Stereochemistry Constitution, conformation. , and . Absolute and relative configuration. Optical activity. Fischer- and Cahn-Ingold-Prelog-convention (CIP).

Stereochemistry: in three dimensions; the relationship of physical and chemical properties to the spatial arrangement of the atoms in a . Stereochemistry refers to chemistry in three dimensions. One consequence of a tetrahedral arrangement of bonds to carbon is that two compounds may be different because the arrangement of their atoms in space is different. Isomers that have the same constitution but differ in the spatial arrangement of their atoms are called stereoisomers. Isomer: Isomers are different compounds that have the same molecular formula. They may be either constitutional isomers or stereoisomers. OR One of a set of that have the same molecular formula, but different structure.

Constitutional isomer: (skeletal isomer; structural isomer):Constitutional isomers are isomers that differ in the order in which their atoms are connected. Stereoisomers: Stereoisomers are isomers that have the same constitution but differ in the arrangement of their atoms in space. Tautomer: Any molecule in a set of constitutional isomers that are conceptually related by the shift of a hydrogen atom and one or more p bonds. Tautomerism refers to an interconversion between two structures that differ by the placement of an atom or a group.

The keto and enol forms are constitutional isomers. Using older terminology they are referred to as tautomers of each other. Conformation: The shapes that a molecule can adopt due to rotation around one or more single bonds. OR Nonidentical representations of a molecule generated by rotation about single bonds. Conformational isomers (conformers): Isomers that have the same connectivity sequence and can be interconverted by rotation around one or more single (σ) bonds. OR Conformations of a single molecule.

conformers configurational isomers

Configuration: The three-dimensional arrangement of atoms or groups in a molecule, usually in reference to stereoisomers. Stereoisomer (configurational isomer): One molecule in a set of isomers that differ by the position of atoms in space, but are not constitutional isomers or conformational isomers. OR Isomers which have the same constitution but which differ in respect to the arrangement of their atoms in space. Stereoisomers may be either enantiomers or diastereomers. MOLECULAR CHIRALITY Everything has a mirror image, but not all things are superposable on their mirror images. Mirror-image superposability characterizes many objects we use every day. Cups and spoons, chairs and beds are all identical with their mirror images. Many other objects though—and this is the more interesting case—are not. Your left hand and your right hand, for example, are mirror images of each other but can’t be made to coincide point for point, palm to palm, knuckle to knuckle, in three dimensions.

snail

Chiral: Term describing an object that is not superposable on its mirror image. Achiral: Opposite of chiral. An achiral object is superimposable on its mirror image.

Enantiomers and Diastereomers A molecule is chiral if its two mirror-image forms are not superposable in three dimensions. The opposite of chiral is achiral. A molecule that is superposable on its mirror image is achiral. In organic chemistry, chirality most often Consider chloro-difluoromethane (ClF2CH), in occurs in molecules that contain a carbon that which two of the atoms attached to carbon is attached to four different groups. An are the same. As is evident from these example is bromochlorofluoromethane drawings, it is a simple matter to merge the (BrClFCH). two models so that all the atoms match.

Since the two mirror images of bromo- Since mirror-image representations chlorofluoromethane are not superposable, of chlorodifluoromethane are superposable BrClFCH is chiral. on each other, ClF2CH is achiral. The two mirror images of bromochlorofluoromethane have the same constitution. That is, the atoms are connected in the same order. But they differ in the arrangement of their atoms in space; they are stereoisomers. Stereoisomers that are related as an object and its nonsuperposable mirror image are classified as enantiomers. (optical isomer): One of a pair of molecules that are non-superimposable mirror images. Every chiral molecule has an enantiomer pair. Always two molecules have enantiomer relationship – enantiomer pairs. Just as an object has one, and only one, mirror image, a chiral molecule can have one, and only one, enantiomer. Enantiomers: has same distances, angles between atoms which are not connected directly same chemical and physical properties (the usual physical properties such as density, melting point, and boiling point are identical within experimental error for both enantiomers of a chiral compound. They are indistinguishable in ACHIRAL ENVIROMENT. (Important: in a CHIRAL ENVIROMENT this equality breaks off, enantiomers are distinguishable, separable, e.g. optical activity!)

