Stereoismerism Jeannecrassou

Home , Axial chirality, Chirality (chemistry), Inherent chirality, Planar chirality

CHIRASKOOL

Jeanne Crassous

Phosphore et Matériaux Moléculaires http://pmm.univ-rennes1.fr/

Institut des Sciences Chimiques de Rennes UMR CNRS 6226 Université Rennes1, Av. du Général Leclerc 35042 C Rennes Cedex, France, H I [email protected] R A F U N Historical aspects and properties of enantiomers Definitions Symmetry aspects Symmetry point groups for achiral molecules Symmetry point groups for chiral molecules Molecules with stereogenic centers Asymmetric carbon, chiral amines, sulfoxides, phosphines, … Half-sandwich complexes, metallocenes Tetrahedral or spiro-type complexes Octahedral Complexes Molecules displaying axial chirality Examples of allenes Atropoisomerism and axial chirality Planar chirality Inherent chirality Helicenes, fullerenes Trefoil knots and topological chirality Selected examples: stereochemistry of helicene derivatives

Some (simplified) history…

Bartholin (1669) birefringence Iceland Spar – Spath d’Islande (CaCO3) Malus (1808) Polarization of light

Direction of propagation

Wave seen Polarization plane by the observer Abbey Haüy (1809) modern crystallography, hemihedry Mitscherlich (1819) polymorphism

Arago (1811) Herschel (1820)

Hemihedral crystals of quartz They ‘turn the light’ : they have a rotatory power The Biot’s polarimeter (1815)

Solutions of camphor, glucose, tartaric acid They ‘turn the light’ : they have a rotatory power (optical rotation)

Camphor tree Grapes (tartaric acid) The tartrates by Pasteur (1848)

1820 Kessler (Alsacian chemist) Synthesis of a mysterious acid after refining the potassium acid tartrate from vinification

Was named paratartaric acid or racemic (Gay-Lussac 1828)

Berzelius : same composition as tartaric acid but different crystals (isomerim)

Mitscherlich (1844) : the crystals of double salts of sodium and ammonium of tartaric acid and of racemic acid are identical!

Biot ‘s polarimeter: optical rotation was zero

The tartrates by Pasteur (1848) 168 years ago!

Tartrate In alcohol

1848 Pasteur : hemihedral crystals (microscope)

Louis PASTEUR 1822-1895

First spontaneous resolution !

Pictures given by Dr. Thierry RUCHON (CEA) Tartrate Tartrate ‘Left’ ‘right’ Tartrate solutions

They ‘turn the light’ : they have an optical rotation Solutions of racemic tartrate

Optical rotation: zero

Link between crystal and substance (molecule)!

Le Bel and van’t Hoff (1874) Theory of the asymmetric carbon

Joseph Achille LE BEL (1847-1930) Jacobus Henricus VAN’T HOFF (1852-1911) « Sur les relations qui existent entre les formules atomiques des corps organiques et le pouvoir rotatoire de leur dissolution » « La chimie dans l’espace »

First Nobel prize in chemistry (1901) There exist two products corresponding to a tetrasubstituted methane

H C F Br Lord Kelvin (Sir William Thompson) Baltimore Lectures, 1884 I call any geometrical figure, or group of points, chiral, and say that it has chirality, if its image in a plane mirror, ideally realized, cannot be brought to coincide with itself. « J’appelle chiral toute figure géométrique ou tout ensemble de points qui n’est pas superposable à son image dans un miroir. Je parle alors de chiralité ».

Laurence Barron (1980’s) A more recent physical definition: True and False chirality True chirality is shown by systems existing in two distinct enantiomeric states that are interconverted by space inversion, but not by time reversal combined with any proper spatial rotation. Pointing the role of time reversal symmetry in optical activity and pointed out that time-even pseudoscalar observables are the hallmark of genuine chirality. Circularly polarized light: true chiral influence B.k: true chiral influence Only B: cannot induce an enantiomeric excess Absolute asymmetric synthesis under physical fields: facts and fictions. Chem. Rev. 98, 2391-2404. « L’univers est dissymétrique »

Pasteur (1883) Louis PASTEUR 1822-1895

« Me demanderez-vous : quelles sont les forces dissymétriques qui président à l’élaboration des principes immédiats naturels? … les forces cosmiques dissymétriques…. Un des liens entre la vie à la surface de la terre et le cosmos…. » Recent results Photon energy-Controlled Symmetry Breaking with Circularly Polarized Light

L. Nahon (GDR), U. Meierhenrich, Angew. Chem. 2014, 53, 210 (See also Bonner, Kagan, Nicoud,….)

Synchrotron wavelength at 200 nm CPL light on an amorphous film Alanine with ee up to 4.2 % A. Fresnel (1817) Circular birefringence

A. Cotton (1895) Circular Dichroism (Cotton effect), then Magnetic CD

Chirality, magnetism and light, L. D. Barron, Nature 2000, 405, 895 Magneto-optical properties of chiral systems Breaking of parity symmetry by chirality leads to optical activity. Breaking of time reversal symmetry by a magnetic field leads to the Faraday effect. Breaking both symmetries leads to an additional new effect: magnetochiral anisotropy. Dielectric constant for CPL: DL/ DL/ DL/ ( ,,)()k B     () k ()B  () k B - dependent on relative orientation of light and field Luminescence of Eu(D/L)tfc - independent of polarization 3 DL L-tfcL - enantioselective:    1,0

0,5

)

II()()B k  B  k 3 g  - II()()B k  B  k 0,0 g (10 0,0

-0,5 )

- Rikken, Raupach,

g (10 -1,0 -0,3 Nature 1997, 390, 493 D-tfcD 0,0 0,5 B (T) N. Avarvari, C. Train (GDR) 590 600 610 620  (nm) Tastes and odors

