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D E F I N I C E
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Halogenová vazba ( XB též X-bond )
je silná, specifická a směrová nekovalentní
interakce, při které interaguje atom halogenu s
nukleofilem (Lewisovou bazí). Halogen se v
tomto případě chová jako elektrofil (Lewisova
kyselina).
D-X .... XB donor
Lewis acid
elektrofil
( F (vdW = 0,147 nm) )
Cl (vdW = 0,175 nm)
Br (vdW = 0,185 nm)
I (vdW = 0,198 nm)
D X A
A ......... XB akceptor
Lewis base
nukleofil
N (vdW = 0,155 nm)
O (vdW = 0,152 nm)
S (vdW = 0,180 nm)
Se (vdW = 0,190 nm)
Cl, Br, I,
F-, Cl-, Br-, I-,
π-systém
Halogenová vazba mezi halogenem a dusíkem
bývává označována jako dusíková vazba
(nitrogen-halogen bond) .
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Vodíková vazba versus Halogenová vazba
The hydrogen bond is an attractive interaction between a hydrogen atom from a
molecule or a molecular fragment X–H in which X is more electronegative than H,
and an atom or a group of atoms in the same or a different molecule, in which there
is evidence of bond formation. Pure Appl. Chem., 2010, in press.
The halogen bond is an attractive interaction between a halogen atom X from a
molecule or fragment R–X in which R is a group more electronegative than X or is X
itself, and an atom or a group of atoms A in the same molecule R–X or in a different
molecule B, where there is evidence of bond formation.Phys. Chem. Chem. Phys., 2010, 12, 7736–7747.
... in which X is more electronegative than H ...
a co inverzní vodíková vazba !?!? Bδδδδ+-Hδδδδ- ····· Na+
... in which R is a group more electrone gative than X ... ????
http://www.halogenbonding.eu http://www.iupac.org/web/ins/2009-032-1-100
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A hydrogen (halogen) bond is said to exist when (1) there is evidence of
a bond, and (2) there is evidence that this bond sterically involves a
hydrogen (halogen) atom already bonded to another atom.
Pimentel and McClellan 1960
Vodíková vazba versus Halogenová vazba
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H I S T O R I E
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0
10
20
30
40
50
60
70
80
200019901980197019601950
Halogenová vazba 127
D X A
MOLECULAR COMPLEXES
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Halogenová vazba
„In this paper, we have shown how ubiquitous the occurrence of XB is.
Despite this fact, XB has received limited attention and recognition.“
P. Metrangolo, H. Neukirch, T. Pilati, G. Resnati
Acc. Chem. Res. 2005, 38, 393.
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„The ability of halogen atoms to function as general, effective, and reliable sites for
directing molecular recognition processes was completely ignored until the 1990s.“...
„Although recognized in small molecules for quite some time, the implications of
halogen bonding in biomolecular systems are only now coming to light.“
...
The current Protein Data Bank (December 2008 release) contains over 1000
structures in which the ligands are halogenated. It was found that 154 protein
structures associated with halogen-oxygen contacts satisfy the criteria, leading to a
total of 248 distinct X· · ·O interactions.
Halogen Bonding - A Novel Interaction for Rational Drug Design?
J. Med. Chem. 2009, 52, 2854–2862
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Historie halogenové vazby
1811 Cl2·····(H2O)x Davy H.: Phil. Trans. Roy. Soc. 1811, 101, 155.
1863 I2·····NH3 Guthrie F.: On the iodide of iodammonium.
J. Chem. Soc. 1863, 16, 239-244.
1896 X2·····N(CH3)3 Remsen I., Norris J.F.: The action of halogens on the
methylamines. Am. Chem. J. 1896, 18, 90-95.
1949 I2·····C6H6 Benesi H.A., Hildebrand J.H.: A Spectrophotometric
Investigation of the Interaction of Iodine with Aromatic
Hydrocarbons. J. Am. Soc. Chem. 1949, 71, 2703.
1954 Hassel O., Hvoslef J.: The Structure of Bromine
1,4-Dioxanate. Acta. Chem. Scand 1954, 8, 873.
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The Structure of Bromine 1,4-Dioxanate
Hassel, O.; Hvoslef, J.
Acta. Chem. Scand 1954, 8, 873.
