Eterocicli-Eteroaromatici Aromaticità: molecola ciclica ... · quinoline isoquinoline cinnol ine...

Eterocicli - Eteroaromatici

Aromaticita:molecolaciclica,planarechecontiene4n+2π(Huckel-VonDering)Applicabilefinoa3ciclicondensatiefinoan=6

Aromatico:6elettroni πdelocalizzati nel cicloElettronricchi:6elettroni su 5atomiFurano etiofene:undoppietto interno impegnato ed uno esterno libero- sono basi diLewis(leganti)eHacceptorPirrolo:unsolodoppietto interno – nobasico –noHacceptor,si Hdonor(acido)

Aromatico:6elettroniπdelocalizzatinelcicloElettronpovero:AzotopiuelettronegativodelC,localizzasudiselanuvolaelettronicaPiridina:doppiettoesterno–basico–HacceptornoHdonor


NH

N

NH

N

imidazolo pirazolo

NH

N

N

1,2,3-triazolo

N

NH

N

1,2,4-triazolo

NNH

N

1,2,5-triazolo

N

NH

N

1,3,4-triazolo

N

NH

N

N

1,2,3,4-tetrazolo

O

N

ossazolo

S

N

tiazolo

ON

N

1,2,3 oxadiazolo

N

ON

ON

isossazolo

SN

isotiazolo 1,2,4-oxadiazolo

NO

N

furazolo

Azoli

Elettronricchi.PresentanosempreunO,SoNHchecontribuisceconildoppiettointernoall’aromaticita.Hannopoiuno(opiù)azotiditipo“piridinico”conundoppiettodoppiettoesternobasico:possonoessereHacceptoreHdonor(sefornitidiNH).L'introduzionedieteroatomidiminuiscel'aromaticitaglobaleinquanto"localizza"glielettronipepolarizzailegami.PertantoinucleiazolicipossonoancheessereapertiperattacconucleofiloalC


O

dibenzofuran

NH

9H-carbazole

N8aH-carbazole

ONH

7H-furo[3,2-f]indole

NH

NH

1,7-dihydropyrrolo[3,2-f]indole

Azoli benzocondensati

NN

N

N

N

N

NN

N

NN

NN

N

N

1,3,5-triazine1,2,4-triazine1,2,3-triazinepyrazinepyrimidinepyridazine

N

NN

N

1,2,4,5-tetrazine


Azine

L’introduzionediNaggiuntividiminuiscelabasicitadegliNpiridiniciel’aromaticitàdelsistema,ancheseingeneraleisistemiaseiterminisonopiùresistentiall’aperturadiquellia5


Azine condensate

NN N

NN

N

N

N

quinoxalinequinazolinecinnolineisoquinolinequinoline

NN

phthalazine

N

4H-quinolizine

NN NN

N N

NNN

N

N N

N

N N

NN

N

1,8-naphthyridine pyrido[2,3-c]pyridazine pyrido[2,3-d]pyrimidine pyrido[3,4-d]pyrimidine pyrido[2,3-b]pyrazine pteridine

45

Furano,tiofene epirrolo,rettività.

Comportamento acido-basedelpirrolo.


NH

O

X X

HEl

X

HEl

X

El

X XEl

H

El

H

Calculated π-electron densities:

1.2

X

1.067

H

El

1.078

1.710

X

1.090

1.647

El

1.087

X

1.000

Regioselectivity

X

El

ElH

C-3-H+

minor

major

X

Preferred for X=NH, NR, S

Preferred for X=O

H

El

Still aromatic

vs.

