Halogen Bond
Applications in Organic Synthesis

Literature Seminar
2018/7/14
M1 Katsuya Maruyama
1Contents
1. Introduction
2. Property of Halogen Bond
3. Application to Organic Synthesis

21. Introduction3

Non-covalent Interactions

Non-covalentInteractions

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History of Halogen bond1814 I2-NH3, I2-amylose complex formation
1819 I2+I- -> I31883 quinoline-CHI3 adduct
18XX Br2 or Cl2-amine adduct
195X X-ray crystallographic study
1983 analysis in solution
199X F2-NH3, F2-OH2 adduct2007 concept of σ-hole was introduced
2013 halogen bond definition by IUPACpapers containing “halogen bonding” in title or abstract

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. 5

2. Property of Halogen Bond6

Halogen Bond (XB)
Features

XB donor(Lewis acid)

XB acceptor(Lewis base)-Directionality
Strength tunability
Hydrophobicity
Donor atom size

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 molecularentity and a nucleophilic region in another, or the same, molecular entity.”
Metrangolo, P.; Resnati, G. et al. Chem. Rev. 2016, 116, 2478–2601.

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σ-holeElectrostatic potential
VS,max=25.1 kcal mol-1

VS,max=51.4 kcal mol-1

VS,max=20.2 kcal mol-1

VS,min=-5.9 kcal mol-1

SCl2
σ-hole mediated interactionsgroup 14: tetrel bond
15: pnicogen bond
16: chalcogen bond
17: halogen bond

As(CN)3SiCl4
Donor atomMore polarizable
Less electronegative

More positive σ-holeMetrangolo, P.; Resnati, G. et al. Chem. Rev. 2016, 116, 2478–2601.

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Origin of σ-Hole
CF3Br : 4s24px24py24pz1

Origins of σ-holee- riche- poor

1. 4pz : half filled, localized between C and Br to form C-Br σ bond.
2. Appear along with polarization by XB acceptor.

complexation
Clark, T. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2013, 3, 13–20.

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XB StrengthElectrostatic potential of CF3X

CF4σ-hole

CF3Br

CF3Cl

CF3I

Astatine as XB donor
XB strength- Astatine can be extremely good XB donor.
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
Introduction of electron-withdrawing group

C6H5ClC6F5ClC6H5BrC6F5Br

C6H5I

C6F5I

- Introduction of EWG -> strong XB
Metrangolo, P.; Resnati, G. et al. Chem. Rev. 2016, 116, 2478–2601. 11

Unexpected Trend of XB Strength
Comparison of CY3I...Cl- (Y=F, Cl, Br, I) complex
Electrostatic potential and interaction energy
Molecular orbital

HOMO

Electrostatic potential
isolated

CF3I

CI4

In the presence of
1e- on C-I bondCl-- Charge-transfer (orbital-orbital interaction)is also important.
Huber, S. M.; Infante, I. et al. Chem. Commun. 2012, 48, 7708–7710. 12

Geometry
CSD crystal structure containing X…N halogen bond

I-N
Br-N
Cl-N

Slight elongation

80-90% of the sum of
Van der Waals radii

Metrangolo, P.; Resnati, G. et al. Chem. Rev. 2016, 116, 2478–2601. 13

Directionality
Possible factors for directionality

1. Charge transfer

2. Lone pair repulsion3. σ-hole (electrostaticinteraction)

DFT calculation (NEDA: Natural Energy Decomposition Analysis)

CF3I…Cl-linear

1e- on perpendicular side

Directionality

perpendicular

Contribution of- 1, 2 is large.
- 3 is small.

not disfavored

Huber, S. M.; Infante, I. et al. Phys. Chem. Chem. Phys. 2013, 15, 10350–10357.

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Directionality
Effect of halogen atom

Effect of distance

C6F5I-pyridine

Interaction energy

Interaction energy

C6F5X-pyridine

R: interaction
maximum- Electrostatic interaction is responsiblefor directionality.
Tsuzuki, S. et al. Chem. - A Eur. J. 2012, 18, 951–960.

3. Application toOrganic Synthesis16

XB in Organic Synthesis
Activation of substrate (catalyst, activator)

Facilitating handling of reagents or catalysts

Recovered by
precipitation

Alignment of substrate

CF3I: gas

Optical resolution

Bulfield, D.; Huber, S. M. Chem. - A Eur. J. 2016, 22, 14434–14450.

