chapter 2
DESCRIPTION
rTRANSCRIPT
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REACTIVITY OF HETEROCYCLIC
COMPOUNDS
Jose Luis VicarioDepartment of Organic Chemistry IIFaculty of Science and TechnologyUniversity of the Basque [email protected]://www.ehu.es/GSA
Chapter 2
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SUMMARY
Relevance of heterocycles as chemical reagents
Acid-base behavior of nitrogen heterocycles
Reactivity of heterocycles.
Reactivity of five-membered heterocycles: pyrrol, furane and thiophene
Reactivity of six-membered heterocycles: pyridine
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RELEVANCE OF HETEROCYCLES AS CHEMICAL REAGENTS
Heterocycles participate in most of the chemical processes associated with life.
Energetic processes (ATP, .)
Nerve impulse transmission (neurotransmitters, )
Processes associated with vision
Metabolic processes
Transmision of genetic information
Transmision of genetic information
Effect on virus and bacteria
And many more
HETEROCYCLES AS REAGENTS IN BIOLOGICAL PROCESSES
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RELEVANCE OF HETEROCYCLES AS CHEMICAL REAGENTS
The reactivity of heterocycles is crucial in many chemical processes used in industry
Pharmaceutical industry (drugs)
Catalysts in petroleum processing
Catalysts and reagents in Fine Chemical Synthesis
Dyes (OLED-s, etc..)
Agrochemicals
Health-care consumables
Additives in polymer manufacturing
And many more
HETEROCYCLES AS REAGENTS IN INDUSTRIAL CHEMISTRY
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
ACIDITY AND BASICITY
Measuring of the acidity of a substance: The pKa
Strong acids have low pKa values. The conjugate base is a weak base. The equilibriumis shifted to the right
H A A H+
Ka = [A-] [H+] / [HA]
pKa = -log Ka = log [HA ] / [A-] + pH
Weak acids have high pKa values. The conjugate base is a strong base. The equilibriumis shifted to the left
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
PYRROLE-TYPE HETEROCYCLES
Bronsted acidity
NH
NH+
pKa = 17,5 Pyrrole is a weak acid Pyrrolyl anion is a strong base
Bronsted basicity
Pyrrole is a weak base: Protonation breaks aromaticity (lone pair participates in conjugationand thus it is not readily available
NH+
NHH
Non-aromatic cationAromatic compound
H
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
PYRIDINE-TYPE HETEROCYCLES
Bronsted acidity
Pyridinium cation is a strong base Pyridine is a weak base
Bronsted basicity
Pyridine does not have any acidic hydrogen (no N-H group) Can not behave as Bronsted acid
The lone pair at nitrogen does not participate in conjugation Pyridine is a Bronsted base
NH
N
+ H+ pKa = 5,23
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
HETEROCYCLES CONTAINING PYRIDINE- AND PYRROL-TYPE MOIETIES
E. g. Imidazole
Imidazole is an amphoteric compoundN
N
H
Acidic compoundPyrrol-type heteroatom linked to hydrogen atom
Basic characterPyridine-type heteroatom with anElectron lone pair on sp2 orbital of Nitrogen atom
N
NH
N
N+ H+ pKa =14,2 Imidazole can donate NH hydrogen
Imidazole is a 103.3 (2000) times stronger acid than pyrrole (pKa = 17.5)
Comparing acidity: imidazole vs pyrazole
Imidazole can donate the lone pair on pyridine-like nitrogen
Imidazole is a 101.72 (2000) times stronger base than pyridine (pyridinium cation pKa = 5.23)
Comparing basicity: imidazole vs pyridine
HN
NH
+ H+ pKa =6.95N
NH
All these effects can be rationalized in terms of resonance-stabilized forms
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
RELEVANCE OF ACID-BASE BEHAVIOR OF HETEROCYCLES IN BIOCHEMICAL PROCESSES
Enzymes are proteins which participate in the chemical reactions associated with life processes by catalyzing them
Enzymes can also be used in chemical synthesis (both in academic laboratories or in inductrial processes) Enzymes are fully substrate-selective catalysts and only work on aqueous buffered media The catalytic action takes place at the enzyme active site. The rest of the protein domains are only required
as an architectural feature associated with stability and shape of the complete molecule.