H2NCOCH2 CO2H H2NCOCH2 CO2H asparagine H2N H H NH2

S amère R sucrée

O O carvone

S odeur de cumin R odeur de menthe verte

limonène

R odeur d'orange S odeur de citron Mint candies

Eight different forms (left and right-handed)

refreshing

R R ( ) (+ ) ( + ) ( + ) R - R O H O H O H O H R S

n é o i s o m e n t h o l m e n t h o l n é o m e n t h o l i s o m e n t h o l

O H O H O H O H (- ) (+ ) ( -) (- )

Different physical properties between racemates and enantiomers see teaching course 2 (Laure Guy) What about natural and medicinal compounds? Different properties of enantiomers

O O O O H NH HN N OH N * O O N Quinquina H3CO H H O O N R-(+)-thalidomide S-(–)-thalidoqmuiidneine anti-vomitif tératogène

O O O OH OH OHO NH HN H H ON * O O O N NHiPr NHiPr H HO O O NCH3 R-(+)-thalidomide S-(–)-thalidomide S-propanolol : -bloquant R-propanolol : contraceptif anti-vomitif térHatOogène Anti-vomitive teratogen morphine OH OH H H HCO2H HO2C H O O NMHeiPr MeNHiPr

MeO OMe

S naproxeneS naSp-rporxoèpna:e nanti o: laonl t:-i iinflamatoryn-fblalomqmuaantotire RRR-p nrnaproxeneoapparonxoèlonle : :c oinna:t crinactiveaticf eptif Different pharmacodynamics and pharmacokinetics of enantiomeric pharmaceuticals HO CO H H 2 HO H CO2H CO2H HO2C H NH H NH Me 2 Me 2 HO HO MeO OMe L-DOPA : anti-Parkinson D-DOPA : maladies oculaires S naproxène : antiinflammatoire R naproxène : inactif

HO CO2H HO CO2H

H NH2 H NH2 HO HO

L-DOPA : anti-Parkinson D-DOPA : maladies oculaires « L’univers est dissymétrique »

Pasteur (1883) Louis PASTEUR 1822-1895

« J’ai fait vivre des petites graines de penicillium glaucum, de cette moisissure qu’on trouve partout, à la surface de cendres et d’acide paratartrique, et j’ai vu l’acide tartrique gauche apparaître. »

The firt enzymatic resolution!

“Most natural organic products, the essential products of life, are asymmetric and possess such asymmetry that they are not superimposable on their images.” Why? The Universe is dissymmetric

The 20 amino-acids essential for life are L

All natural sugars are D

What is its origin?

Extraterrestrial life CPL in space (Orion) Parity violation (matter is intrinsically chiral)

DNA Parity : a broken symmetry

P Parity operation : (x, y, z) (-x, -y, -z)

1956 1957 Lee and Yang Wu et al.

Prediction of Parity First experimental violation in weak observation interaction in -decay of cobalt 60

Chen Ning Yang Tsung-Dao Lee Chien-Shiung Wu (Nobel prize in Physics 1957) Wu experiment on beta decay of Cobalt-60.

1957 : Wu et al. – First experimental observation in -decay of cobalt 60.

Beta emission is preferentially in the direction opposite to the nuclear spin … Wu 1957

1974 : M.-A and C. Bouchiat – PV effects in highly forbidden transitions in cesium

1979 : Barkov and Zolotorev Optical rotation in heavy metals vapors (Bi,Cs,Pb)

What about molecules? Parity violation (PV) in molecules: a fundamental effect

The broken mirror

Comes from the weak nuclear interaction

(one of the four fundamental forces: electromagnetic, gravitational, weak and strong nuclear forces):

R S Interaction between elementary particles

DEPV = 2EPV -17 A fundamental effect DEPV c.a. 10 kT

Provoques a spatial symmetry breaking A big challenge to measure it! between the right and the left-handed molecules PV measurements by highly-accurate IR spectroscopy

C. Chardonnet, C. Daussy, A. Amy-Klein, C. Bordé, B. Darquié… Laboratoire de Physique des Lasers, Villetaneuse, Villetaneuse Chardonnet et al., Phys. Rev. Lett. 1999, 83, 1554 Review: Simultanous measurement of transition frequencies Crassous et al., Org. Biomol . Chem. 2005, 3, 2218 In the two enantiomers of CHFClBr

The broken mirror Due to parity violation two enantiomers do not have the same absorption spectrum F F Letokhov, Phys. Lett. 1975, 53A, 275 C H H C Cl Br Br Cl R S

DEPV D n -17 DEPV c.a. 10 kT

nv4 4= 1 1 Proposition to search for PV effect h n ultrastable (R ) in CHFClBr spectrum h n ( S ) CO2 laser Kompanents et al., Opt. Commun. 1976, 19, 414

