Halogen Bond Applications in Organic Synthesiskanai/seminar/pdf/Lit_K_Maruyama_M1.pdfHalogen Bond...
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Halogen BondApplications in Organic Synthesis
Literature Seminar
2018/7/14
M1 Katsuya Maruyama
1
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Contents
2
1. Introduction
2. Property of Halogen Bond
3. Application to Organic Synthesis
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1. Introduction
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Non-covalent Interactions
4
Non-covalent
Interactions
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History of Halogen bond
5
papers containing “halogen bonding” in title or abstract
1814 I2-NH3, I2-amylose complex formation
1819 I2+I- -> I3-
1883 quinoline-CHI3 adduct
18XX Br2 or Cl2-amine adduct
195X X-ray crystallographic study
1983 analysis in solution
199X F2-NH3, F2-OH2 adduct
2007 concept of σ-hole was introduced
2013 halogen bond definition by IUPAC
Applications of halogen bond
- Crystal engineering
- Supramolecule
- Biological systems
- Medicinal chemistry (protein-ligand interaction)
- Organic synthesis Metrangolo, P.; Resnati, G. et al. Chem. Rev. 2016, 116, 2478–2601.
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2. Property of Halogen Bond
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Halogen Bond (XB)
7
Definition of halogen bond (IUPAC, 2013)
“A halogen bond occurs when there is evidence of a net attractive interaction
between an electrophilic region associated with a halogen atom in a molecular
entity and a nucleophilic region in another, or the same, molecular entity.”
XB donor
(Lewis acid)
XB acceptor
(Lewis base)
Features
- Directionality
- Strength tunability
- Hydrophobicity
- Donor atom size
Metrangolo, P.; Resnati, G. et al. Chem. Rev. 2016, 116, 2478–2601.
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σ-hole
8
SCl2 As(CN)3 SiCl4
σ-hole mediated interactions
group 14: tetrel bond
15: pnicogen bond
16: chalcogen bond
17: halogen bond
VS,max=25.1 kcal mol-1
VS,min=-5.9 kcal mol-1
VS,max=51.4 kcal mol-1 VS,max=20.2 kcal mol-1
Electrostatic potential
More polarizable
Less electronegative
More positive σ-hole
Metrangolo, P.; Resnati, G. et al. Chem. Rev. 2016, 116, 2478–2601.
Donor atom
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Origin of σ-Hole
9
CF3Br : 4s24px24py
24pz1
1. 4pz : half filled, localized between C and Br to form C-Br σ bond.
2. Appear along with polarization by XB acceptor.
complexation
e- rich e- poor Origins of σ-hole
Clark, T. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2013, 3, 13–20.
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XB Strength
10
CF4 CF3Cl CF3Br CF3I
XB strength
Electrostatic potential of CF3X
- Astatine can be extremely good XB donor.
Astatine as XB donor
σ-hole
Metrangolo, P.; Resnati, G. et al. Chem. Rev. 2016, 116, 2478–2601. Montavon, G.; Galland, N. Nat. Chem. 2018, 10, 1–7.
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XB strength
11
C6F5ClC6H5Cl
C6F5BrC6H5Br
C6F5IC6H5I
Introduction of electron-withdrawing group
- Introduction of EWG -> strong XBMetrangolo, P.; Resnati, G. et al. Chem. Rev. 2016, 116, 2478–2601.
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Unexpected Trend of XB Strength
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CF3I
CI4
isolatedIn the presence of
1e- on C-I bond
- Charge-transfer (orbital-orbital interaction)
is also important.
Comparison of CY3I...Cl- (Y=F, Cl, Br, I) complex
Electrostatic potential and interaction energy Molecular orbital
Cl-
HOMO
Electrostatic potential
Huber, S. M.; Infante, I. et al. Chem. Commun. 2012, 48, 7708–7710.
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Geometry
13
CSD crystal structure containing X…N halogen bond
I-N
Br-N
Cl-N
80-90% of the sum of
Van der Waals radii
Slight elongation
Metrangolo, P.; Resnati, G. et al. Chem. Rev. 2016, 116, 2478–2601.
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Directionality
14
Possible factors for directionality
1. Charge transfer 2. Lone pair repulsion 3. σ-hole (electrostatic
interaction)
linear perpendicular
DFT calculation (NEDA: Natural Energy Decomposition Analysis)
CF3I…Cl-
Contribution of
- 1, 2 is large.
- 3 is small.
Directionality
not disfavored
1e- on perpendicular side
Huber, S. M.; Infante, I. et al. Phys. Chem. Chem. Phys. 2013, 15, 10350–10357.
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Directionality
Tsuzuki, S. et al. Chem. - A Eur. J. 2012, 18, 951–960.
C6F5X-pyridine
R: interaction
maximum
Inte
racti
on
en
erg
y
Inte
racti
on
en
erg
y
C6F5I-pyridine
- Electrostatic interaction is responsible
for directionality.
Effect of halogen atom Effect of distance
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3. Application to
Organic Synthesis
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XB in Organic Synthesis
Alignment of substrate
Recovered by
precipitation
Facilitating handling of reagents or catalysts
CF3I: gas
Optical resolution
Activation of substrate (catalyst, activator)
Bulfield, D.; Huber, S. M. Chem. - A Eur. J. 2016, 22, 14434–14450.