Aromaticity disrupted

-

ElC-2

Section one - Chemistry of Heteroaromatics

14

Densità elettroniche calcolate

Reattività rispetto alle SEAr pirrolo >furano >tiofene >>benzene

Polipirrolo oneri dipirrolo (pyrroleblack)


Furano,tiofene epirrolo,sintesi delnucleo

LudwigKnorr1859-1921

CarlPaal1860-1935

Azoli:reattività

Imidazole and pyrazole – Structure and Properties

� Imidazole: colourless prisms, mp 88 °C; pyrazole: colourless needles, mp 70 °C � Bond lengths and 1H NMR chemical shifts as expected for aromatic systems:

� Resonance energies: both systems have lower resonance energies than pyrrole (i.e. <90 kJmol-1)

� Electron density: relative to pyrrole, the additional (electronegative) N atom decreases the overall electron density

on the remaining carbons. The precise distribution is rather uneven: � for imidazole: C4 & C5 are electron rich, C2 is electron deficient � for pyrazole: C4 is electron rich, C3 & C5 are electron deficient

� → both pyrazole and imidazole are: � significantly less reactive towards electrophilic aromatic substitution (SEAr) than pyrrole (but >benzene) � reactive towards nucleophilic aromatic substitution (SNAr) at certain Cs (cf. pyrrole which does not react

with nucleophilies)

1H NMR:

1.33 Å1.36 Å

1.35 Å

cf. ave C-C 1.48 Å ave C=C 1.34 Å ave C-N 1.45 Å

bond lengths:

7.1 ppm1.38 Å

7.7 ppmNN

H

N

NH1.37 Å

N

NH

7.1 ppm1.35 Å1.36 Å

1.37 Å1.42 Å

1.31 Å

NN

H

7.6 ppm6.3 ppm 7.6 ppm

imidazole pyrazole imidazole pyrazole

NN

H

N

NH

NH

p-electron densities:1.087

1.647

1.0900.957

1.649

0.972

1.5020.884

1.5021.0561.056 1.278

1.105

imidazole pyrazole pyrrole

2

4

5

34

5

Imidazole and pyrazole – Structure and Properties

� Imidazole: colourless prisms, mp 88 °C; pyrazole: colourless needles, mp 70 °C � Bond lengths and 1H NMR chemical shifts as expected for aromatic systems:

� Resonance energies: both systems have lower resonance energies than pyrrole (i.e. <90 kJmol-1)

� Electron density: relative to pyrrole, the additional (electronegative) N atom decreases the overall electron density

on the remaining carbons. The precise distribution is rather uneven: � for imidazole: C4 & C5 are electron rich, C2 is electron deficient � for pyrazole: C4 is electron rich, C3 & C5 are electron deficient

� → both pyrazole and imidazole are: � significantly less reactive towards electrophilic aromatic substitution (SEAr) than pyrrole (but >benzene) � reactive towards nucleophilic aromatic substitution (SNAr) at certain Cs (cf. pyrrole which does not react

with nucleophilies)

1H NMR:

1.33 Å1.36 Å

1.35 Å

cf. ave C-C 1.48 Å ave C=C 1.34 Å ave C-N 1.45 Å

bond lengths:

7.1 ppm1.38 Å

7.7 ppmNN

H

N

NH1.37 Å

N

NH

7.1 ppm1.35 Å1.36 Å

1.37 Å1.42 Å

1.31 Å

NN

H

7.6 ppm6.3 ppm 7.6 ppm

imidazole pyrazole imidazole pyrazole

NN

H

N

NH

NH

p-electron densities:1.087

1.647

1.0900.957

1.649

0.972

1.5020.884

1.5021.0561.056 1.278

1.105

imidazole pyrazole pyrrole

2

4

5

34

5

Azoli:reattività

Azoli:sintesi

ammidina

pirazolone

Azoli:sintesi eapplicazioni sintetiche

Indolo:reattività

Indolo:sintesi

Azine,rettività.

Quinoline

N

Isoquinoline

N

Quinoliziniumcations

N

chapt. 25

N NN

pKa 5.2 pKa 4.9 pKa 5.5

Reaction with electrophiles

Protonation on N

Electrophilic Ar subst

N

E

N

N

E

N

Major isomers shown

E

E

Benzene more electron rich

than pyridine

Azine,rettività.