nv4 4= 0 0

E C–F Upper limit : 10 Hz (~ 1000 cm-1) New molecules for PV measurements Theoretical calculations of PV effects : 5 EPV  Z relativistic calculations Pr Schwerdtfeger, Aukland (New Zealand) T. Saue, R. Bast, Université Paul Sabatier, Toulouse (France) Z: atomic numberF F F F C H Os Re F FC H PH CH Cl Cl Os 3 O 3 C H Br C H I Cl PH Re Os3 Cl CH3 Cl Cl C H Cl C H Cl PH O Re Br I Cl 3 CH3 DCnPl NC = B1.r7 mHz DCnPl NC = 2I 4 mHz Cl Cl OCl Cl Cl DnPNC f=o r1 C.7– mF Hstzretching DnPNC f=o r2 C4 –mFH sztretching Cl for C–FD nsPtrNeCtc =h i1n.g7 mHz for C–FD nstPrNeCtc =h i2n4g mHz Cl for C–F stretching for C–F stretching DnPNC = 1,30 Hz DnPNC = 1,09 Hz P. Schwerdtfeger, T. Saue, et al., Phys. Rev. A 2005, 71, 012103D nPNCfo =r 1O,3s=0C H sztretching DnPNC f o=r 1R,0e9= OH zstretching for Os=CDn sPtaNretC t9 c=0h 1in, 3cgm0 -H1 z for Re=DOn PsaNtrtCe 9 t=c8 h19i ,nc0gm9 -H1 z P. Schwerdtfeger, R. Bast J. Am. Chem. Soc. 2004, 126, 1652 at f9o0r 1O scm=C-1 stretching at f9o8r 9R cem=O-1 stretching -1 -1 Largeat PV901 values cm at 989 cm Intense Re=O stretching band accessible to the Chiral oxo-rhenium complexes CO2 laser O O CH3 CH3 Re S SPh PhS Re S S S S S S Re Re O O S O O C A Se méthyltrioxorhénium IR: n Re=O : DnPV(calc) = 0.1-1 Hz MTO Inorg. Chem. 2006, 45, 10230 Laure Guy, J. Crassous, B. Darquié et al. (GDR) Chem. Comm. 2009, 4841 Phys. Chem. Chem. Phys. 2013, 15, 10952 Chirality: an economic reality!!!

enantiopure racemic achiral From: Chiral drugs

Other markets: agricultural chemicals, electronic chemicals, flavors and fragrances Commercial patenting Anti-inflammatory H C CH H C CH 3 3 3 3 CH CH Racemic drug CH2 CH2 -Invention, development, patents, Clinical studies, market - 5 years exclusivity (USA) H CO H HO2C H 2 CH3 - Side effects CH3 - Expiration of patents R-Ibuprofène S-Ibuproféne

« Chiral Swich »

Pure enantiomer (+)

- Selected patent - Better therapeutic properties - Similar indications - 3 years exclusivity (USA)

Other example: Omeprazole (racemic, anti-ulcer drug) became Esomeprazole (enantiopure, AstraZeneca, Nexium®) in 2002

Definitions

Stereoisomers are isomeric molecules that have the same molecular formula and sequence of bonded atoms (constitution), but that differ only in the three-dimensional orientations of their atoms in space. In general: 2n stereoisomers

CO2H CO2H CO2H R S S (Z and E comprised) H C OH HO C H HO C H R S Relative configuration HO C H H C OH HO C H R CO H CO2H 2 CO2H (R,R)* or R*,R* : R,R and S,S naturel Absolute configuration

(+) acide tartrique (–) acide mésotartrique (R,R)-(+) and (S,S)-(-)

acide racémique (±) meso form: achiral

The two mirror images are called enantiomers from Greek ἐνάντιος (enantíos), meaning "opposite", and μέρος (méros), meaning "part")

Diastereoisomers (or diastereomers) : stereoisomers that are not enantiomers Conformers vs. stereoisomers 2D-Chirality and prochirality

Prostereoisomerism in cis and trans-but-2-ene

2D-achiral 2D-chiral

Homotopic faces Enantiotopic faces Enantiotopic faces in cis-olefines

identical enantiomers 2D-Chirality and prochirality

Enantiotopic faces in carbonyles

enantiomers

Prostereogenic elements in olefines Symmetry operations

C4 1. Identity E C2 C3 C•∞

2. Rotation C (2p/n radians) O N n H H H (principal axis) H H 3. Reflexion over a mirror or a symmetry plane denoted  Higher order

C2 C3 H H H O vertical H H horizontal v' h H H v H C3

4. Symmetry inversion, denoted i. C3 H Staggered ethane, its H H i inversion point, and its H H H symmetry planes  C2  C2 d  d d d d Overall symmetry: D3d C2 5. Rotation-reflexion of order n, or improper rotation, denoted Sn (S2n)

Cn S4 Sn = Cnh = hCn

H H Unique only if n is even C If n is odd: a combination of other operations h h H H

S3 = C3h Symmetry point groups

A molecule can be classified according to its symmetry point group: all its symmetry operations that keep it unchanged (axis, plane, centre). It exists at least one fixed point that is invariant upon all the symmetry operations (point group symmetry) . Schoenflies notation is used here.

A molecule is chiral if it does not possess any improper axis Sn

NO YES Cn, Dn, I, T, O non oui

S2n

Cn n >2 

kC C C1 C2 C n S C C n n k>1 2 n i s n> 2

kC2 C2 D2 Ci Cn Th Cn h v k >1 nC 2 D Cn n h

nC2 nC2 C5 I C Dnd D nv Cn Cn nh

T C4 O C5 Ih

T C O CHIRAL ACHIRAL d 4 h Cl CH3 H H H Cl H C C Cl Cl Symmetry point groups for chiral moleculesF Br Br F CH3 Cl H Cl Cl CH H H Cl 3 1,3-dichloroallène 2,2'-dichloro-6,6'-diméthyl- C C H biphényle F F Cl Chiral molecules belong to CCl 1, CBnr ou DBnr (or C lmore rarely to T, O, I ) Cl groupe C2 groupe C groupe C1 CH3 2 1,3-dichloroallène 2,2'-dichloro-6,6'-diméthyl- biphényle C3 CH Which means point groups that have only proper rotationgroupe axesC2 3 O groupe C1 groupe C2