Dioxant.t. = 12 °Ct.v. = 101 °C
Bromt.t. = -7 °Ct.v. = 59 °C
Dioxan-brom komplext.t. = 68 °Ct.v. = 95 °C
0,231 nm ( ve volném Br2 je to 0,228 nm )
O Br
Br Br
0,271 nm ( vdW = 0,152 + 0,185 = 0,337 nm )
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Historie halogenové vazby
1962 Hassel O., Rømming C.: Direct structural evidence for weak charge-
transfer bonds in solids containing chemically saturated molecules.
Q. Rev. Chem. Soc. 1962, 16, 1.
1968 Halogen bridge similarities to HB
Bent H.A.: Structural chemistry of donor-acceptor interactions.
Chem. Rev. 1968, 68, 587-648.
1969 Mulliken R.S., Person W.B.: Molecular complexes: a lecture and reprint
volume, Wiley-Interscience, New York, 1969.
1969 Nobel prize to Derek H. R. Barton and Odd Hassel "for their contributions
to the development of the concept of conformation and its application in
chemistry„
1970 Structural Aspects of Interatomic Charge-Transfer B onding
O. Hassel, Science 1970, 170, 497-502.
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Historie halogenové vazby
1999 Legon, Anthony C.: Prereactive complexes of dihalogens XY with Lewis
bases B in the gas phase: a systematic case for the haloge n analogue
B...XY of the hydrogen bond B...HX.
Angew. Chem., Int. Ed. 1999, 38 (18), 2687-2714.
1982 HF·····F2 anti-HB
F. A. Baiocchi, T. A. Dixon and W. Klemperer
J. Chem. Phys. 1982, 77, 1632-16.
1978 Halogen bond Dumas J.M., Peurichard H., Gomel M.J.
Chem. Res. (S), 1978, 54-57.
1976 HF·····ClF anti-HB
S. E. Novick, K. C. Janda and W. Klemperer
J. Chem. Phys. 1976, 65, 5115-5121.
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Historie halogenové vazby
2010 Zhou P., Tian F., Zou J., Shang Z.
Rediscovery of Halogen Bonds in Protein-Ligand Comp lexes.
Mini-Reviews in Medicinal Chemistry, 2010, 10, 309-314.
2004 Auffinger, P.; Hays, F. A.; Westhof, E.; Ho, P. S.
Halogen bonds in biological molecules.
Proc. Natl. Acad. Sci. USA 2004, 101, 16789-16794.
2008
Halogen Bonding in Supramolecular Chemistry
Angew. Chem. Int. Ed. 2008, 47, 6114-6127.
2008 Metrangolo, P.; Resnati, G.
Halogen Bonding: Fundamentals and Applications
Structure and Bonding 2008, 126; Springer: Berlin.
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M E CH A N I S M U S
( PODSTATA, PůVOD )
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Atomy halogen ů v molekule
2. Elektronová hustota u halogenu tvoří elipsoid rozšířený ve směru kolmém na
kovalentní vazbu, kterou je vázán (polar flattening)
= halogen je amfifilní povahy !!!a) ve směru kolmém na kovalentní vazbu je elektron donorem (Lewis base)
b) ve směru kovalentní vazby je elektron akceptorem (Lewis acid).
1. Jsou na periferii molekuly = ideální pozice pro intermolekulární interakce.
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CF3-I
electropositive crownσσσσ-hole
IIIIIIIIIIIIIIIIIIIIIII
IIIIII
IIIIII
IIIIII
IIII
elektron-donor
kontakt s elektrofilem
90°– 120°
elektron-akceptor
kontakt s nukleofilem
160°– 180°
Halogenová vazba ( XB )
elektrostatická interakce
electroneutral „ring“
electronegative„belt“
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Červené body odpovídají krystalům jodofluorouhlovodíkům.
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Atomy halogen ů v molekule
J. Mol. Model. 2007, 13, 291.
CF3-F CF3-Cl
CF3-Br CF3-I
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Auffinger, P.; Hays, F. A.; Westhof, E.; Ho, P. S.
Halogen bonds in biological molecules.Proc. Natl. Acad. Sci. USA 2004, 101, 16789-16794.
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Donor halo genové vazb y
I > Br > Cl ( > F )
CF3CF2–I > CH3CH2–I
( F2 > R–F ) není potvrzeno
≡C(sp )-X > =C(sp2 )-X > -C(sp3 )-X
Akce ptor halo genové vazb y
anion > neutrální molekula
Halogenová vazba
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E N E R G E T I K A
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5 kJ.mol -1 ( 1 kcal.mol-1 ) až 200 kJ.mol -1 ( 43 kcal.mol-1 )
R—Cl Cl—
R
........I2 I-........ = I3-
Vodíková vazba versus Halogenová vazba
! V mnoha p řípadech m ůže být vazba halogenová siln ější než vodíková !