Racemic mixture (racemate): Mixtures containing equal quantities of enantiomers are called racemic mixtures. (A 1:1 mixture of enantiomers.) Racemic mixtures are optically inactive. Stereoisomers that are not related as an object and its mirror image are called diastereomers; diastereomers are stereoisomers that are not enantiomers. More molecules can diastereomers not only two molecules.

All together 26 = 128 stereoisomers (configurational isomer) – from these strychnine is just 1! + 1 enantiomer + 126 diastereomers

Diastereomers: different distances, between atoms which are not connected directly different chemical and physical properties (they are distinguishable) in ACHIRAL ENVIROMENT (separable, different reactivity). Consequences: • every non conformer and non enantiomer stereoisomer is • diastereomers are not mirror images  chirality is not crucial (necessary) Example: geometric isomers: geometric isomers are a subtype of diastereomers SYMMETRY IN ACHIRAL STRUCTURES Certain structural features can sometimes help us determine by inspection whether a molecule is chiral or achiral. For example, a molecule that has a plane of symmetry or a center of symmetry is superposable on its mirror image and is achiral. A plane of symmetry bisects a molecule so that one half of the molecule is the mirror image of the other half. The achiral molecule chlorodifluoromethane, for example, has the plane of symmetry . A plane of symmetry defined by the atoms H-C-Cl divides chlorodifluoromethane into two mirror-image halves.

A point in a molecule is a center of symmetry if any line drawn from it to some element of the structure will, when extended an equal distance in the opposite direction, encounter an identical element. The cyclobutane derivative lacks a plane of symmetry, yet is achiral because it possesses a center of symmetry. (a) Structural formulas A and B are drawn as mirror images. (b) The two mirror images are superposable by rotating form B 180° about an axis passing through the center of the molecule. The center of the molecule is a center of symmetry. Any molecule with a plane of symmetry or a center of symmetry is achiral, but their absence is not sufficient for a molecule to be chiral. A molecule lacking a center of symmetry or a plane of symmetry is likely to be chiral, but the superposability test should be applied to be certain. Symmetry elements

All molecules which have a plane of symmetry (or a rotary-reflection axis, symmetry

element Sn) are achiral (and thus superimposable with their mirror images). Chiral Molecules Terms of chirality: in the molecule there IS NOT a plane of symmetry (mirror plane) or a center of symmetry  axis of symmetry IS allowed!! Groups of chiral molecules: - asymmetrical molecules (is not any symmetry elements) - disymmetric molecules with axis of symmetry

chiral achiral 1. THE STEREOGENIC CENTER

Molecules of the general type

are chiral when w, x, y, and z are different substituents. A tetrahedral carbon atom that bears four different substituents is variously referred to as a chiral center, a chiral carbon atom, an asymmetric center, or an asymmetric carbon atom. A more modern term is stereogenic center, and that is the term that we’ll use. ( is synonymous with stereogenic center.) Carbons that are part of a double bond or a triple bond can’t be stereogenic centers! Noting the presence of one (but not more than one) stereogenic center in a molecule is a simple, rapid way to determine that it is chiral. For example, C-2 is a stereogenic center in 2- butanol; it bears a hydrogen atom and methyl, ethyl, and hydroxyl groups as its four different substituents. By way of contrast, none of the carbon atoms bear four different groups in the achiral alcohol 2-propanol. A carbon atom in a ring can be a stereogenic center if it bears two different substituents and the path traced around the ring from that carbon in one direction is different from that traced in the other. The carbon atom that bears the methyl group in 1,2-epoxypropane, for example, is a stereogenic center. The sequence of groups is O-CH2 as one proceeds clockwise around the ring from that atom, but is CH2-O in the anticlockwise direction. Similarly, C-4 is a stereogenic center in limonene.