R2 H

O

OR3

O

R2O

NH3

NH

R2 R2

R

R3O

O

OR3

O

NR2 R2

R

R3O

O

OR3

O

RO O

RO

OR

Top Ten Methods to Synthesize Pyridines

RO O

N

1. Hantzsch Pyridine Synthesis

Watanabe, Y.; Shiota, K.; Hoshiko, T.; Ozaki, S. Synthesis 1983 761; Pfister, J. R.Synthesis 1990, 689;Singer, A; McElvain, S.M. Org. Synth., Coll. Vol. II 1943, 214-216.

A mixture of aldehyde, β-ketoester, 60 mL of ethanol, and 10 mL of concentrated aqueous ammonia was heatedfor 3 h on a steam bath. To a solution of the above compound in 15 mL of acetone is added a solution of cericammonium nitrate in 3.5 mL water. The orange color of the reagent disappears immediately on addition of eachdrop. After stirring for 10 min, the resulting solution is concentrated to a small volume under reduced pressure.To this mixture is added 20 mL of water and the mixture is extracted with methylene chloride. The organic phase is washed with brine, dried over MgSO4, and evaporated under reduced pressure.

2. Guareschi-Thorpe Condensation

NH3

Section one - Chemistry of Heteroaromatics

N

85

HO OH

RN

+

Holder, R.W.; Daub, J.P.; Baker, W.E.; Gilbert, R.H.; Graf, N.A. J. Org. Chem. 1982, 47, 1445-1450.I. Guareschi, Mem. Reale Accad. Sci. Torino II 1898, 46, 7, 11, 25.

+or NH4OAc,AcOH

In a round-bottom flask were combined the diester (0.4 mol), the cyanoester ((0.6 mol), ammonium acetate (0.1 mol), glacial acetic acid (0.5 mol), and benzene (100 mL). The flask was equipped with a Dean-Stark tube fitted to acondenser attached to a CaCl2 drying tube. The solution was heated at reflux for 45 h. The cooled benzene solutionwas washed with with 75 mL portions of water, dried over CaCl2, and concentrated. Distillation through a 10 cm Vigreaux column afforded the product.

oxid

Azine,sintesi

ArthurRudolfHantzsch1857-1935

Azine,sintesi

Bischler–Napieralski reaction

Skraup reaction

Azine,sintesi

Lipidi

Ilipidi costituiscono lafrazione solubile insolventi apolari derivata dauntessuto.Sono una famiglia eterogenea dimolecole organiche principalmente apolari costituite perlamaggior parteda

Trigliceridi

Cere

Steroidi Fosfolipidi Terpeni

Trigliceridi

Fosfogliceridi

Steroidi:tutti sintetizzati apartire dalanosterolo ecolesterolo.Sono coinvolti nella differenziazione cellulare,crescitaeproliferazione.

Steroidi

Steroidi

Terpeni,acido retinoico ederivati.Sono coinvolti nella differenziazione cellulare proliferazione,apoptosi emediatori dellainterazione cellula/cellula.Sono ottenuti permetabolismo ossidativo dalcaroteneodaaltre luteine/xantophille.Ilretinolo

è coinvolto nel fenomeno della visione.

Terpeni

Cn(H2O)n Monosaccaridi,oligosaccaridi,polisaccaridi.Poliidrossi aldeidi (aldosi)epoliidrossichetoni (chetosi),treosi,tetrosi,pentosi,esosi,eptosi

gliceraldeideglicerolo

D-monosaccaride: unmonosaccaride che halastessaconfigurazione della D-gliceraldeide nel penultimo C(lostereocentro più lontano dalC=O).Cioè hal’OH adestra nellaproiezione diFischer.

L-monosaccaride: unmonosaccaride che halastessaconfigurazione della L-gliceraldeide nel penultimo C(lostereocentro più lontano dalC=O).Cioè hal’OH asinistra nellaproiezione diFischer.