Imidazole is a weak base which at physiological pH is in equilibrium with its protonated form
Very often enzymes which catalyze reactions through acid-base mechanisms operate with an hystidineresidue at the active site
Acid-Base catalytic enzymes
Imidazolering
Imidazole ring participates as a proton bank, accepting protons on its free base form and donating them when it is protonated
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
RELEVANCE OF ACID-BASE BEHAVIOR OF HETEROCYCLES IN BIOCHEMICAL PROCESSES
Epoxide hydrolase functions in detoxification during drug metabolism. It converts epoxides to trans-diols, which can be conjugated and excreted from the body. Epoxides result from the degradation of aromatic compounds. Deficiency in this enzyme in patients receiving aromatic-type anti-epileptic drugs such as phenytoin is reported to lead to DRESS syndrome (a syndrome, caused by exposure to certain medications, that may cause fever or inflammation of internal organs. The syndrome carries about a 10% mortality .
Example: Epoxide hydrolase
Enzyme active site
Phenytoin(antiepileptic)
Enzyme crystal structure
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
HETEROCYCLES AS METAL LIGANDS
Heterocycles can act bound to metals through their lone pairs (Bronsted basicity) forming coordinationcompounds
Coordination compound (metal complex): A chemical entity formed by a central metal atom(typically a transition metal) surrounded by groups of neutral or ionic molecules called ligands
Ligands Central atom
n +/ -
Complex charge
n -/ +
Counterion charge
counterion
Heterocycles can play the role of metal ligands by donating a pair (monodentate ligand) or more thanone pair of electrons (polydentate ligand or chelatingligand) to the metal therefore forming a coordinated
The coordinating ability (cationic capacity) is relatedto its basicity (proton affinity)
The coordination index of the complex refers to thenumber of ligands directly attached to the central ion
The number of ligands (heterocycles) that are coordinated with a metal depends on the type andnumber of orbitals available in the outer layer ofmetal.
The complex may be neutral (no net charge) or ionic(with positive or negative net charge)
The metals that form complexes are generallytransition metals. They provide the empty d orbitalsof the penultimate level to accommodate the ligandwhich donates the electron pair
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ACID-BASE BEHAVIOR OF NITROGEN HETEROCYCLES
HETEROCYCLES AS METAL LIGANDSMetal complexes with pyridine: Pyridine complexes with all metals through its nitrogen lone pair(highly basic). Therefore pyridine is a monodentate ligand. Geometry depends on metal atom
Ag (I): Linear
N
N
AgN
AlCl
ClCl
Al (III): tetrahedral
N
Cu
N
ClCl
Cu (II): square planar
N
Co
N Cl
Cl
Cl
Cl
2
Co (IV): Octahedral
Chlorophyl B
Heme group
Other examples: Protoporphyrin is widely found in nature
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X Reaction rate
NH 5,3 107
O 1,4 102
S 1
REACTIVITY OF FIVE-MEMBERED HETEROCYCLES
GENERAL REACTIVITY TREND
Most important five-membered heterocycles : Furane, thiophene and pyrrol
Electrophilic aromatic substitution (SEAr): They are pipipipi-excedent systemsOrder of reactivity: Model system
Typical reactions:
Diels-Alder-type reactivity: They are electron-rich dienes
Electrophilic addition: Leads to loss of aromaticityResonance-stabilization energies: Benzene > thiophene > pyrrol > furane
This means that furane has the highest tendency to undergo electrophilic addition
Pyrrol > Furane > Thiophene > Benzene
X+ (CF3CO)2O
75o CCl2C2H4
X COCF3 + CF3CO2H
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REACTIVITY OF PYRROL
ELECTROPHILIC AROMATIC SUBSTITUTION
Electrophilic aromatic substitution normally occurs at carbon atoms instead of at the nitrogen. Also it occurs preferentially at C-2 (the position next to the heteroatom) rather than at C-3 (if
position 2- is occupied it occurs at position 3). This is because attack at C-2 gives a more stable intermediate (it is stabilized by three resonance
structures) than the one resulted from C-3 attack (it is stabilized by two resonance structures) .