Cl CH3 C CH3 CH H 3 3 O H H Cl O HO MeO OMeOOMeOOMHe OMeOOMe C C H O HO CH3 F F Cl Cl Br Br Cl Cl O CH3 cyclotrivératryOlène (CTV) O O 1,3H-dOichloroallènOeMe OH 2O,2M'-edichloro-6,6'-diméthyl- O OMe groupe C3 HO biphényle H3C groupe C2 O groupe C1 groupe C2 Group C1 cyclotrivératrylène (CTV) C tri-o-thymotide (TOT) 3 O groupe C3 Cl Group C H3C groupe C3 C CCHH 3 O O O 3 33 O O O H V O 3– H H Cl C tri-o-thymotide (TOT) Group C3 O 3 N H CH3 groupe C C C Cl O 3 F Br Br F Cl DutastaOMe OM,e MartinezO O O M(GDR)e O Cl Cl CH 3– O 3 O O (C ) O HO OMe OH OMe 2 3 en tout 1,O3-Mdiechloroallène 2,2'-dichloro-6,6'-diméthyl- OMe O O HO biphényle O O OMe III O MeO O Rh groupe C OMeOMe O O OMe O groupe C cyclotrivératry2lène (CTV) groupe C O 1 Group C 2 (C ) O O 2 2 3 en tout O O groupe C3 O O O O H3C OMe MeO O OMe O III O C3 Cl CH Rh CH 3 O 3 tri-o-thymotide (TOT) O O H C3 cryptophane-A O O H H Cl CH O 3 groupe C3 groupe D3 H O C C Cl F F 3– Cl Br Br Cl Cl O cryptophane-A O groupe D3 HO CH3 OMe OMe OH OMe O 1,3-dichloroallène HO 2,2'-dichloro-6,6'-diméthyl- groupe D O OMe 3 bOipMheéOnyMlee O OO Group D3 O cyclotrivératrylène (CTV) O groupe C2 (C ) O Groupgroupe D D33 groupe C1 grGroupoupe C2 C 2 3 enCollet, tout Brotin, Dutasta (GDR) 2O Me O O groupe C3 O OMeH C MeO O 3 O RhIII C3 CH O C3 O tri-o-thymotide (TOT) O 3 O O groupe C3 CH3 O cryptophane-A O 3– O O HO OMe OH OMe groupe D3 OMe O HO OMe OMe O O OMe O O O groupe D3 cyclotrivératrylène (CTV) (C2)3 en tout O OMe O O groupe C MeO O O OMe O III 3 H3C Rh O O tri-o-thymotide (TOT) O C3 O O groupe C3 cryptophane-A O 3– O groupe D3 O OMe OMe O O OMe O groupe D O 3 (C2)3 en tout O OMe O O O OMe MeO O O RhIII O O O O O cryptophane-A O groupe D3

groupe D3 S2 Br b) a) H3C H H H

H i Cl Cl H N Cl H

groupe Cs H CH3

Br groupe Ci (= S2)

H H3C CH c) 3 e) O Symmetry point groups for achiral molecules C3 O C H 2 H O O CH 3 H O H CH3 h  Contain improper symmetry Sn, with planes et centers of symmetry h groupe S4 groupe C2h groupe C3h Examples d) C4 S2 S2 C3 Br Br b) b) Cl H Cl a) H C O F F a) 3 H3C H H C2 H H H H P S CH F F Cl H H C 3 v 3 F H H CH3 i Cl H Cl Cl Cl Cl H H N i Cl H groupe C2v N groupe C3v groupe C grouspe Cs groupe C4v CH H H 3 CH3 groupe C (= S ) f) Br Br groi upe 2Ci (= S2)

H C C Fe H3C H 2 H3C CH3 CH e) O c) c) 3 e) O groupe D2d C3 C3 groupe D O C2 H 2d groupe D O C2 H H 5d O O H O O CH3 CH3 H O H CH3 h H O  H CH h h g) 3 h Cl groupe S4 groupe C2h groupe S4 groupe C2h groupe C3h groupe C3h Cl Cl P Fe Cl Cl d) C4 d) C C4 3 groupe D3h C3 groupe D groupe D3h 5h Cl H Cl Cl H O F F Cl C2 O C P SF F 2 CH F FS MoléculesCl ChiralesH : StéréochimieH C et Propriétés.P 3 Editions du CNRS. ISBN 2-271-06329-9 v Cl 3 CH FF F  H H C CH3 3 A. Collet,v J. Crassous, J. -P. Dutasta3, L. GuyC (GDR)H , 2006 F groupe C 3 2v groupe C groupe C2v 3v groupe C3v groupe C4v groupe C4v

f) f)

Fe C C2 Fe C C2

groupe D2d groupe D2d groupe D2d groupe D5d groupe D2d groupe D5d

g) g) Cl Cl Cl Cl P Fe Cl Cl PCl Fe Cl Cl Cl groupe D3h groupe D groupe D3h 5h groupe D3h groupe D groupe D3h 5h T, O, I groups

Cubic groups that have no symmetry planes but proper axes of symmetry of different orders. Very rare

group T A barium atom substituted with 4 cyclohexanetriols

B. Morgenstern et al. Angew. Chem. Int. Ed., 2001, 40, 4179.

C3 symmetry Other examples from cubic groups : a) M. Farina, C. Morandi, Tetrahedron, 1974, 30, 1819 ; b) L. R. MacGillivray, J. L. Atwood, Angew. Chem. Int. Ed., 1999, 38, 1018 ; c) A. Rassat, Angew. Chem. Int. Ed., 2003, 42, 611. A Self‐Assembled [Fe4L4] Capsule with a T symmetry (chiral)

All D or all L

J. R. Nitschke et al., J. Am. Chem. Soc. 2012, 134, 5110 Td, Oh, Ih. Achiral molecules with more than one principal symmetry axis

Td group: principal symmetry axis of order 3 (CH4, adamantane)