One final, very important point about stereogenic centers. Molecules that have one and only one stereogenic center are chiral molecules. Molecules with more than one stereogenic center may or may not be chiral. A molecule could have more asymmetric atoms (stereocenter): Numbers of stereoisomers ≤ 2n where n is the numbers of in the molecule (or stereogenic axis or plane) STEREOGENIC CENTERS OTHER THAN CARBON Atoms other than carbon may also be stereogenic centers. Silicon, like carbon, has a tetrahedral arrangement of bonds when it bears four substituents. A large number of organosilicon compounds in which silicon bears four different groups have been resolved into their enantiomers. Trigonal pyramidal molecules are chiral if the central atom bears three different groups. If one is to resolve substances of this type, however, the pyramidal inversion that interconverts enantiomers must be slow at room temperature. Pyramidal inversion at nitrogen is so fast that attempts to resolve chiral amines fail because of their rapid racemization.

O O a a a C Si N N N S S b b b b b e b b e d e d e d e d e d d d datív kötés! töltéses dBute!! piramidális dative bond ammoniumrendszer!ion Pyramidalinverzinversionió

Tricoordinate sulfur compounds are chiral when sulfur bears three different substituents. The rate of pyramidal inversion at sulfur is rather slow. The most common compounds in which sulfur is a stereogenic center are sulfoxides such as Chirality without asymmetric center 2. – stereogene axis Allene isomers An allene is a compound in which one carbon atom Allene is a nonplanar molecule has double bonds with each of its two adjacent carbon characterized by a linear carbon chain and centres. Allenes are classified as polyenes with cumulated two mutually perpendicular π bonds. dienes. The parent compound of allene is propadiene. Planes defined by H(C-1)H and H(C-3)H are mutually perpendicular.

The nonplanarity of allenes has an interesting stereochemical consequence. 1,3-Disubstituted allenes are chiral; they are not superposable on their mirror images. The 4 substituents at the end of the double Even an allene as simple as 2,3-pentadiene has been bonds in allene lie in planes that are obtained as separate enantiomers. oriented 90° to one another. Look at the allene (bottom line) in the following drawing. One set of substituents (R3, R4) are located in the plane of the screen; the other set of substituents (R1, R2) are located in a plane perpendicular to the screen. Allenes can generate enantiomers. Spiro compounds (hindered rotation about single bonds)

Atropisomers are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers. 3. Planar chirality – stereogene plane It describes the shape of certain chiral molecules that lack a tetrahedral stereocenter. Planar chirality may arise if an appropriately substituted planar group of atoms or ring system is bridged by a linker-chain extending into the space above or below of this plane. Common examples are the planar chirality of cyclophanes, some di- or poly-substituted or alkenes as shown below. Even (E)-cyclooctene is a planar chiral compound.

(CH2)m (CH2)m

O O CH2 CH2

X X [n]ciklofánok (n = m + 2) (E)-cyclooctene 4. Helical chirality

Helicenes are chiral as they can exist in enantiomeric left- or right-handed forms. Typical examples for helical structures are provided by the helicenes (benzologues of phenanthrene). With four or more rings, steric hindrance at both ends of these molecule prevents the formation of planar conformations, and helicenes rather adopt non-planar, but helical and enantiomeric structures with C2 symmetry. Fischer projection Stereochemistry deals with the three-dimensional arrangement of a molecule’s atoms. It is possible to convey stereochemical information in an abbreviated form using a method devised by the German chemist Emil Fischer. Fischer projections are always generated the same way: the molecule is oriented so that the vertical bonds at the stereogenic center are directed away from you and the horizontal bonds point toward you. A projection of the bonds onto the page is a cross. The stereogenic carbon lies at the center of the cross but is not explicitly shown. It is customary to orient the molecule so that the carbon chain is vertical with the lowest numbered carbon at the top as shown for the Fischer projection of (R)-2-butanol. Fischer projection A tetrahedral carbon atom is represented in a Fischer projection by two crossed lines. The horizontal lines represent bonds coming out of the page, and the vertical lines represent bonds going into the page.