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1.- Formation of electrophile
2.- Electrophilic aromatic substitution
Formylation: Vilsmeier-Haack:
N H
OH3C
CH3+ POCl3 N H
OHH3C
H3C ClN H
ClH3C
CH3
NH H
N(CH3)2
OH
NH
HN(CH3)2
OH
NH(CH3)2
NH H
O
NH
Cl CH
N(CH3)2+ NH
H
HN(CH3)2 NH H
N(CH3)2
3.- Hydrolysis of iminium salt
NH
1) POCl3, DMF2) Base (aq.)
REACTIVITY OF PYRROL: SEAr
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1.- Formation of electrophile
2.- Electrophilic aromatic substitution
Acylation: Houben-Hoesch:
3.- Hydrolysis of imine
NH
+ R CN
HCl (aq.)
REACTIVITY OF PYRROL: SEAr
R C N + HCl R C NH
NH
R
NH NH
R
NH2
HCl H2O
NH
RNH2
OH2
NH4NH R
O
NHR C NH+ N
H
H
RNH N
H
R
NH
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Friedel-Crafts acylation (thermal or LA-catalyzed)
Bromination
Polyhalogenation
Diazotization
nitration
sulfonation
Other reactions:
REACTIVITY OF PYRROL: SEAr
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Addition to 3-position?: Using steric effects
REACTIVITY OF PYRROL: SEAr
E.g.
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And the second substitution?:
REACTIVITY OF PYRROL: SEAr
a) Monosubstituted pyrrole with electron withdrawing group
(incoming Electrophile directed to m-position i.e.
position 4)
One example:
Less reactive than pyrrol
a) Monosubstituted pyrrole with electron donating group
(incoming Electrophile directed to p or o-positions
i.e. position 3 or 5)More reactive than pyrrol
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Metallation of pyrrol:
Most acidic proton
Ortho-metallationMetallation at 3-position?
Metallation of N-substituted pyrrol:
Steric effect(be careful with basic o-directing
groups capable of chelation)
Metal-Halogen exchange(Requires introduction of the
halogen at 3-position)
REACTIVITY OF PYRROL
METALLATION
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Pyrrole is an electron-rich 1,3-diene: Diels-Alder reactivity
REACTIVITY OF PYRROL
CYCLOADDITION CHEMISTRY
Diels Alder reaction involves addition of a compound containing a double or a triple bond (2 e it is Called dienophile) across the 1,4- position of a conjugated system (4 e, 1,3-diene), with the formation of a six membered ring.
The heterocyclic compounds can react as a 1,3-diene in D. A. reaction with reactive dienophiles (e.g. maleic anhydride, or benzyne) or with less reactive dienophiles (e.g. acrylonitrile) in presence of catalyst.
The diene can be activated by E.D.G while the dienophile by EWG.Thus N-alkyl pyrrole and N-amino pyrrole are more reactive than pyrrole itself in D.A reaction but less reactive than furan (The order of reactivity in D.A reaction is the reverse of aromaticity order:) .
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1.- From 1,4-dicarbonyl compounds (Paal-Knorr synthesis): Generally Substituted pyrrole may
be synthesized through the cyclization of 1,4-diketones in combination with ammonia
(NH3) or amines, The ring-closure is proceeded by dehydration (condensation), which
then yields the two double bonds and thus the aromatic system. The formation of the
energetically favored aromatic system is one of the driving forces of the reaction.
SYNTHESIS OF PYRROLES
2.- Pyrrole is obtained by distillation of succinimide over zinc dust.
3.- Pyrrole is obtained by heating a mixture of furan, ammonia and steam over alumina
catalyst.
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4.- By passing a mixture of acetylene and ammonia over red hot tube
SYNTHESIS OF PYRROLES
5.- Knorr-pyrrole synthesis: This involves the condensation of -amino ketones with a -
diketone or a -ketoester to give a substituted pyrrole.
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REACTIVITY OF FURANE AND THIOPHENE
FURANE AND THIOPHENE COMPOUNDS. OCCURRENCE
Furanes as flavor agents.
OSH
2-Furylmetanethiol
Constituent of coffee flavor
O
Rose furan
Constituent of rose scent
O
Mentofuran
Constituent of mint oil
Isosoraleno
preservation of cosmetics
Psolarene
Drug for psoriasis
Angelicin
O OO OOO
OO O
Furocumarines are coumarins with a fused furan ring. These show high UV-absorption which can be used for the generation of singlet oxygen. Therefore these compounds are used as antioxidants (for the preservation of food and cosmetics)
and also as UV filters.