Carboidrati

2.3. Conformation of Pyranoses andFuranoses

The concepts of conformation are fundamentalto a proper understanding of the structure–prop-erty relationships of carbohydrates, most nota-bly of the regio- and stereoselectivities of theirreactions. The conformational analysis ofmonosaccharides is based on the assumptionthat the geometry of the pyranose ring is essen-tially the same as that of cyclohexane and,analogously, that of furanoses the same as thatof cyclopentane—a realistic view, since a ringoxygen causes only a slight change inmoleculargeometry. Hence, the rhombus-shaped Haworthformulas which imply a planar ring, and theequally flat dashed-wedged line configurationaldepictions by Mills (Fig. 5) are inadequate to

represent the actual three-dimensional shape ofthe rings and the steric orientation of the ringsubstituents (OH and CH2OH groups). For thesix-membered pyranose ring a number ofrecognized conformers exist [16]: two chairs(1C4,

4C1), six boats (e.g., 1;4B and B1,4 inFig. 6), six skews and twelve half-chairs (e.g.,oS2 and

5H4 forms).Although there are exceptions, most aldo-

hexoses adopt the chair conformation thatplaces the bulky hydroxymethyl group at theC-5 terminus in the equatorial position. Hence,b-D-hexopyranosides are predominantly in the4C1 chair conformation, since each of the alter-native forms outlined in Figure 6, most notablythe 1C4 chair, are energetically less favored.For glucose, this preference means that, inthe a-form, four of the five substituents are

Figure 3. The D-aldose family tree (up to aldohexoses) in their acyclic forms:Commonnames and Fischer projection formulas,with secondary hydrogen atoms omitted for clarity

4 Carbohydrates: Occurrence, Structures and Chemistry

equatorial, and one is forced to lie axial; in theb-form, all substituents are equatorial (Fig. 7).This situation is unique for glucose; the otherseven D-aldohexoses contain one or more axialsubstituents.

The hexulose counterpart to the conforma-tional forms of D-glucose is the D-fructoseisomerization scheme depicted in Figure 8.Whilst the crystalline product is the b-D-fruc-topyranose in the 2C5 chair conformation asevidenced byX-ray analysis [17], on dissolutionin water, equilibration is essentially instanta-neous to yield a mixture mainly containing theb-p-form (73% at 25 !C, the only sweet one infact), together with the b-f- (20%), a-f- (5%)

and a-p-forms (2%) [18]. The acyclic formthrough which equilibration occurs is presentonly to a minute extent.

The principal conformations of the furanosering are the envelope (E)—one atom lyingabove or below a plane formed by the otherfour ring atoms—or the twist (T) arrangement,in which three ring atoms are in a plane and theother two above and below, respectively. Asenergy differences between the various E and T

Figure 4. The D-ketohexose (or D-hexulose) family tree:Trivial names, systematic designation (in brackets) andFischer projection formulas† Not regarded as being a sugar, due to absence of anasymmetric carbon atom.

Figure 5. Haworth and Mills projection formulas for theb-anomers of D-glucopyranose and D-glucofuranose (in theformula at the center and at the bottom, the carbon andC-hydrogen atoms are omitted for clarity)

Figure 6. Conformational forms of pyranose rings: chair(C), boat (B), skew (S) and half-chair (H).To designate each form, the ring atom numeral lying abovethe plane of reference appears as a superscript preceding theletter, those below the plane are written as subscripts andfollow the letter

Carbohydrates: Occurrence, Structures and Chemistry 5

Carboidrati

HO

HOCH2 OH

HHO

CH2OH

OHH H

C=O

CH2OH

HOH

CH2OH

OHH

HO HOH

HOHOCH2

HO HCH2OH

OH

D-Fructose

1

23456

55

1

22(b)

b-D-Fructofuranose(b-D-Fructose)

a-D-Fructofuranose(a-D-Fructose)

(a)

1

Carboidrati

conformations are small, the form actuallyadopted depends on the type of ring substitution(hexoses, hexuloses, pentoses), their configura-tion, their solvation and the type of intra- orintermolecular hydrogen bonding present.Accordingly, the exact conformation of anindividual furanose is usually not known—except for the crystalline state when an X-raystructural analysis is available. Thus, the planarHaworth and Mills projection formulas are thepreferred way of drawing furanose forms(Fig. 9).