Rules for projecting: Carbon chain, the ends of the carbon chain could be different in oxidation state (lower and higher oxidation states)

1. Cox− C* − Cred orientation: „North-South”  24 possibilities is reduced to 4

2. Cox on the top („North”)  4 possibilities is reduced to 2 3. A Cox− C* − Cred („North-South” axis) has to be closed to the plane of projecting 2 possibilities is reduced to 1 Manipulations of Fischer projections The chiral molecule can be drawn in many ways, it’s sometimes necessary to compare two projections to see if they represent the same or different enantiomers. To test for identity, Fischer projections can be moved around on the paper, but only two kinds of motions are allowed; moving a Fischer projection in any other way inverts its meaning. A Fischer projection can be rotated on the page by 180°, but not by 90°or 270°. Only a 180° rotation maintains the Fischer convention by keeping the same substituent groups going into and coming out of the plane. In the following Fischer projection of (R) glyceraldehyde, for example, the -H and -OH groups come out of the plane both before and after a 180°rotation.

A 90° rotation breaks the Fischer convention by exchanging the groups that go into the plane and those that come out. In the following Fischer projections of (R) glyceraldehyde, the H and OH groups come out of the plane before rotation but go into the plane after a 90°rotation. As a result, the rotated projection represents (S) glyceraldehyde. Manipulations of Fischer projections

A Fischer projection can have one group held steady while the other three rotate in either a clockwise or a counterclockwise direction. The effect is simply to rotate around a single bond, which does not change the stereochemistry. PROPERTIES OF CHIRAL MOLECULES: OPTICAL ACTIVITY The experimental facts that led van’t Hoff and Le Bel to propose that molecules having the same constitution could differ in the arrangement of their atoms in space concerned the physical property of optical activity. Optical activity is the ability of a chiral substance to rotate the plane of plane-polarized and is measured using an instrument called a polarimeter. The light used to measure optical activity has two properties: it consists of a single wavelength and it is plane-polarized. The wavelength used most often is 589 nm (called the D line), which corresponds to the yellow light produced by a sodium lamp. Except for giving off light of a single wavelength, a sodium lamp is like any other lamp in that its light is unpolarized, meaning that the plane of its electric field vector can have any orientation along the line of travel. A beam of unpolarized light is transformed to plane-polarized light by passing it through a polarizing filter, which removes all the waves except those that have their electric field vector in the same plane. This planepolarized light now passes through the sample tube containing the substance to be examined, either in the liquid phase or as a solution in a suitable solvent (usually water, ethanol, or chloroform). The sample is “optically active” if it rotates the plane of polarized light. The direction and magnitude of rotation are measured using a second polarizing filter (the “analyzer”) and cited as, the observed rotation. Optical activity Enantiomers can be differentiated in chiral environment. The normal (monochromatic) light can be transformed to plane-polarised light by Nicol prism.

Plane-polarised light can be divided to two opposite circularly polarised light: these are chiral  chiral-chiral interaction between the light and material!

A pure enantiomer differently interacts with the two light types – the plane turns (a). To be optically active, the sample must contain a chiral substance and one enantiomer must be present in excess of the other. A substance that does not rotate the plane of polarized light is said to be optically inactive. All achiral substances are optically inactive.

What causes ? The plane of polarization of a light wave undergoes a minute rotation when it encounters a chiral molecule. Enantiomeric forms of a chiral molecule cause a rotation of the plane of polarization in exactly equal amounts but in opposite directions. Mixtures containing equal quantities of enantiomers are called racemic mixtures. Racemic mixtures are optically inactive. When one enantiomer is present in excess, a net rotation of the plane of polarization is observed.

If only one enantiomer is present a sample is considered to be optically pure.