Oh group: principal symmetry axis of order 4

Ih group: principal symmetry axis of order 5

Principal axis: the one with the highest n in Cn

F F F S F F F

adamantane SF6 C60

groupe Td groupe Oh groupe Ih A molecule is in general flexible and can adopt different conformations. Each conformation has its own symmetry. In average, the symmetry can be higher.

chair boat average

Cyclohexane C2 S6

v

S6 C2v D6h 1,2-Dichloroethane (–) (+) Cl Cl Cl Cl H H H H Cl H H H H H H H Cl H

g– a g+

Gaucheconform conformationation gauche Antico conformationnformation anti Gaucheconfo rconformationmation droite achirale M configurationconfiguration M Achiral P configurationconfiguration P

Ph   -36° Br

Cl Cl Blocked conformation in the solid state O H , H H Ph H F. Toda, K. Tanaka, R. Kuroda, Chem. Commun., 1997, 1227. S-(–) Molecules with stereogenic centers

Asymmetric carbon, chiral amines, sulfoxides, phosphines, … Half-sandwich complexes, metallocenes Tetrahedral or spiro-type complexes Octahedral Complexes Molecules displaying axial chirality

Examples of allenes Atropoisomerism and axial chirality

Planar chirality

Inherent chirality

Helicenes, fullerenes Trefoil knots and topological chirality

Selected examples: stereochemistry of helicene derivatives D D H R NaNO2, KBr LiAlT4 C C C H H CO2H CO2H D CT2OH NH2 Br T

Cr O 2– Molecules2 7 with stereogenic centers Cryptochiral neopentane Isotopic chirality H R C D CO2H C. G. Bochet, W. Hug, et al. Nature 2007, 446, 526 T I. Marek et al. Angew. Chem. 2015, 54, 13106 Arigoni, … R-[1H,2H,3H]acetic acid S The D/L configuration in sugars Emil Fischer (Nobel prize 1902) Molecules with stereogenic centers

Group 14 Si, Ge, Sn, Pb Si Si Ge H Ge H CH3 CH3 H H C2H5 C2H5

 = +33,4 (c 1=3,5 +33.4 ; pent=a n+ e3()3C,4 13.5,(c 13,5 ; ppentane)entane)  = +23,6 (=c 5+23.6,5 ; benz e=(n C+e2) 35.5,,6 (c 5benzene,5 ; benzene)) D D D D D

Recent examples of silicon‐stereogenic silanes

Enantiotopic X groups J. O. Bauer, C. Strohmann, Angew. Chem. Int. Ed. 2014, 53, 720

Recent reviews: R. J. P. Corriu, C. Guerin, J. J. E. Moreau, in J. O. Bauer, C. Strohmann, EurJIC, 2016, 18, 2868 The Chemistry of Organic Silicon Compounds, ed. S. Patai L.-W. Xu et al. Chem. Soc. Rev., 2011, 40, 1777 and Z. Rappoport, John Wiley & Sons, New York, 1989, pp. 305–370. Group 15 Molecules with stereogenic centers N, P, As, Sb, Bi Arsines and phosphines Configurational stability Ahlrichs et al., Theor Chim Acta 1991, 82, 271

MeO

Ph O P P O Ph P NH N(CH2CH2Cl)2 O OMe Scopulariopsis brevicaulis R n-Pr As n-Pr As OH (moisissure de pain) Me Et Et (R,R)-DIPAMP A MeO Chiral ligand for asymmetric catalysis Me Me Ph Ph . . Ph O P . . P P P O n-Pr n-Pr Ph P NH N(CH2CH2Cl)2 OMe t1/2 = 3 h 20 min in methylnaphtalene (130°C) Cyclophosphamide –1 Ea (inversion) = 125-150 kJ mol (tertiary phosphines)(R,R)-D IPAMP (antitumoralA agent)

Molecules with stereogenic centers

Group 15

Chiral amines

J. Lacour, J. -V. Naubron (GDR) et al., Angew. Chem. Int. Ed. 2011, 50, 3677

20 D a 11R d d a c b c b c b a d 5S 2,8-Dimethyl-6H,12H-5,11- CIP rules methanodibenzo[b,f][1,5]diazocine Molecules with stereogenic centers

Group 15

Chiral amines

J. Lacour, J. -V. Naubron (GDR) et al., Angew. Chem. Int. Ed. 2011, 50, 3677

20 D a 11R d d a c b c b c b a d 5S H H 2,8-Dimethyl-6H,12H-5,11- CIP rules methanodibenzo[b,f][1,5]diazocine C H C H N N (C) N C N C C H C C (C) (C) N C H a H C C C C C OMe (C) (C) b H O H C C (C) O C H C H O (C)

(O) Molecules with stereogenic centers

Group 16 Chiral sulfoxide O- - O- O O- PhMgPBhrMgBr S+ + OS-+menthyl S S+ - - O-menthyl Ph O p-tolOyl O-Ph O- Menthyl p-tolyl PhMPhMgBrgBrPhMg Br p-tolypl-tolyl + + + + S O-mSenthOyl-menthyl S S sulfinate S-(–)S-(–) Ph R-P(+h)R-(+) p-tolyl p-tolyl 25 p-tolyl p-tolyl S-(-2)5 R-(+)2 5  = -19=9 -(1c9 29 ;( ca c2é ;t oanceé)tone)  = +252 (c 2 ; acétone) D  D  = +22 (c 2 ; acétone) 25S-(–D) S-(–) R-(+D) R-(+) D = -199 (C 2, acetone) = +22 (C 2, acetone) 25 25 25 25  = -199 (c= 2- 1; 9a9c é(cto 2n e; )acétone)  = +22 (c= 2 + ; 2a2c é(cto 2n e; )acétone) D D D D NH NH S S + Me S + - NH NHMe SBF4 - O O BF4 Me Et S S Me Et + + sulfoximineMe Me S S- - sOulfoximiOne sulfosnuiulfmoniuBmF4 BF4 sulfoximine sulfoniumMe Et Me Et sulfoximsinuelfoximine sulfoniumsulfonium

