Dummkopf, wo hast du die
lone-pairs hingepackt? *
A survey of halogens
Peter W Kenny
* Idiot, where have you put the lone pairs? (PWK thanks
Ulrich Zachariae for essential linguistic assistance)
‘In 1839 Bouchardat, a medical writer in Paris, recounts that, when
dogs were being surreptitiously poisoned with strychnine in Paris, and
an antidote was asked for, first Guibourt recommended powdered
galls, and then Donné asked for iodine tincture, whereupon Bouchardat
himself, approving the use of iodine, said that they should use it in
potassium iodide solution.’
A.B. Prescott The Periodides, JACS, 1895, 17, 775-781.
Halogen chemistry teaser
I2(s) + I-(aq) I3
Scifinder free energy
Plot of date of first preparation for
halogen fluorides as function of atomic
number of halogen
BrF7 has been claimed in a patent; BrF, IF & IF3 appear
to be unstable with respect to disproportionation
X C-X BDE/kJmol-1
H 338 430
F 514 220
Cl 394 267
Br 318 238
I 253 240
CRC Handbook of Chemistry and Physics, 88th edition, 2007-2008
More Halogen Chemistry
Bond dissociation energies for diatomic molecules
CF3: Nitro without tears?
Three fluorine atoms can be easily accommodated on a single
tetrahedral carbon atom. Try this with oxygen or nitrogen!
Nitro (sm = 0.71; sp = 0.78); CF3 (sm = 0.43; sp = 0.54)
Bonus question: Against what sort of fire would
you not want to deploy a halon extinquisher?
Halogens in Medicinal Chemistry
Hydrophobicité, Stabilité, Electronégativité
• Tune potency & lipophilicity
– Cl most commonly used for this purpose
• Block phase 1 (oxidative) metabolism
– F most commonly used but Cl also works
• Electronegative substituent
– Tune pKa (usually of bases)
– Increase electrophilicity (e.g. CF3 ketones as serine protease
– CF3 can be placed next to heteroaromatic nitrogen without
reactivty risks associated with chloro.
Halogens, lipophilicity & hydrogen bonding
Structure logPoct/wat logPalk/wat logP 2
2.13 0 2.24 -0.11 0.14
2.27 0.14 2.46 -0.19 0.10
2.84 0.71 2.93 -0.09 0.09
2.99 0.86 3.10 -0.11 0.09
3.25 1.12 3.33 -0.08 0.09
1.56 -0.57 0.96 0.60 0.42
1.85 -0.28 1.44 0.41 0.34
0.64 -1.49 -0.48 1.12 0.62
Direct interactions Indirect interactions
Steric clash Hydrophobic Conformational
strain & entropy
A taxonomy of non-covalent interactions
Organic Fluorine Hardly Ever Accepts Hydrogen Bonds
J.D. Dunitz and R. Taylor
Chem. Eur.J. 1997, 3, 89-98
Contacts between fluorine & hydogen bond donors in
PTP-1B complex with dianionic difluorophosphonate
F to H: 3500mM
F to H: 315mM
AstraZeneca in house crystal structure; IC50 values from Kotoris
et al, JCS Perkin 1, 2000, 1271-1281
Inductive effect (electronegativity) of
fluorine feeds off concentrated of
negative charge of dianionic phosphonate:
A perfect storm?
Evidence for C-F….C=O Interactions?
Olsen et al, Angew. Chem. 2003, 42, 2507-2511
Ar Ki pKi
Phenyl 0.31 6.51
2-Fluorophenyl 0.50 6.30
3-Fluorophenyl 0.36 6.44
4-Fluorophenyl 0.06 7.24
Halogen bonding: Close contacts between carbonyl
oxygen & halogens observed in crystal structures
Lommerse et al, JACS, 1996, 118, 3108-3116
Riley & Merz, J. Phys Chem. A, 2007, 111, 1688-1694
Halogen bonding studied by QM calculations on
halobenzene-formaldehyde dimers. Complex
stability increases with atomic number of
halogen. Read this if you thought BSSE was a
particularly unpleasant form of mad cow disease.
Clark et al, J. Mol. Model., 2007, 13, 291-296
The s-hole and halogen binding. Electrostatic
potential computed on molecular surface for CF4,
CF3Cl, CF3Br & CF3I.
Lommerse et al, JACS, 1996, 118, 3108-3116
Includes InterMolecular Perturbation Theory
calculations in addition to analysis of crystal
Halogen bonding & computational chemistry
Dimethylamino group splayed inward
reflecting incipient nucleophilic
addition to carbonyl group. Halogen
chemistry indicates increased ability
to expand valence shell going down
Schweizer et al, Helv Chim Acta 61,
Partial bond formation
Is this the basis for heavy halogen interactions?
Covalency is simply a continuation of
polarisation by other means
Clausewitz on covalency
Minimised electrostatic potential (Vmin) for
halobenzenes & hydrogen bond acceptors
Vmin has been shown to be a useful predictor for hydrogen bond bascity. See Murray
& Politzer, JOC, 1991, 56, 3734-3739 and Kenny, JCS Perkin 2, 1994, 199-202
Electrostatic potential on C-X axis for
fluorobenzene, chlorobenzene & aza analogs
A view of the s-hole for 5-chloropyrimidine
See also Clark et al, J. Mol. Model., 2007, 13, 291-296
• Are VDW (or similar) radii relevant to aqueous
solvation or hydrogen bonding?
• Are halogens the problem or should we look to the
left (on the periodic table)?
• Are halogens as boring as their location in the
periodic table would suggest?
• Is anybody other than Bismarck looking for lone
• Will we ever get Ant onto facebook?
It’s the robot!
Dr Head tenders incorrect response to question:
Which ‘Lost in Space’ character is most like Ant?
The correct answer is of course Dr Zachary Smith
Hold still Gabri, and I’ll have
that ear wax out faster than
you can say ‘Vlad the
Documentary evidence that Tudor is a real medical doctor
Please come back next year to find out about the lanthanides!