions to furan:to furan: Not generalNot general
Needs a hot dienophile...
EAS at C3 allows for resonance forms which doEAS at C3 allows for resonance forms which do
not disrupt the benzene ring:no...
Pyridine: AzabenzenePyridine: Azabenzene
Can be viewed as aCan be viewed as a cyclic aromatic imine:cyclic aromatic imine:...
N
:
N
::
-
+
δδ++
δδ++
The inductive effect of nitrogen can be pictured byThe inductive effect of nitrogen can be pictured...
Pyridine Spectral DataPyridine Spectral Data
1313
C NMRC NMR
N
:
136.1
124.1
150.4
11
H NMRH NMR
N
:
7.46
7.06
8.50
N
:
N
...
-HCN-HCN
C=NC=N
wetwet
C-HC-H
MassMass
IRIR
mm//zz = 79 (= 79 (MM ++
))
N
:
Pyridine is a (weak)Pyridine is a (weak) basebase
PyridinePyridine Pyridinium ionPyridinium ion
ppKKaa = 5.29= 5.29
Compar...
Preparation ofPreparation of
PyridinesPyridines
(a condensation reaction) Arthur R. Hantzsch
(1857-1935)
Mechanism:Mechanism:
―― = e pair= e pair
Reactions of PyridineReactions of Pyridine
Pyridine is relatively (to benzene)Pyridine is relatively (to benzene) electron...
ActivatingActivating substituentssubstituents improveimprove yieldsyields
Pyridine undergoes relatively easyPyridine undergoes relatively easy
nucleophilicnucleophilic aromatic substitutionaromati...
Think of the C=N bond as imine-likeThink of the C=N bond as imine-like
Alexej J. ČičibabinAlexej J. Čičibabin
(1871-1945)(...
Quinoline andQuinoline and
Isoquinoline:Isoquinoline:
BenzopyridinesBenzopyridines
N
N
QuinolineQuinoline IsoquinolineIsoq...
CH
O
NH2
+
H
O
N
Preparation of Quinoline andPreparation of Quinoline and
IsoquinolineIsoquinoline
1.1. Friedländer Synthe...
2. Bischler-Napieralski Synthesis2. Bischler-Napieralski Synthesis
POClPOCl33, P, P22OO55,,
100 ºC100 ºC
Pd, 200 ºC,Pd, 20...
EAS away from heteroaromatic ring andEAS away from heteroaromatic ring and αα (for both quinoline(for both quinoline
and i...
Chichibabin Reaction of QuinolineChichibabin Reaction of Quinoline
and Isoquinolineand Isoquinoline
Alkaloids and DrugsAlkaloids and Drugs
LSD: Albert HofmannLSD: Albert Hofmann
100 years old!100 years old!
Allowable drug ...
Chapter25杂环化合物
Chapter25杂环化合物
Chapter25杂环化合物
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Chapter25杂环化合物

  1. 1. Chapter 25:Chapter 25: HeterocyclesHeterocycles
  2. 2. HeterocylesHeterocyles – Cyclic molecules that– Cyclic molecules that contain at least 1 heteroatom (O, N, S)contain at least 1 heteroatom (O, N, S) • OxacyloalkaneOxacyloalkane: Oxygen-containing heterocycle: Oxygen-containing heterocycle • AzacycloalkaneAzacycloalkane: Nitrogen-containing heterocycle: Nitrogen-containing heterocycle • ThiacyloalkaneThiacyloalkane: Sulfur-containing heterocycle: Sulfur-containing heterocycle Numbering starts at heteroatomNumbering starts at heteroatom
  3. 3. Aromatics:Aromatics:
  4. 4. 1.1. Intramolecular SIntramolecular SNN2 reaction2 reaction XX :: CHCH22−− LL (CH(CH22))nn 2.2. Special reaction for oxacyclopropanesSpecial reaction for oxacyclopropanes RCO3H+ O Preparation of HeterocloalkanesPreparation of Heterocloalkanes
  5. 5. Three- and four-membered rings open:Three- and four-membered rings open: ReactionsReactions Usual conditionsUsual conditions areare basicbasic..