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Early Report of XB Mediated Catalysis
Reduction of quinoline by Hantzsch ester

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 (CF (CF ) I)32 7
Additive
Reaction
inhibition
Bolm, C. et al. Synlett 2008, No. 6, 900–902.

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Activation Types of XB Catalyst(1) Direct activation of reactant(2) Anion abstraction from reactant(3) Activation of another activator

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(1) Direct Activation of Reactant
Diels-Alder reaction

Huber, S. M. et al. Chem. Commun. 2014, 50, 6281–6284.

C–H halogenation of heteroarenes

Calculated TSΔG‡ (kcal mol-1)
catalyst (-) 29.5
catalyst (+) 26.5

Mechanism

Incrementof acidity

Liang, F.; Ren, B. et al. Org. Biomol. Chem. 2018, 16, 886–890.

XB20

(3) Activation of Another Activator
Dehydroxylative coupling of alcohol through Si-X bond activation

Plausible mechanism

Verification of mechanism- Anion exchange isn’t likely.

- Generation of carbocation

Takemoto, Y. et al. Org. Lett. 2015, 17, 3000–3003.

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(2) Anion Abstraction from Reactant
Ritter-type Solvolysis

Huber, S. M. et al. Angew. Chemie - Int. Ed. 2011, 50, 7187–7191.

Addition to oxocarbenium ion

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
Cationic vs polyfluoro XB donor

Structure comparison
Iodopyridinium XB donor

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.

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(2) Anion Abstraction from Reactant
Complex structure(DFT calculation)

Cationic vs polyfluoro XB donor

Polyfluoro XB donor

1Br-4a-c~ -3 kcal mol-1

Iodopyridinium XB donor

X=IX = Br
X=HBr-~ -8 kcal mol-1- Cation backbone is effective in spite of the presence of counteranion.
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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Oxidation of Heterobenzyl position to C(sp2)=O or C(sp3)-O
Oxidation to C(sp2)=OPlausible mechanism

(2)

(1)

(1) Imine-enamine tautomerization(2) XB lowers the activation energyof electron transfer from XB
acceptor to donor.

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
NBS or I2 conditions

Problem
Background electron transfer to form benzyl radical, then ketone.
I2+TBHP conditions

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Secar, G. et al. Chem. Eur. J. 10.1002/chem.201801717

Oxidation of Heterobenzyl position to C(sp2)=O or C(sp3)-OOxidation to C(sp3)-O
Active species
IodineAcetyl hypoiodite

XB formation

Imine-enamine
tautomerization- Activation by hydrogen bond is less likely.

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
Strong acid:
Cannot form XB complex with acid,I2 remains in its free form.
(acyl hypoiodite isn’t generated)

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
Plausible mechanism

Secar, G. et al. Chem. Eur. J. 10.1002/chem.201801717

31Enantioselective Reaction Involved by XB
Michael/Henry reaction

XB donor

Arai, T. et al. Synlett 2017, 28, 122–127.

Mannich reaction

XB donor

up to99% yield
98% eeArai, T. et al. Chem. Commun. 2018, 54, 3847–3850.

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Enantioselective Reaction Involved by XB
Alkylation of sulfenate anion

up to99% yield
99% eeChiral phase-transfer catalyst

Kee, C. W.; Tan, C. H. et al. Angew. Chemie - Int. Ed. 2014, 53, 11849–11853.

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Enantioselective Reaction Involved by XB
R TSPlausible mechanism
1.2 kcal mol-1
more stable

R:S= 95.5 : 4.5
S TS
byproduct

sulfenate anion

Kee, C. W.; Tan, C. H. et al. Angew. Chemie - Int. Ed. 2014, 53, 11849–11853.

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sp3 XB Donor
Fluorobissulfonylmethyl Iodide

Mukaiyama aldol reaction

Hydrogen transfer
FBDT-I73-99%

X-ray crystal structure

quinoline
FBDT-I

Shibata, N. et al. ACS Catal. 2018, 8, 6601−6605.

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Summary• Application of XB in synthesis and organocatalysis is inearly stage and many example are before the stage ofpractical application.
• XB may overcome hydrogen bond in some situations
if appropriate reaction design is done.

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