When a sample consists of a mixture of enantiomers, the effect of each enantiomer cancels out, molecule for molecule.

For example, a 50:50 mixture of two enantiomers or a will not rotate plane polarised light and is optically inactive. Optical activity When rotation is quantified using a polarimeter it is known as an observed rotation, because rotation is affected by path length (l, the distance where the light travels through a sample) and concentration (c, how much of the sample is present that will rotate the light). When these effects are eliminated a standard for comparison of all molecules is obtained, the specific rotation, [a]. a = [a] . c . l Units: a: degree, c: g/cm3 (!!), l: dm (!!) The specific rotation depends on numerous facts: (concentration, solvent) Specific rotation is a physical property of a substance. [α] = the specific rotation in degrees of specified wavelength of light and specified temperature, t = temperature of measurement, λ = wavelength of light; usually the D line from a sodium

vapour lamp (( = 589 nm)  [a]D), α = observed rotation in degrees, l = path length (length of sample tube) in decimetres (one decimetre = 10 cm), c = concentration of sample measured in grams per millilitre of solution Sign of the rotation: Dextrorotatory (d; (+)): A substance that rotates plane polarized light in a clockwise direction (right).

Levorotatory (l; (-)): A substance that rotates plane polarized light in a counterclockwise direction (left).

Note: d (dexter) and l (laevus) prefix are old indication, nowadays these are not used! ABSOLUTE AND RELATIVE CONFIGURATION The spatial arrangement of substituents at a stereogenic center is its absolute configuration. Neither the sign nor the magnitude of rotation by itself can tell us the absolute configuration of a substance. Thus, one of the following structures is (+)-2-butanol and the other is (-)-2-butanol, but without additional information we can’t tell which is which.

Although no absolute configuration was known for any substance before 1951, organic chemists had experimentally determined the configurations of thousands of compounds relative to one another (their relative configurations) through chemical interconversion. To illustrate, consider (+)-3-buten-2-ol. Hydrogenation of this compound yields (+)-2-butanol.

Since hydrogenation of the double bond does not involve any of the bonds to the stereogenic center, the spatial arrangement of substituents in (+)-3-buten-2-ol must be the same as that of the substituents in (+)-2-butanol. The fact that these two compounds have the same sign of rotation when they have the same relative configuration is established by the hydrogenation experiment; it could not have been predicted in advance of the experiment. Sometimes compounds that have the same relative configuration have optical rotations of opposite sign. For example, treatment of (-)-2-methyl-1-butanol with hydrogen bromide converts it to (-)-1-bromo-2-methylbutane.

This reaction does not involve any of the bonds to the stereogenic center, and so both the starting alcohol (-) and the product bromide (+) have the same relative configuration. When, in 1951, the absolute configuration of a salt of (+)-tartaric acid was determined, the absolute configurations of all the compounds whose configurations had been related to (+)-tartaric acid stood revealed as well. Thus, returning to the pair of 2-butanol enantiomers that introduced this section, their absolute configurations are now known to be as shown.

COO Rb H OH H OH HO H HO H COO Rb COO Na COO Na salt of (+)-tartaric acid In other words…

Determination of the absolute configuration of a molecule requires another molecule whose configuration is known. It is difficult! By chemical transformation (chemical correlation) it could not be determined. But only the enantiomer property could be established. Chemical correlation If the chemical transformation do not affect the stereocentre then the configuration of the two compound is the same!

Important! There is NOT connection between the optical rotation and configuration!

The correlation can be done for any molecule BUT the configuration of the reference compound is crucial.

The determination of the configuration of the reference compound is must be carried out with an independent method BUT the suitable methods are limited! → e.g. x-ray diffraction In other words… Anomalous X-ray scattering (in the presence of heavy atoms) With these results and by chemical correlation the absolute configuration of (+)-glycerine aldehyde could be determined. 1900 Fischer develops the first systematic method for depicting stereochemistry (Fischer projections) and a notation for designating configuration (D/L notation).