The capacity to absorb UV light makes them useful for binding to bioactive compounds which are released after irradiation (serve as an antenna).
Furocumarines
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REACTIVITY OF FURANE AND THIOPHENE
REACTIONS
Electrophilic aromatic substitution Electrophilic addition (loss of aromaticity) Cycloaddition
Order of reactivity: Remember, The order of reactivity is the reverse of aromaticity order
Pyrrol > Furane > Thiophene > Benzene
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REACTIVITY OF FURANE AND THIOPHENE
ELECTROPHILIC AROMATIC SUBSTITUTION
Similar reactivity pattern as pyrrole
Electrophilic aromatic substitution only occurs at carbon atoms instead of at the oxygen. Also it occurs preferentially at C-2 (the position next to the heteroatom) rather than at C-3 (if
position 2- is occupied it occurs at position 3). This is because attack at C-2 gives a more stable intermediate (it is stabilized by three resonance
structures) than the one resulted from C-3 attack (it is stabilized by two resonance structures) .
Order of reactivity: Remember Pyrrol > Furane > Thiophene > Benzene
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Reaction type Reagents and conditions Product
Halogenation Br2 / dioxane, 0oC
Nitration NO2+ AcO-, 5oC
Sulfonation Pyridine-SO3 complex, 100oC
Formylation 1) POCl3 , Me2NCHO2) CH3COO- Na+
furfural
Acetylation
REACTIVITY OF FURANE AND THIOPHENE
ELECTROPHILIC AROMATIC SUBSTITUTION
O SO3H
O NO2
O CHO
O
O O/ SnCl4
O CO-CH3
O Br
+ E+
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REACTIVITY OF FURANE AND THIOPHENE
ELECTROPHILIC AROMATIC SUBSTITUTION through lithiation
+ RLiE+
Highly reactive nucleophile
1) t-BuLi, THF, -78C2) DMF, 0C
1) t-BuLi, THF, -78C2)
, 0C
3) H2O
1) t-BuLi, THF, -78C2) R-X, 0C Cross-coupling
(Low yield, needs Pd or Cu-catalysis)
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REACTIVITY OF FURANE AND THIOPHENE
ELECTROPHILIC ADDITIONS (oxidation)
1,4-addition (typical 1,3-diene reactivity)+ X2
Furane as 1,4-dicarbonyl equivalent
Br2, MeOH HCl (aq.)
OMe O
HBr Br
O-HBr + MeOH
+ +
- HBr
MeO Br OMeO OMe
Mechanism: (Z)
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REACTIVITY OF FURANE AND THIOPHENE
CYCLOADDITIONS (Diels-Alder reactivity)
Endo-diastereoselectivity+
Example: Application to the synthesis of a natural product
Cantharidin
Poison secreted by many species of blister beetle and by the Spanish fly It is secreted by the male and given to the female during mating. Afterwards
the female will cover its eggs as a defense against predators. Diluted solutions of cantharidin can be used to remove warts (papiloma)
and tattoos and to treat the small papules of Molluscum contagiosum When ingested by humans, a dose of 10mg is potentially fatal. (causes
severe damage to the lining of the gastrointestinal and urinary tract, and may also cause permanent renal damage
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REACTIVITY OF FURANE AND THIOPHENE
CYCLOADDITIONS (Diels-Alder reactivity)
Initial approach:
+
but:
+heat
endo
so:
+ heat
Still endo!!!
1) H2, Pd/C2) Raney-Ni
Cantharidin
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REACTIVITY OF FURANE AND THIOPHENE
REACTIVITY OF THIOPHENE
High aromatic character, pipipipi-excedent aromatic ring with high tendency to undergo electrophilic aromatic substitution
SEAr reactions preferably to C-2. Less reactive towards addition reactions (loss of aromaticity). Only undergoes cycloaddition reactions with good dienophiles
Example: Application to the synthesis of a natural product
()-muscone
Active ingredient of musk (natural perfume and highly appreciated) Musk is extracted from a glandular secretion of the musk deer which is
native from central Asia de Asia Central Physiological function: pheromone For obtaining 1 kg of muscone 3000 animals have to be killed (chemical
synthesis required) Natural muscone is enantiomerically pure (-)-muscone Synthetic muscone is prepared in racemic form but is much less active
1) BuLi2) Br(CH2)10Br
1) KCN2) HCl (aq.)