Esomeprazole Transition metal complexes « chiral at metal » half-sandwich complexes

First resolution of a T4 organometallic complex

H. Brunner, Angew. Chem. Int. Ed. , 1969, 8, 382 Review: H. Brunner, Angew. Chem. Int. Ed. , 1999, 38, 1194 Chiral three-legged piano-stool

See also J. A. Gladysz et al. Organometallics 2001, 20, 3087 Resolution of diastereoisomers by crystallization Chiral rhenium complexes CIP rules for metallocenes

Configuration of chiral metallocenes at the tetrahedral metal center The Cahn, Ingold, Prelog* (CIP) system. Based on atomic numbers priority

Descriptors that describe the enantiomeric relationship (R/S, M/P, C/A, D/L, D/L), or diastereoisomerism (E/Z, cis/trans, fac/mer, threo/erythro, etc.).

5 5 h -cyclopentadiényle ligand : ligand h -C5H5 is considered as a “pseudo-atom” with atomic number equal to the sum of atomic numbers of the linked atoms, i. e. Z = 5  6 = 30

5 Therefore: I > h -C5H5 > PPh3 > NO > CO

7 6 3 Similarly: ligands h -C7H7 , h -C6H6 and h -C3H5 the respective atomic numbers are 42, 36 and 18. + - PF6 (b) (a)

Mn Mn CO (d) CO (d) (a) I (c) ON PPh3 PPh3 (c) (b) A RMn B RMn

J. Tirouflet et al. J. Organomet. Chem., 1974, 73, 67 *Prelog: Nobel 1975 See also: Eike B. Bauer, Chem. Soc. Rev., 2012, 41, 3153-3167 The C, A nomenclature

O O S

Re Re Re S SePh S SPh S SPh S S S S S S L. Guy, J. Crassous et al. Chem. Comm. 2009, 4841 SPY-5-52-C SPY-5-53-C SPY-5-14-C

3 S Se 2 S S 3 S S 1 3 4 5 O 5 O 1 S

S S S S S S 2 4 C 1 4 C 2 5 C

Clockwise Clockwise Clockwise See also: O O H. Amouri, M. Gruselle (GDR) O Re S I Re Re Chirality in Transition Metal Chemistry: S SEt S SPh-4-Br S S Molecules, Supramolecular Assemblies S S S S and Materials, SPY-5-52-C SPY-5-54-C SPY-5-53-C Wiley-VCH, 2009.

3 S I 2 S S 2 S S 1 4 3 5 O 5 O 5 O

S S S S S S 2 4 C 1 3 C 1 4 C

Clockwise Clockwise Clockwise Configurational lability 1H NMR Racemization Epimerization

M=Rh, Ir

RMn SMn

2 diastereomers, coalescence process RM ,SC and SM ,SC

RRu ,SC SRu ,SC

1 [At] by H NMR integration; lnZ=k.t, Z = ([Ao] − [A∞])/([At] − [A∞]) First order kinetics

t1/2: 25 min in CDCl3 at 12 °C t1/2: 49.5 min in toluene at 20 °C

Review: H. Brunner, Eur. J. Inorg. Chem. 2001, 905 Tetrahedral or spiro-type Cu(I) complexes

M L M D

Configurational lability, transfer of chirality from ligand to Cu

N N Cu N N

+ D-[Cu(L)2] E. R. Riesgo, A. Credi, L. de Cola, R. P. Thummel, Inorg. Chem., 1998, 37, 2145 Distorted square-planar (SP-4) complexes Phenyl-pyridine: bidentate C^N chelate ligand

5 4 6

N N Cl N1 N Cl SEt2 LiPhPy 3 + Pt 2 Pt Li Pt 1' SEt 6' Et2S Cl 2 2' 5' 3' 4' C = S > C1 > N in trans labilization Cis-arrangement Trans-effect

Chassot, L.; Müller, E.; von Zelewsky, A.Inorg. Chem.1984, 23, 4249

Cis-biscycloplatinated complex exclusively

Because the steric problem coming from two hydrogen's, the square planar metal center will have three kinds of conformation.

N N Pt N N Pt N N Pt S S

M L M D 52 Octahedral Coordination Complexes Alfred Werner’s discovery (1893)

First example of a chiral complex devoid of any carbon atoms

Alfred Werner (1866 – 1919)

Nobel prize 1913

A. Werner, Z. Anorg. Chem. 1893, 3, 267 X=Cl, Br Resolution of cation 2+ [Co(NH3)(en)2X] by crystallization of diastereoisomeric salt of (+) or (- )-3-bromocamphre-9-sulfonate (1897)

A. Werner, V. King, Ber. Dtsch. Chem. Ges. 1911, 44, 1887. I. Bernal, G. B. Kauffman, J. Chem. Ed. 1987, 64, 604. E. Meggers, Eur. J. Inorg. Chem. 2011, 2911. E. C. Constable, Chem. Soc. Rev. 2013, 42, 1637.