  6. 6. For ringsFor rings larger than fourlarger than four, ring strain driving force is, ring strain driving force is absentabsent:: NeedNeed strongstrong acid:acid: But, recallBut, recall acidicacidic opening of oxacyclopropanes:opening of oxacyclopropanes: O + HBr Br OH Br BrHBr
  7. 7. For azaheterocycloalkanes: Acid just protonates theFor azaheterocycloalkanes: Acid just protonates the nitrogen to ammonium salt. Ring opening can be done bynitrogen to ammonium salt. Ring opening can be done by Hofmann degradation:Hofmann degradation: N H 1. CH3I excess 2. Ag2O N 1. CH3I excess 2. Ag2O Other chemistry is the same as for acyclic systems, e.g.:Other chemistry is the same as for acyclic systems, e.g.: N H HNO2 N NO S S O H2O2 S OO CH3I S CH3 I - + H2O2
  8. 8. Heterocyclopentadienes:Heterocyclopentadienes: Pyrrole, Furan, and ThiophenePyrrole, Furan, and Thiophene The lone pairs participate in theThe lone pairs participate in the aromaticaromatic cycliccyclic six e system: Like the cyclopentadienyl anionsix e system: Like the cyclopentadienyl anion PyrrolePyrrole FuranFuran ThiopheneThiophene N H O S : : :: : - The distribution of 6The distribution of 6 ππ electronselectrons overover five atomsfive atoms makes thesemakes these systems relatively e-rich,systems relatively e-rich, compared to benzene.compared to benzene. CyclopentadienylCyclopentadienyl anionanion
  9. 9. ResonanceResonance OrbitalsOrbitals Relative to benzene: Electron richRelative to benzene: Electron rich
  10. 10. N H : N H : δδ-- δδ--
  11. 11. mm//zz = 67 (= 67 (MM ++ )) N H : MM ++ - CN/HCN/HCNH- CN/HCN/HCNH
  12. 12. ννN-HN-H ~~
  13. 13. Paal-Knorr synthesis of pyrroles andPaal-Knorr synthesis of pyrroles and its variationsits variations Synthesis of HeterocyclopentadienesSynthesis of Heterocyclopentadienes O O : : : O :: : P2O5
  14. 14. O O : H : :H O O : H : : -H+ H+ O O : H : H : O H : OH -H+ H+ O : OH2 : : -H2O O :: H -H+ O :: Mechanism:Mechanism:
  15. 15. Goes via thioketone and then enethiolGoes via thioketone and then enethiol O O : : : P S S P S S S : :: S O : : :H S O : H : : : : Mechanism:Mechanism:
  16. 16. N O (H3C)2HC : : : H Mechanism:Mechanism: Goes via enamineGoes via enamine
  17. 17. 1.1. Electrophilic Aromatic Substitution:Electrophilic Aromatic Substitution: Activated!Activated! Attack atAttack at C2C2 is preferred generallyis preferred generally But often also attack atBut often also attack at C3C3 ReactionsReactions GoodGood GoodGood
  18. 18. Examples:Examples: Relative reactivityRelative reactivity: B: Benzene << thiophene < furan < pyrrole MixtureMixture
  19. 19. Recall:Recall: 2.2. BasicityBasicity of pyrrole (and otherof pyrrole (and other heterocyclopentadienes)heterocyclopentadienes) Relatively (cf. normal amines)Relatively (cf. normal amines) nonbasicnonbasic: Lone pair is: Lone pair is tied uptied up byby resonanceresonance.. Protonation occurs on carbon!Protonation occurs on carbon! NH2 O + H + NH2 OH + : : : : : NH2 + H + NH2 CH3 + : Or:Or: ppKKaa of normalof normal alkane-alkane- ammoniumammonium ~ 10~ 10
  20. 20. 3. Pyrrole is quite3. Pyrrole is quite acidicacidic Reason isReason is spsp22 -hybridization of attached carbons-hybridization of attached carbons and cyclic delocalization of charge.and cyclic delocalization of charge. Like cyclopentadienyl anionLike cyclopentadienyl anion Compare:Compare:
  21. 21. 4. Ring opening4. Ring opening Mechanism is the reverse of synthesis:Mechanism is the reverse of synthesis: General for all heterocyclopentadienesGeneral for all heterocyclopentadienes H2O: O :: H H+ O :: :
  22. 22. ReductiveReductive desulfurizationdesulfurization: Unique for: Unique for thiophenesthiophenes O O : :: O O : H :: -H+ O O : H : H : O H : HO H+ -H+ O : H2O : : : :
  23. 23. 5. Diels-Alder5. Diels-Alder cycloadditionscycloadditions to furan:to furan: Not generalNot general Needs a hot dienophileNeeds a hot dienophile 6.6. BenzofusionBenzofusion: Indole: Indole N H : Cf. naphthaleneCf. naphthalene