Tf2OH3PO4
Raney-Ni
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REACTIVITY OF PYRIDINE
GENERAL REACTIVITY
UNSUBSTITUTED PYRIDINES
REACTIONS AT NITROGEN
AN: Pyridine as nitrogen nucleophile
REACTIONS AT CARBON ATOMS
SNAr: Pyridine as carbon electrophile
SEAr: Pyridine as carbon nucleophile
C-SUBSTITUTED PYRIDINES
REACTIONS AT CARBON ATOMS
SNAr: Pyridine as carbon electrophile
SEAr: Pyridine as carbon nucleophile
N-SUBSTITUTED PYRIDINESREACTIONS AT CARBON ATOMS
SNAr: Pyridine as carbon electrophile
Pyridine
Acid-Base: Pyridine as a Bronsted base
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REACTIVITY OF UNSUBSTITUTED PYRIDINE
REACTIONS AT NITROGEN
AN: Pyridine as nitrogen nucleophile: The nitrogen lone pair (it does not participate in conjugation) reacts with electrophiles
Acid-Base: Pyridine as a Bronsted base
+ HCl Pka = 5.2
N-Acylation: +
N-Alkylation: + R-X
N-Nitrosation: + RONO
N-Sulfonation: + SO3
N-Oxidation: + H2O2
Ylide formation: +Base
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REACTIVITY OF UNSUBSTITUTED PYRIDINE
REACTIONS AT CARBON ATOMS
SEAr: Pyridine as nitrogen nucleophile: Behaves essentially as benzene, although due to its p-defficient character reactions are slower and require harsher conditions
+ E+C-3 attack
Regioselectivity:
N+ E+
N E N E N E
N
E
N
E
N
E
N
E
N
E
N
E
C-2 attack
C-3 attack
C-4 attack
Poor contribution
Poor contribution
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REACTIVITY OF UNSUBSTITUTED PYRIDINE
REACTIONS AT CARBON ATOMS
SNAr: Pyridine as nitrogen electrophile: DOES NOT behave as benzene. Reaction does not proceed via benzyne intermediates. Pyridine should be regarded essentially as a cyclic imine
+ Nu-C-2 attack
Mechanism:
Hydride anion is a bad leaving group Second step is very slow Sometimes the elimination does not take place:
N
+ Nu-N Nu
H
Addition elimination
Hydroxylation:High temp.
KOH
Amination: NaNH2
Chichibabin reaction
Cyanation:KCN
Alkylation: RLi or RMgX
High temp.
Loss of aromaticity slow reaction
Highly reactive organometallic reagentsPrevious N-acylation can be carried out for
accelerating the reaction
Loss of aromaticity slow reaction
EXAMPLES
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REACTIVITY OF C-SUBSTITUTED PYRIDINE
REACTIONS AT CARBON ATOM
SEAr: Pyridine as carbon nucleophile:
+ E+
C-2 attack
Deactivating substituent: No reactionActivating substituent Reactivity: Higher than the corresponding unsubstituted pyridine
Regioselectivity: orto and/or para with respect to the activating substituent
Halogenation of methylpyridines:
CH2Cl2, r.t.X2, AlCl3
EXAMPLE
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REACTIVITY OF C-SUBSTITUTED PYRIDINE
REACTIONS AT CARBON ATOM
SNAr: Pyridine as electrophile:
+ Nu-
Alkylation of 2-methoxypyridine
THF, -78CMeMgBr
EXAMPLE
X should be a good leaving group (Halogen, sulfonate, etc.) High reactivity (X is a better leaving group than hydride) Regioselectivity controlled by the stability of intermediate anion
Mechanism:
+ Nu-N Nu
X
elimination addition
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REACTIVITY OF N-SUBSTITUTED PYRIDINE
REACTIONS AT CARBON ATOM
SNAr: Pyridinium ions as electrophiles:
+ Nu-
Stabilization through elimination
NaCN
Highly reactive (positive nitrogen results in enhanced electrophilicity Final product arises from the evolution of the addition intermediate Evolution of addition intermediate depends on different factors
R=good leaving group
Product
aromatization
tBuOOHoxidation
Resonance-stabilized R=bad leaving group
Stabilization through ring opening
RMgBr HCl