30 stereosiomers, all chiral, and 15 pairs of enantiomers 3+ [Co(en)3] (en = NH2CH2CH2NH2) has three bidentate ligands positioned like a three bladed propeller arrangement.

gauch e droite

Left-handed L Right-handed D

Chiral phosphorated anion Cl Cl Cl Cl Cl Cl

Cl O Cl O Cl Cl O – O O – O P P O O O Cl O O Cl O Cl Cl Cl Cl D -TRISPHAT Cl Cl D,S) -BINPHAT Cl Cl Cases with 2 types of different ligands ligands a and b

We define an isomerism cis/trans for complex M[a4b2] and an isomerism mer/fac for complex M[a3b3]

The terminology mer comes from 3 ligands a (or b) arranged alond one « meridian » (the molecule is considered spherical). Isomer fac has its three ligands on the same side. With bidentate ligands, the configuration of each stereoisomer needs two descriptors .

(a) (b) a a a a a a a b b b b a M M M M b a b a b a b a b a a b cis trans mer fac

M[a4b2] M[a3b3] (c)

a a b b b b b b a b b a M M M M a a a a a a a a b b b b fac L fac D mer L mer D

M[(a-b)3] Phosphorescent chiral cyclometallated complexes

M. E. Thompson et al., J. Am. Chem. Soc. 2003, 125, 7377

N N Ir Ir N N N N

mer-LIr mer-DIr

Idem for the fac isomer

Chiral OLEDs: J.-L. Zuo et al., Scientific Reports 2015, 5, 14912 Molecules displaying axial chirality: examples of allenes First optically active allene (1935) Point-group symmetry H C C C C C C OH d, C2, 2 C2 ee = 5% O ee = 5% D2d symmetry SO3H achiral recrystallization recristallisation

ee ee= =100%100%  , C 17 v 2 17  = +437 (benzene) 546 = +437546 (benzene) C2v symmetry achiral A natural chiral allene: a pheromone

H C (CH ) CH C symmetry 3 2 6 2 H 2 C C C chiral H CO2CH3 23 23   == – -112828 (c ( 0C, 60.6, ; he xhexane)ane)  D Cs symmetry achiral Example of a chiral cumulene t-Bu t-Bu C C C C C C1 symmetry chiral Cl

Cl Even number of = Molecules displaying axial chirality: examples of allenes

Point-group symmetry Allenophanes

d, C2, 2 C2

D2d symmetry achiral

v, C2

C2v symmetry achiral

C2 symmetry chiral



Cs symmetry achiral

Cotton effects at 253 nm C1 symmetry chiral D =790 M-1 cm-1

P. Rivera-Fuentes, F. Diederich, Angew. Chem. Int. Ed. 2012, 51, 2818 Atropoisomerism and axial chirality

We can define it as a conformational isomerism in which the conformers can be isolated . This concept is tightly linked to the conformational barrier and to the conditions in which the conformers can be isolated. A conformational barrier DG≠ around 92 kJ mol–1 at 300 K corresponds to a half-life time of 15 min. Atropoisomerism can exist around single bonds of different types : sp3–sp3, sp3–sp2, sp2–sp2. Biphenyle derivatives display such atropoisomerism (sp2–sp2). For compounds non substituted in ortho position: very low inversion barrier, below 9 kJ mol–1 in the gas phase gazeuse, with torsion angle between aromatic rigns around 45°. In the solide state: a great proportion are planar. Substituents in ortho position induces steric congestion and therefore atropoisomerism. This is the case for tri and tetra-ortho-substituted compounds.

In average X 'X X 'X

D2d symmetry achiral

Y 'Y Y 'Y

In average C2v symmetry A natural binaphtyl derivative: gossypol achiral HO CHO OHC OH OH HO C2 symmetry chiral

CH3 H3C C symmetry 1 C. Wolf, Dynamic Stereochemistry of Chiral chiral Compounds: Principles and Applications, 2008, RSC Publishing

Atropoisomerism and axial chirality

In average allene biphenyle D2d symmetry a' a' achiral b b Z1 Z2 Z2 Z1 a b' b' a In average C symmetry 2v a' a' S a' P a' achiral M R a b a a b a C symmetry 2 b' b' chiral Cl CH3 CH H 3 C1 symmetry C C C Cl chiral H Cl CH3 Atropoisomerism and axial chirality

Triptycènes Cyclotrivératrylènes 2 3 sp3–sp3 sp –sp

Brotin, Dutasta, Martinez, Châtelet (GDR)

C. Wolf, Dynamic Stereochemistry of Chiral Compounds: Principles and Applications, RSC Publishing, 2008.

Planar chirality Such type of chirality mainly concerns cyclic alkenes, cyclophanes, metallocenes. Planar chirality comes from the arrangement of groups out of a plane called chiral plane. It is linked to the rest of the molecule and imposes a steric congestion so thatH it H cannot be in a symmetry plane. The chiral plane contains a maximum of atoms. H For example, in trans-cyclooctène, the chiral plane is the one which contains the H CO2H double bond. CO2H In [2,2]paracyclophane carboxylic acid , the chiral plane is the one with the acidic function.

One can also define planar chirality in terms of prostereoisomerism. The labeling of the two enantiotopic faces of a prochiral plane makes it appear enantiomeric structures, such as in chiral chromium tricarbonyle complex.

Ferrocenes are other examples of chiral metallocenes when (for example) they display two different substituents in the same cyclopentadienyle.