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Early Report of XB Mediated Catalysis
Activation
by XB
NMR experiment (in CD2Cl2)13C: 0.01-0.06 ppm lower field shift (quinoline)19F: ~0.06-0.1 ppm lower field shift (CF3(CF2)7I)
Additive
Reaction
inhibition
Reduction of quinoline by Hantzsch ester
Bolm, C. et al. Synlett 2008, No. 6, 900–902. 18
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Activation Types of XB Catalyst
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(1) Direct activation of reactant
(2) Anion abstraction from reactant
(3) Activation of another activator
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(1) Direct Activation of Reactant
20
C–H halogenation of heteroarenes
Calculated TS
ΔG‡ (kcal mol-1)
catalyst (-) 29.5
catalyst (+) 26.5
Mechanism
Diels-Alder reaction
Increment
of acidity
XB
Huber, S. M. et al. Chem. Commun. 2014, 50, 6281–6284.
Liang, F.; Ren, B. et al. Org. Biomol. Chem. 2018, 16, 886–890.
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(3) Activation of Another Activator
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Plausible mechanism
Dehydroxylative coupling of alcohol through Si-X bond activation
Verification of mechanism
- Generation of carbocation
- Anion exchange isn’t likely.
Takemoto, Y. et al. Org. Lett. 2015, 17, 3000–3003.
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(2) Anion Abstraction from Reactant
22
Ritter-type Solvolysis
Addition to oxocarbenium ion
Huber, S. M. et al. Angew. Chemie - Int. Ed. 2011, 50, 7187–7191.
Huber, S. M. et al. Angew. Chemie - Int. Ed. 2013, 52, 7028–7032.
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(2) Anion Abstraction from Reactant
Ritter-type Solvolysis
Monodentate XB donors
Bidentate XB donors (imidazolium type)
Huber, S. M. et al. Angew. Chemie - Int. Ed. 2011, 50, 7187–7191.
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(2) Anion Abstraction from Reactant
24
Cationic vs polyfluoro XB donor
Problems of cationic XB donor
- Solubility
- Synthetic accessibility
- Presence of counteranion
- Stability
Huber, S. M. et al. J. Fluor. Chem. 2013, 150, 14–20.
Iodopyridinium XB donor Polyfluoro XB donor
Structure comparison
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X = I
X = Br
X = H
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1 4a-c
- Cation backbone is effective in spite of the presence of counteranion.
(2) Anion Abstraction from Reactant
Cationic vs polyfluoro XB donor
~ -3 kcal mol-1
~ -8 kcal mol-1
Complex structure
(DFT calculation)
Br-
Br-
Iodopyridinium XB donor
Polyfluoro XB donor
Huber, S. M. et al. J. Fluor. Chem. 2013, 150, 14–20.
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Oxidation of Heterobenzyl position to C(sp2)=O or C(sp3)-O
Oxidation to C(sp2)=O
Oxidation to C(sp3)-O
Secar, G. et al. Chem. Eur. J. 10.1002/chem.201801717
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(1) Imine-enamine tautomerization
(2) XB lowers the activation energy
of electron transfer from XB
acceptor to donor.
Oxidation of Heterobenzyl position to C(sp2)=O or C(sp3)-O
Oxidation to C(sp2)=O
Plausible mechanism
(2)
(1)
Secar, G. et al. Chem. Eur. J. 10.1002/chem.201801717
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-
Oxidation of Heterobenzyl position to C(sp2)=O or C(sp3)-O
Oxidation to C(sp3)-O
Problem
Background electron transfer to form benzyl radical, then ketone.
NBS or I2 conditions
I2+TBHP conditions
Secar, G. et al. Chem. Eur. J. 10.1002/chem.201801717
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Oxidation of Heterobenzyl position to C(sp2)=O or C(sp3)-O
Iodine Acetyl hypoioditeActive species
Oxidation to C(sp3)-O
XB formation
- Activation by hydrogen bond is less likely.
Imine-enamine
tautomerization
Secar, G. et al. Chem. Eur. J. 10.1002/chem.201801717
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Strong acid:
Cannot form XB complex with acid,
I2 remains in its free form.
(acyl hypoiodite isn’t generated)
Oxidation of Heterobenzyl position to C(sp2)=O or C(sp3)-O
Oxidation to C(sp3)-O
Secar, G. et al. Chem. Eur. J. 10.1002/chem.201801717
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Oxidation of Heterobenzyl position to C(sp2)=O or C(sp3)-O
Plausible mechanism
Oxidation to C(sp3)-O
Secar, G. et al. Chem. Eur. J. 10.1002/chem.201801717
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Enantioselective Reaction Involved by XB
32
Michael/Henry reaction
Mannich reaction
up to
99% yield
98% ee
XB donor
XB donor
Arai, T. et al. Synlett 2017, 28, 122–127.
Arai, T. et al. Chem. Commun. 2018, 54, 3847–3850.
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Enantioselective Reaction Involved by XB
33
Alkylation of sulfenate anion
Chiral phase-transfer catalyst
up to
99% yield
99% ee
Kee, C. W.; Tan, C. H. et al. Angew. Chemie - Int. Ed. 2014, 53, 11849–11853.
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R : S
= 95.5 : 4.5
1.2 kcal mol-1
more stable
Plausible mechanism
Enantioselective Reaction Involved by XB
R TS
S TS
byproductsulfenate anion
Kee, C. W.; Tan, C. H. et al. Angew. Chemie - Int. Ed. 2014, 53, 11849–11853.
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FBDT-I
sp3 XB Donor
35
Fluorobissulfonylmethyl Iodide
Hydrogen transfer
FBDT-I
quinoline
73-99%
X-ray crystal structure
Mukaiyama aldol reaction
Shibata, N. et al. ACS Catal. 2018, 8, 6601−6605.
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Summary
36
• Application of XB in synthesis and organocatalysis is in
early stage and many example are before the stage of
practical application.
• XB may overcome hydrogen bond in some situations
if appropriate reaction design is done.