Dummkopf, wo hast du die
lone-pairs hingepackt? *
A survey of halogens
Peter W Kenny
AstraZeneca
* Idiot, where have you p...
‘In 1839 Bouchardat, a medical writer in Paris, recounts that, when
dogs were being surreptitiously poisoned with strychni...
X C-X BDE/kJmol-1
O-X BDE/kJmol-1
H 338 430
F 514 220
Cl 394 267
Br 318 238
I 253 240
CRC Handbook of Chemistry and Physic...
Halogens in Medicinal Chemistry
Hydrophobicité, Stabilité, Electronégativité
• Tune potency & lipophilicity
– Cl most comm...
Halogens, lipophilicity & hydrogen bonding
Structure logPoct/wat  logPalk/wat  logP 2
H
2.13 0 2.24 -0.11 0.14
2.27 0.1...
Direct interactions Indirect interactions
Non-classical
e.g. heavy
halogen
Electrostatic
e.g. hydrogen
bonding
Dispersion
...
Organic Fluorine Hardly Ever Accepts Hydrogen Bonds
J.D. Dunitz and R. Taylor
Chem. Eur.J. 1997, 3, 89-98
Jawohl!
Contacts between fluorine & hydogen bond donors in
PTP-1B complex with dianionic difluorophosphonate
P
F F
O
O
O
33mM
F to...
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-Fluoropheny...
Cl…O=C Br…O=C
X
O
Halogen bonding: Close contacts between carbonyl
oxygen & halogens observed in crystal structures
Lommer...
Riley & Merz, J. Phys Chem. A, 2007, 111, 1688-1694
Halogen bonding studied by QM calculations on
halobenzene-formaldehyde...
Dimethylamino group splayed inward
reflecting incipient nucleophilic
addition to carbonyl group. Halogen
chemistry indicat...
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 pre...
Electrostatic potential on C-X axis for
fluorobenzene, chlorobenzene & aza analogs
F
ArF ArCl
ArCl
r
A view of the s-hole for 5-chloropyrimidine
N
N
Cl
x
z
y
See also Clark et al, J. Mol. Model., 2007, 13, 291-296
Some questions
• Are VDW (or similar) radii relevant to aqueous
solvation or hydrogen bonding?
• Are halogens the problem ...
It’s the robot!
Dr Head tenders incorrect response to question:
Which ‘Lost in Space’ character is most like Ant?
The corr...
Hold still Gabri, and I’ll have
that ear wax out faster than
you can say ‘Vlad the
Impaler’
Documentary evidence that Tudo...
Please come back next year to find out about the lanthanides!
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A survey of halogens (2008 EuroCUP)

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Slides from my presentation at OpenEye's 2008 EuroCUP meeting. Halogen bonding has been around for a lot longer than people think.

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A survey of halogens (2008 EuroCUP)

  1. 1. Dummkopf, wo hast du die lone-pairs hingepackt? * A survey of halogens Peter W Kenny AstraZeneca * Idiot, where have you put the lone pairs? (PWK thanks Ulrich Zachariae for essential linguistic assistance)
  2. 2. ‘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 -(aq) 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
  3. 3. X C-X BDE/kJmol-1 O-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?
  4. 4. 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 inhibitors) – CF3 can be placed next to heteroaromatic nitrogen without reactivty risks associated with chloro.
  5. 5. Halogens, lipophilicity & hydrogen bonding Structure logPoct/wat  logPalk/wat  logP 2 H 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 N O O N I Br Cl F N
  6. 6. Direct interactions Indirect interactions Non-classical e.g. heavy halogen Electrostatic e.g. hydrogen bonding Dispersion forces Steric clash Hydrophobic Conformational strain & entropy Non-covalent interactions A taxonomy of non-covalent interactions
  7. 7. Organic Fluorine Hardly Ever Accepts Hydrogen Bonds J.D. Dunitz and R. Taylor Chem. Eur.J. 1997, 3, 89-98 Jawohl!
  8. 8. Contacts between fluorine & hydogen bond donors in PTP-1B complex with dianionic difluorophosphonate P F F O O O 33mM 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?
  9. 9. 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 N N N O O N Ar Nein!
  10. 10. Cl…O=C Br…O=C X O Halogen bonding: Close contacts between carbonyl oxygen & halogens observed in crystal structures Lommerse et al, JACS, 1996, 118, 3108-3116 a r a r a r
  11. 11. 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 structures Halogen bonding & computational chemistry
  12. 12. Dimethylamino group splayed inward reflecting incipient nucleophilic addition to carbonyl group. Halogen chemistry indicates increased ability to expand valence shell going down group Schweizer et al, Helv Chim Acta 61, 2783-2808 (1978) Partial bond formation Is this the basis for heavy halogen interactions?
  13. 13. Covalency is simply a continuation of polarisation by other means Clausewitz on covalency
  14. 14. 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
  15. 15. Electrostatic potential on C-X axis for fluorobenzene, chlorobenzene & aza analogs F ArF ArCl ArCl r
  16. 16. A view of the s-hole for 5-chloropyrimidine N N Cl x z y See also Clark et al, J. Mol. Model., 2007, 13, 291-296
  17. 17. Some questions • 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 pairs? • Will we ever get Ant onto facebook?
  18. 18. 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
  19. 19. Hold still Gabri, and I’ll have that ear wax out faster than you can say ‘Vlad the Impaler’ Documentary evidence that Tudor is a real medical doctor
  20. 20. Please come back next year to find out about the lanthanides!

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