5 kJ.mol -1 ( 1 kcal.mol-1 ) až 167 kJ.mol -1 ( 40 kcal.mol-1 )
HF F-........ = HF2-
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I N T E R M O L E C U L A R I N T E R A C T I O N S
5 až 200 kJ/mol Halogenová vazb a
0 až 167 kJ/mol Vodíková vazba
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Vodíková vazba versus Halogenová vazba
1. Ze studie pomocí infračervené spektroskopie vyplývá, že fluorované
uhlovodíky obsahující vyšší halogeny mohou rušit vodíkové vazby N-H....N, O-H....O, S-H....S, N-H....O=C a pravděpodobně dalších
typů.
2. Perfluorované uhlovodíky nemají žádný vliv na vodíkové vazby.3. Perfluoralkylchloridy (Rf-Cl) mají pouze slabý vliv.
4. Fluorované uhlovodíky obsahující Br či I mají silný vliv ( I > Br > Cl )
5. Pokud flurované alkylchloridy či alkylbromidy obsahují vodík je jejich vliv větší, např.: CF3-CHCl2 > CF3-CCl3
6. Je zde přímý vztah mezi schopností rušit vodíkovou vazbu a
anestetickou účinností látky.
===> Halogenová vazba je často siln ější než vazba vodíková !!!
On the Hydrogen Bond Breaking Ability of Fluorocarbons Containing Higher HalogensT. Di Paolo, C. Sandorfy, Can. J. Chem. 1974, 52, 3612.
Fluorocarbons Anesthetics Break Hydrogen BondsT. Di Paolo, C. Sandorfy, Nature 1974, 252, 471.
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Halogenová vazba v roztoku
Chemical Physics 2010, 374, 30-36.
CF3-I·····NMe3 v xenonu při -100 °C (173 K)
∆∆∆∆H°exp = -28,7 kJ/mol
∆∆∆∆H°vyp = -39,3 (g) / -31,9 (l) kJ/mol
CF3-Br·····NMe3 v kryptonu při -150 °C (123 K)
∆∆∆∆H°exp = -18,3 kJ/mol
∆∆∆∆H°vyp = -27,1 (g) / -18,6 (l) kJ/mol
CF3-Cl·····NMe3 v argonu při -177 °C (96 K)
∆∆∆∆H°exp = -8,9 kJ/mol
∆∆∆∆H°vyp = -15,6 (g) / -7,0 (l) kJ/mol
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Halogenová vazba v roztoku
Chemical Physics 2010, 374, 30-36.
MP2/6-311++G(d,p) + LanL2DZ*
Cs C3v
Van’t Hoff plots
CF3-I·····NMe3∆∆∆∆H°exp = -28,7 kJ/mol v xenonu (ca. -100 °C)
∆∆∆∆H°exp = -25(3) kJ/mol v benzenu (ca. 25 °C)
∆∆∆∆H°exp ( CF3-H·····NMe3 ) = -14,6 kJ/mol
∆∆∆∆H°exp ( CF3-Br·····NMe3 ) = -18,3 kJ/mol4,3 kJ/mol
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Halogenová vazba v roztoku
ChemPhysChem 2009, 10 (12), 2105-2115.
CF3-Cl·····OMe2
∆H°exp = -6,8 kJ/mol+2,1
CF3-Cl·····NMe3
∆H°exp = -8,9 kJ/mol
CF3-Br·····OMe2
∆H°exp = -10,2 kJ/mol+8,1
CF3-Br·····NMe3
∆H°exp = -18,3 kJ/mol
CF3-I·····OMe2
∆H°exp = -15,5 kJ/mol+13,2
CF3-I·····NMe3
∆H°exp = -28,7 kJ/mol
∆H°exp = -17,8 kJ/mol
komplex 1:2
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J. Phys. Chem. A 2009, 113, 14052–14059
I(2) CARS = noisy light coherent anti-Stokes Raman scattering
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G E O M E T R I E
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Vodíková vazba HB versus Halogenová vazba XB
D X A
160 - 180°
! Směrovost halogenové vazby je v ětší než v p řípadě vodíkové vazby !
D H A
110 - 180°
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V Ý Z N A M
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J Ó D
Z halogenů má nejvyšší polarizabilitu – nejlepší donor XB
� Nejobvyklejší halogenová vazba mezi biologickými molekulami.