  24. 24. EAS at C3 allows for resonance forms which doEAS at C3 allows for resonance forms which do not disrupt the benzene ring:not disrupt the benzene ring: LeavesLeaves aromaticityaromaticity DisruptsDisrupts aromaticityaromaticity N H : E H + N H + H E H Etc. Etc. Attack at C3:Attack at C3: Attack at C2:Attack at C2:
  25. 25. Pyridine: AzabenzenePyridine: Azabenzene Can be viewed as aCan be viewed as a cyclic aromatic imine:cyclic aromatic imine: The nitrogen isThe nitrogen is spsp22 -hybridized, the lone-hybridized, the lone pair is perpendicular to the aromaticpair is perpendicular to the aromatic ππ system.system. ImineImine The N does not donateThe N does not donate e-density; rather, ite-density; rather, it withdraws by inductionwithdraws by induction Cf. benzeneCf. benzene
  26. 26. N : N :: - + δδ++ δδ++ The inductive effect of nitrogen can be pictured byThe inductive effect of nitrogen can be pictured by dipolar resonance forms:dipolar resonance forms:
  27. 27. Pyridine Spectral DataPyridine Spectral Data 1313 C NMRC NMR N : 136.1 124.1 150.4 11 H NMRH NMR N : 7.46 7.06 8.50 N : N :: - + δδ++ δδ++
  28. 28. -HCN-HCN C=NC=N wetwet C-HC-H MassMass IRIR mm//zz = 79 (= 79 (MM ++ )) N :
  29. 29. Pyridine is a (weak)Pyridine is a (weak) basebase PyridinePyridine Pyridinium ionPyridinium ion ppKKaa = 5.29= 5.29 Compare pCompare pKKaa of Rof R33NH ~ 9-10NH ~ 9-10 ++ N : + H + N H +
  30. 30. Preparation ofPreparation of PyridinesPyridines (a condensation reaction) Arthur R. Hantzsch (1857-1935)
  31. 31. Mechanism:Mechanism: ―― = e pair= e pair
  32. 32. Reactions of PyridineReactions of Pyridine Pyridine is relatively (to benzene)Pyridine is relatively (to benzene) electron poorelectron poor, therefore, therefore EASEAS only underonly under extremeextreme conditions and only at C3conditions and only at C3
  33. 33. ActivatingActivating substituentssubstituents improveimprove yieldsyields
  34. 34. Pyridine undergoes relatively easyPyridine undergoes relatively easy nucleophilicnucleophilic aromatic substitutionaromatic substitution Leaving groups are typicallyLeaving groups are typically halideshalides;; 2- and2- and 4-4-halopyridines are particularlyhalopyridines are particularly reactivereactive
  35. 35. Think of the C=N bond as imine-likeThink of the C=N bond as imine-like Alexej J. ČičibabinAlexej J. Čičibabin (1871-1945)(1871-1945)
  36. 36. Quinoline andQuinoline and Isoquinoline:Isoquinoline: BenzopyridinesBenzopyridines N N QuinolineQuinoline IsoquinolineIsoquinoline
  37. 37. CH O NH2 + H O N Preparation of Quinoline andPreparation of Quinoline and IsoquinolineIsoquinoline 1.1. Friedländer SynthesisFriedländer Synthesis 2-Aminobenzene-2-Aminobenzene- carboxaldehydecarboxaldehyde EnolizableEnolizable carbonylcarbonyl compoundcompound 85%85% AldolAldol ImineImine HH22O, NaOH,O, NaOH, 5050 ºCºC Paul Friedländer (1857 - 1923)
  38. 38. 2. Bischler-Napieralski Synthesis2. Bischler-Napieralski Synthesis POClPOCl33, P, P22OO55,, 100 ºC100 ºC Pd, 200 ºC,Pd, 200 ºC, - H- H22 NH O R H + N R N R -H-H22OO
  39. 39. EAS away from heteroaromatic ring andEAS away from heteroaromatic ring and αα (for both quinoline(for both quinoline and isoquinoline); like naphthalene.and isoquinoline); like naphthalene. ReactionsReactions
  40. 40. Chichibabin Reaction of QuinolineChichibabin Reaction of Quinoline and Isoquinolineand Isoquinoline
  41. 41. Alkaloids and DrugsAlkaloids and Drugs LSD: Albert HofmannLSD: Albert Hofmann 100 years old!100 years old! Allowable drug quantities approved by Mexico, April 28, 2006: Opium: 5 g Heroin: 25 mg Marijuana: 5 g Cocaine: 500 mg LSD: 0.015 mg MDA: 200 mg Ecstasy: 200 mg Mescaline: 1 g Peyote: 1 kg Psilocybin (pure): 100 mg Mushrooms: 250 mg Amphetamines: 100 mg Dexamphetamines: 40 mg Phencyclidine (PCP, or Angel Dust): 7 mg Methamphetamines: 200 mg Nalbuphine (synthetic opiate): 10 mg (Since the beginning of mankind.......)(Since the beginning of mankind.......)
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