CHO CHO H OH HO H

CH2OH CH2OH D-(+)- glyceraldehyde(+) (-L)-(-)-glyceraldehyde L because the OH group is on the left hand side.

1905 Rosanoff arbitrarily assigns the configuration of the structure corresponding to (+)- glyceraldehyde as being D-glyceraldehyde. 1951 Bijvoet determines the absolute configuration of the sodium rubidium double salt of (+)- tartaric acid using anomalous dispersion X-ray crystallography.

COO Rb H OH H OH HO H HO H COO Rb COO Na COO Na Na, Rb salt of (+)-tartaric acid In other words… BY knowing the absolute configuration of one molecule using chemical correlation the configuration of compound can be determined (getting absolute configuration from relative configuration)!

Cox?? Cred?? CH2CH3 F Can the absolute configuration of all compounds be indicated as H Cl H Cl D/L? CH Cox?? Cred?? 3 Br

It suffers from serious deficiencies when trying to extend the notation to molecules with multiple chiral centres and molecules that differ structurally from these reference compounds.

Assignment of the configurational symbols D or L will not therefore automatically allow the unambiguous construction of a three- dimensional model for most molecules. → new model is necessary

Nowadays the D/L nomenclature is satisfactory used for carbohydrates and a-amino acids. The new model: CIP convention

Cahn, Ingold and Prelog introduced CIP convention, this systematic notation during the period 1951-1956. The notation allows us to define in an unambiguous manner the absolute configuration of a drawn stereogenic centre by assigning it as either (R) or (S). Correlation with an arbitrary standard is not involved.

R S

A clockwise decreasing order is assigned the (R)-configuration (cf. Latin, rectus). An anti-clockwise decreasing order defines an (S)-configuration (cf. Latin, sinister) THE CAHN–INGOLD–PRELOG R–S NOTATIONAL SYSTEM Cahn, Ingold, and Prelog first developed their ranking system to deal with the problem of the absolute configuration at a stereogenic center, and this is the system’s major application. The Table shows how the Cahn–Ingold–Prelog system, called the sequence rules, is used to specify the absolute configuration at the stereogenic center in (+)-2-butanol.

the next slide Rule 1: is that atoms of higher atomic number take precedence over those of lower atomic number. Lone pairs of electrons are assigned the lowest priority. (firts 1, second 2, etc) order of priority: I > Br > Cl > F > O > N > C > H >lone pair of electrons Rule 2: is that isotopes of higher atomic weight take precedence. order of priority: 3H (tritium) > 2H (deuterium) > 1H (hydrogen)

Rule 3: relates to molecules where two or more of the atoms directly attached to the stereogenic centre are the same. In the compounds below in which two of the atoms attached to the stereogenic central carbon are carbons. In such cases we establish the order of priority of the next atoms along the chain adhering to the ‘principle of outward exploration’. Rule 4: relates to molecules bearing unsaturated groups attached to the stereogenic central atom. In these cases we convert the p-system into a hypothetical saturated ‘equivalent’ system using ghost atoms (in parenthasis) as follows. The ghost atoms are then used to decide the priority. In this way we get: order of priority:

CO2Me > CO2H > CONH2 > COMe > CHO > CH2OH

(C) C X (X) C X (C) C X (X) C X (C) (X)

Rule 5: when the difference between substituents is in configuration then (R) takes precedence over (S), and in case of double bonds: Z > E ACHIRAL MOLECULES WITH TWO STEREOGENIC CENTERS 2,3-butanediol has two stereogenic centers that are equivalently substituted.

Only three, not four, stereoisomeric 2,3-butanediols are possible.

Fischer projections

The (2R,3R) and (2S,3S) forms are enantiomers of each other and have equal and opposite optical rotations. A third combination of stereogenic centers, (2R,3S), however, gives an achiral structure that is superposable on its (2S,3R) mirror image. Because it is achiral, this third stereoisomer is optically inactive. We call achiral molecules that have stereogenic centers meso forms.