2.4. Structural Variationsof Monosaccharides

Sugars may possess functionalities other thanhydroxyl groups. Amino sugars are aldoses,which have a hydroxyl group replaced by an

Figure 7. Cyclic hemiacetal forms of D-glucose in configu-rational representation. In solution, these forms rapidlyinterconvert through the energetically unfavorable acyclicform; in water at 25 !C the two pyranoid forms are nearlyexclusively adopted, the equilibrium mixture amountingto 62% of the b-p and 38% of the a-p anomers. Fromwater, D-glucose crystallizes in the a-pyranose formThe six-membered (pyranose) ring is denoted by the symbolp after the three-letter symbol for the monosaccharide (forexample, Glcp), the five-membered (furanose) ring corre-spondingly is signated by an f (e.g., Glcf).

Figure 8. Forms of D-fructose in solution. In water, themajor conformers are the b-pyranose (b-p, 73% at 25 !C)and b-furanose (b-f, 20%) forms [18]. On crystallizationfrom water, D-fructose adopts the 2C5 chair conformation inthe crystal lattice as evidenced by X-ray analysis [17]

Figure 9. The envelope conformation (top left) is the 3Eform as defined by the C-3 atom lying above the planeformed by the other ring atoms. The defined plane for thetwist form (top right) is the triangle given by C-1, C-4, andO-4, entailing the conformational description 3T2. In aproticsolvents (dimethyl sulfoxide) D-fructose populates the E2

envelope conformation to a substantial extent [18], whilst incrystalline sucrose, the b-D-fructofuranose portion adoptsthe 4T3 twist form [19, 20] (bottom entries)

6 Carbohydrates: Occurrence, Structures and Chemistry

Carboidrati

Ilglucosio è presente infase solida informaciclica(piranosidica).Almomento che viene disciolto inacqua,si innesca unlentoprocesso diapertura/chiusura delsistema emiacetalico cheportadopo 24adunequilibro tra leforme infigura.Laprevalenza è della formabeta(circa63%)rispetto alla alpha(circa37%)esolotracce dellaformaaperta edelle forme furanosidiche

Carboidrati:red-ox

Glucosidi

saccarosio

lattosio

maltosio

Disaccaridi

◆ Amido:usato perimagazzinare glucosio nelle piante• Può essere separato inamilosio eamilopectina:l’idrolis completa (enzimatica oacida)portaaD-

glucosio• Amyiosio:unpolisaccaride costituito dacirca4000unità lineari diglucosio legateconlegami 1-4

alpha(assiale).• Amilopectina:Aunpolisaccaride costituito da5000-10000unità diglucosio conlegami 1-4alphae

ramificate sulla posizione 6-1alphada24-30unità diglucosio 1-4alpha

Glicogeno:lariserva animale dicarboidrati.

Polimero nonlineare diD-glucosio conconnessioni alpha1-4ed alpha1-6.Polimero moltogrande spesso che arriva fino a3000unità Iglucosio.

Polisaccaridi

Cellulosa Unpolimero lineare diD-gucosio 1-4betacostituito dacirca3000unità diglucosio.Peridrolisiacida spinta (oidrolisi enzima)tica)si ottiene D-Glucosio.E’usata comesostegno dalle pianteIlllegno è costituito dafasci dicellulosa tenutoinsieme dalignina.Ilcotone è costituito al90%dacellulosa

Polisaccaridi

Acido ialuronico:polisaccaride acido contenuto nel tessuto connettivoLegame 1-4betatra acido glucuronico eN-acetil glucosamina.Ilsuo MWvaria tra 5.000e20.000.000Da.

Eparina:polisaccaride naturale usato comefarmaco anticolagulante

Polisaccaridi

Amminoacidi (aminoacids):Molecole che contengono ungruppo acido (-COOH,-SO3H)ed uno basico(NH2).