CF3 p-Tol p-Tol (a) CHO (b) S O S O Cr A A CF OC CO 1) LDA, THF, -78 °C 3 CO Fe Fe SiMe B B 3 CHO Fe Fe 2) Me3SiCl CO OC CO Cr CF 3 R (R,pS) CHO 20 a= +333= +33 3(c ( c0.88, 0,88, CHClCHCl3)) 2020 D  = ±=7 5±4 754(c 1, (CcH 1,Cl 3CHCl) ) D 3 CIP rules for planar chirality

The atom of highest priority is the one that is directly bound to the chirality plane, but not a member of it, must first be found. This atom is then known as the pilot atom (P). In 4-bromo[2.2]paracyclophane, the pilot atom is the C bound to the methylene carbon atom that is located right next to the bromine atom in the aromatic ring. Aside from the pilot atom, the next three consecutive atoms of the chirality plane are labelled a, b, and c. If there is a branching, the atom of highest CIP priority is selected in each case. The configuration is called (pS) or M if the atom sequence P - a - b - c is arranged counterclockwise, while it is classified as (pR) or P if the atom sequence is arranged clockwise.

a a 2 b P b Br P 3 Br 8 c 1 4 c 7 5 6 pR or P 9 pS or M 10

For planar chirality in complexes it’s more simple and clearer to use central chirality. In compound A, the chirality is due to the two different subtituent in the Cp. The configuration of the atom of higher priority (

C(1)) is considered as a pseudo-tetrahedral center surrounded by four groups Fe (a), CCH3 (b), CH (c) et COCH3 (d). This unequivocally specifies the configuration.

CH3 (Fe) (b) CH3 C COCH3 O COCH3 (d) C(1) C (O) (c) C Fe H (Fe) Fe (a) (Fe) A 63 1R Inherent chirality (no center, no axis, no plane of chirality)

Carbo[6]helicenes Chiral fullerenes

(a)

M-(-) P-(+) f D2-C76 fC CD(-)282-( A)-C76 CD(+)282-( )-C76 (d) CO Et (b) (c) 2 t-Bu CO2Et

Trefoil knots O OR CO Et RO 2 CO2Et O OR R

M-(+) P-(-) Carbon allotropes

Footbalene or Buckminsterfullerene C60

Ih Symmetry, achiral Stereodescriptors

Schlegel diagrams

C76 ent-C76

D2 Symmetry chiral

Review on chiral fullerenes: C. Thilgen, F Diederich, Chem. Rev. 2006, 106, 5049. Theoretical calculation of circular dichroism of fullerenes Absolute configuration

Collaboration with Prof. Nobuyuki Harada, Sendai (Japon) SCF-CI-DV MO (self consistent field-configuration interaction-dipole velocity molecular orbital)

D   L  R

Crassous, Diederich et al. Angew. Chem. Int. Ed. Engl. 1998, 37, 1919. J. Chem. Soc., Perkin Trans. 2, 1998, 1719. Achiral adducts of C60

The possible [60]fullerene bis-adduct isomers and the stereodescriptors for the highlighted inherently chiral addition patterns. If both addends are identical and C2v-symmetric, the addition patterns cis-1, cis-2, e, and trans-4 are Cs-symmetric, cis-3, trans-3, and trans-2 are C2-symmetric, and trans-1 is D2h-symmetric. Trefoil knots

enantiomers diastereoisomer

G. Rapenne, C. O. Dietrich-Buchecker, J. -P. Sauvage, J. Am. Chem. Soc., 1996, 118, 10932.

Topological chirality: Impossible to interconvert two topological enantiomers by a continuous deformation (i.e. without breaking a bond)

H. L. Frisch, E. Wasserman, J. Am. Chem. Soc., 1961, 83, 3789 J.-C. Chambron, J.-P. Sauvage, et al., Chirality 1998, 10, 125 Thèse : Un nœud obtenu avec 74% de rendement

• 1989 : First knot prepared with 3% de rendement • 1997 : Cyclization by olefin metathesis

2+ PCy 2+ 3 Ph O O O Cl O O O Ru O O Cl PCy H O O 3 O O N N N N 5% mol N N N N Cu Cu Cu Cu CH2Cl2 20°C N N N N N N N N O O O O

O O 74% O O O O O O

Double helicate

G. Rapenne, C. Dietrich-Buchecker, J.P. Sauvage, Chem. Commun. 1997, 2053. Resolution of a Cu(I) trefoil knot

Diastereoselective crystallization

2+ O O O O O

O O N N N N CrCrystalsistaux 2+ N N N N O O O O O O O O O- L,L-[Cu (L) ]2+ 1/ P O O 2 2 O O O O O O O N N N N

N N N N O O 2/ Cristallisation 2+ O O O 2/ Crystallization O O O O Mother liquors O O O O O N N N N Eaux mères N N N N O 2+ O D,D-[Cu2(L) 2] O O O O O

G. Rapenne, C. Dietrich-Buchecker, J.-P. Sauvage, J. Am. Chem. Soc. 1996, 118, 10932. Chiroptical properties – Absolute configuration (X-Ray)

-1 -1 []D = 4000 °g .ml.dm

Circular dichroism Dichroïsme Circulaire

600

400

200

-200

-400

-600

300 400 500 600 700 (+)-Knot = Left-handed

C. Dietrich-Buchecker, G. Rapenne, J.-P. Sauvage, A. De Cian, J. Fischer, Chem. Eur. J. 1999, 5, 1432. Monographs

E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds, J. Wiley & Sons, 1994

V. I. Sokolov, Chirality and Optical Activity in Organometallic Compounds, Gordon and Beach Science Publishers, 1990.

A. Collet, J.Crassous, J. P. Dutasta, L. Guy Molécules Chirales : Stéréochimie et Propriétés. Editions du CNRS. EDP Sciences, 2006.

A. von Zelewsky, Stereochemistry of Coordination Compounds, J. Wiley & Sons, Chichester, 1996.

H. Amouri, M. Gruselle, Chirality in Transition Metal Chemistry: Molecules, Supramolecular Assemblies and Materials, Wiley-VCH, 2009.

C. Wolf, Dynamic Stereochemistry of Chiral Compounds: Principles and Applications, RSC Publishing, 2008.

K. Mislow, Introduction to Stereochemistry, Benjamin, NY, 1965 H. Kagan, La stéréochimie organique, Presses Universitaires de France, 1975