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Hormony štítné žlázy
O
I
OH
I
I
IOH
O
NH2O
NH2
OH
O
I
I
I
OH
THYROXIN ( T4 ) TRIJODTHYRONIN ( T3 )
Zvyšují metabolický obrat, stimulují energetický metabolismus, zvyšují počet receptorů pro katecholaminy v srdečním svalu, zrychlují reflexní odpověď, mohou urychlovat zpětnou resorbci kostní tkáně, způsobují snížení hladiny cholesterolu v krvi, zřejmě také mají blíže neurčenou úlohu při hibernaci. Působí na všechny tkáněkromě mozku, sleziny a varlat, které pro hormony štítné žlázy nemají receptory. Jsou důležitým diferenciačním faktorem během nitroděložního vývoje a krátce po narození, působí zvláště na vývoj mozku.
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B R Ó M
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Human aldose reductase -inhibitor complexProteins: Structure, Function, and Bioinformatics2004, 55 (4), 792-804.
2.98 ÅvdW(O) + vdW(Br) =1,52 + 1,85 = 3,37 Å
vodík OH skupiny je současněvázán ke karbonylu Thr113
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Halogen bonds as orthogonal molecular interactions to h ydrogen bondsA. R. Voth, P. Khuu, K. Oishi, P. S. Ho, Nature Chemistry 2009, 1, 74.
Br
½ vdW
2.8 Å
AccessibleAccessible surfacesurface( ( probeprobe 2.2 2.2 ÅÅ ))
Halogenové a vodíkové vazby sdílející stejný kyslík
karbonylu jsou na sebe kolmé a energeticky nezávislé. Tento ortogonální vztah je důsledkem rovinného a
mimorovinného elektronegativního potenciálu kyslíku,
které jsou rozdílně zahrnuty do vodíkové a halogenovévazby.
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CH L Ó R
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Halotan (CF3-CHClBr)
Byl dlouhodobě nejrozšířenějším prchavým anestetikem, které se v současné
době pro své nežádoucí účinky již dále nevyrábí. Byl syntetizován v roce 1951
a od roku 1955 je klinicky používán. Nedráždí dýchací cesty a snižuje jejich
sekreci, poměrně příjemně voní a má bronchodilatační účinky. Snižuje srdeční
frekvenci a sílu stahu. Způsobuje žilní a mírné tepenné rozšíření průsvitu.
Výsledkem je pokles krevního tlaku. Po opakovaném podání byla popsána
poškození jater (profesionální poškození samotných anesteziologů).
Enfluran (CHF2-CFCl-O-CF2H)
Isofluran (CF3-CHCl-O-CF2H)
INHALAČNÍ ANESTATIKA
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The XWH bridge can be regardedas one hydrogen bond in a water-mediated hydrogenbond bridge to be replaced by a halogen bond. Preliminaryanalysis revealed that the XWH bridges are more thermodynamicallystable than other water-involvedinteractions, andthis stability is further enhanced by the cooperation of thehalogen bond with hydrogen bond. Structure survey demonstratedthat this putative interaction indeedexists in biologicalenvironment and can serve as localstabilizer, chainbinder, and ligand assistor to stabilizethe advanced structuresof proteins and nucleic acids, and to mediate their interactionswith small ligands.
Halogen-water-hydrogen bridges in biomolecules.J. Struct. Biol., 2010, 169, 172-182.
Geometric characteristics and energy landscapes of halogen-water-hydrogen bridges at protein-ligand interfaces.Chem. Phys. Lett. 2010, 485, 348-353.
Halogen-water-hydrogen bridge (XWH bridge)
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J. Phys. Chem. C, 2012, 116 (6), pp 4217–4223, DOI: 10.1021/jp211503x
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Fluorine bonding
A Medicinal Chemist’s Guide to Molecular InteractionsBissantz C., Kuhn B., Stahl M.: J. Med. Chem. 2010, 53, 5061-5084.
Fluorine bonding — how does it work in protein-ligand inter actions?Zhou P., Zou J., Tian F., Shang Z.: J. Chem. Inf. Model. 2009, 49, 2344-2355.
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Zhou, P.; Zou, J.; Tian, F.; Shang, Z. J. Chem. Inf. Model. 2009, 49, 2344-2355.
Fluorine bonding
PDB databáze
655 komplexů proteinu s fluorovaným
substrátem
2966 kontaktůkratších než suma rvdW
2476 kovalentníchC-F vazeb
~70% alkyl-fluoridů~30% aryl-fluoridů