Amminoacidi naturali.Comesopra madiorigine naturale (sono migliaia).

α-Amminoacidi.Molecole doveil gruppo acido (COOH)equello basico (NH2)sono legati allo stesso atomodicarbonio (ibridato sp3)(sono migliaia).

Amminoacidi codificati.Costituenti principali delle proteine.Esiste perognuno diessi uncodice (tripletta)nel DNA.Vengono introdotti nelle proteine durante lasintesi proteica che avviene nei ribosomi.Sono 22(20+2).Sono tutti α-amminoacidi,sono tutti singoli enantiomeri,sono tutti della serie L.

Amminoacidi

Ilvalore medio dipKa perungruppo α-carbossile diuna.a.protonato è 2.19.Ilgruppo α-carbossile diuna.a.èMOLTOpiù ACIDOdell’acido acetico (pKa =4.76).Lamaggiore acidità è attribuibile all’effetto induttivo elettron-attrattore delgruppo –NH3+adiacente Ilvalore medio dipKa perungruppo α-ammonio diuna.a.è 9.47.Ilgruppoα-ammonio diuna.a.è unacido leggermente più fortediuno ione ammonio derivante daun’ammina primariaalifatica (pKa =10.76).Ungruppo α-amminico è una baseleggermente più debole diun’ammina alifatica primaria.

Amminoacidi codificati

Struttura secondaria.Organizzazione delfilamento dovuta ailegami aidrogeno che si realizzano tra i C=Oegli NHdelfilamento.NB.Legame aHmassimo conD-H-A180°

Peptidi eproteine

Proteine:sequenze dialmeno 50aa

Struttura Terziaria – FoldingMisura delfolding:diminuzione dell’entropiaconformazionale bilanciata appena daunguadagno entalpicoAttenzione:Nonconfondere lamisura conlecausedelfenomeno.Forze diinterazione che controllano il folding:Interazioni idrofobiche (ointerazioni lipofiliche preferenziali)Legami aH(diretti oattraverso molecole diacqua)Legami IoniciLegami diCoordinazione (attraverso metalli)Legami adisolfuro

Struttura quaternaria

Proteine

Cinetica enzimatica

Nucleotidi / oligonucleotidi / acidi nucleicii

N

NN

N

NH2

O

OHO

PO

HO

O-

N

NH2

ON

O

OHO

PO

O

O-

NH

N

N

O

NH2N

O

OHO

PO

O-

O

O-

DNA Struttura rigida. Duoble strained. Acido e chimicamente stabile

RNA Struttura flessible. Single strained. Acido e chimicamente instabile (transesterificazione)

N

NN

N

NH2

O

O

PO

O

O-

NH

N

N

O

NH2N

O

O

PO

O

O-

N

NH2

ON

O

O

PO

O

O-

O

HN

O

O N

O

O

PO

O

O-

Gli Oligonucleotidi con gli occhi del chimico

Oligonucleotidi

L’accoppiamento delle basi

Perché il desossiribosio nello stampo ed il ribosio nel messaggero ?

IlDNAnonhasitireattivisulloscheletro,nonhalapossibilitàdidarelegamiaidrogeno.LeunichepossibilitàdiinterazionesonotragliH dellenucleobasi.Quindi,ilDNAsisviluppacomestrutturaestesaofibrosa. Ilfilamentopuòripiegarsipermassimizzareleinterazionitralebasicomplementarioppureappaiarsiconunfilamentoaffine.Ilsistemaèstabileinassenzadigruppinucleofilicheinteragisconosulfosfato.

L’RNAhal’OHinposizione2’cheinteragisceconaltriOH(direttamenteoattraversomolecolediacqua)eguidailripiegamentodelfilamentoconformazionedipossibiliinterazionitralebasi.Quindi l’RNAsisviluppacomeunastrutturaglobulare.Infunzionedell’ambienteincuisitroval’RNAsubiscemodificheconformazionalichepossonopermetterelatransesterificazione dellegamefosfatoconmodificadellasequenzadell’RNA(splicing).

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