9 Stereochemistry استریوشیمی Based on McMurry s Organic Chemistry, 7 th edition
Stereochemistry Some objects are not the same as their mirror images (technically, they have no plane of symmetry) A right-hand glove is different than a left-hand glove. The property is commonly called»دستواره» handedness Organic molecules (including many drugs) have handedness that results from substitution patterns on sp 3 hybridized carbon 1: a tendency to use one hand rather than the other 2 a: the property of an object (as a molecule) of not being identical with its mirror image : CHIRALITY b: either of the two configurations of an object that may exist in forms which are nonidentical mirror images 2
Why this Chapter? Handedness is important in organic and biochemistry Other types of stereoisomers besides cis/trans Molecular handedness makes possible specific interactions between enzymes and substrates effecting metabolism and pharmaceuticals 3
انانتیومر Examples of Enantiomers Molecules that have one carbon with 4 different substituents have a non-superimposable mirror تصویر آیینه ای انطباق ناپذیر image Enantiomers = non-superimposable mirror image stereoisomers Enantiomers have identical physical properties (except for one) Build molecular models to see this 4
کایرالیته Chirality If an object has a plane of symmetry it s the same as its mirror image A plane of symmetry divides an entire molecule into two pieces that are exact mirror images Achiral ناکایرال means that the object has a plane of symmetry Molecules that are not superimposable with their mirror images are handedness) chiral (have Hands, gloves examples of are prime chiral object They have a left and a right version Organic molecules can be Chiral or Achiral 5
مرکزهای کایرالیته Chiral Centers A point in a molecule where four different groups (or atoms) کایرالیته مرکز are attached to carbon is called a chiral center Such carbons are referred to as chirality centers, although other terms such as stereocenter فضایی,مرکز asymmetric center بی تقارن,مرکز and stereogenic center مرکز فضازا have also been used. A chiral molecule usually has at least one chiral center 6
Chiral Centers in Chiral Molecules Groups are considered different if there is any structural variation (if the groups could not be superimposed if detached, they are different) In cyclic molecules, we compare by following in each direction in a ring 7
فعال نوری 9.3 Optical Activity Light restricted to pass through a plane is plane-polarized A polarimeter measures the rotation of plane-polarized light that has passed through a solution Rotation, in degrees, is [ ] قطبیده مسطح Clockwise (+) = dextrorotatory; Anti-clockwise (-) = levorotatory چپ گردان راست گردان Plane-polarized light that passes through solutions of achiral compounds remains in that plane ([ ] = 0, optically inactive) Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active 8
چرخش نوری Measurement of Optical Rotation The more molecules of a chiral sample are present the greater the rotation of the light = concentration dependent To have a basis for comparison, define specific rotation, [ ] D forچرخش an optically active compound مخصوص Specific rotation is that observed for 1 g/ml in solution in a cell with a 10 cm path using light from sodium metal vapor (589 nm) (observed rotation in degrees) [ ] D (pathlength in dm)(concentration in g/ml) l C The specific rotation of the enantiomer is equal in magnitude, but opposite in sign (+)-lactic acid = +3.82; (-)-lactic acid = -3.82 9
9.4 Pasteur s Discovery of Enantiomers Louis Pasteur discovered that sodium ammonium salts of tartaric acid crystallize into right handed and left handed forms The solutions contain mirror image isomers, called enantiomers and they crystallized in distinctly different shapes such an event is rare A (50:50) racemic mixture مخلوط راسمیک of both crystal types dissolved together was not optically active The optical rotations of equal concentrations of these forms have opposite optical rotations Louis Pasteur Chemist 1822-1895 10
تالیدومید THALIDOMIDE One asymmetric carbon atom, exists as 2 enantiomers S-Enantiomer sedative R-Enantiomer Teratogen مسکن عامل ناقص کنندگی جنین تالیدومید به عنوان یک داروی آرامبخش در اواخر دهه 50 میالدی توسط یک شرکت داروسازی آلمانی به نام گروننتال تولید شد و به بازار آمد. از این دارو برای درمان تهوع صبحگاهی زنان باردار و مشکالت بیخوابی استفاده میشد.
Sequence Rules for Specification of Configuration قواعد ترتیب برای مشخص کردن پیکربندی A general method applies to determining the configuration at each chiral center (instead of to the whole molecule) The configuration is specified by the relative positions of all the groups with respect to each other at the chiral center The groups are ranked in an established priority sequence and compared use the same priority ranking as we did for E/Z names The relationship of the groups in priority order in space determines the label applied to the configuration, according to a rule Method Assign each group priority 1-4 according to Cahn-Ingold-Prelog Rotate the assigned molecule until the lowest priority group (4) is in the back, look at remaining 3 groups in a plane Clockwise 1-2-3 movement is designated R (from Latin for right ) Counterclockwise is designated S (from Latin word for left ) 12
Priority (Cahn-Ingold-Prelog) Rules [REVIEW CH. 6] Rule 1: Look at the atoms directly attached to the chiral carbon and assign priority based on highest atomic number Rule 2: (O > N > C > H) If decision can t be reached by ranking the first atoms in the substituents, look at the second, third, or fourth atoms until difference is found Rule 3: Multiple-bonded atoms are equivalent to the same number of single-bonded atoms 13
چپ sinister راست rectus 14
Extended Comparison RULE 2 If atomic numbers are the same, compare at next connection point at same distance Compare until something has higher atomic number Do not combine always compare 15
Dealing With Multiple Bonds: RULE 3 Substituent is drawn with connections shown and no double or triple bonds 16
هیدروکسی بوتانوییک اسید دیاسترومرها 9.6 Diastereomers Molecules with more than one chiral center have mirror image stereoisomers that are enantiomers In addition they can have stereoisomeric forms that are not mirror images, called diastereomers 1 2 3 18
Diastereomers Diastereomers are similar, but they aren t mirror images Enantiomers have opposite configurations at all chiral centers; Diastereomers are opposite at some, but not all chiral centers Diastereomers have different physical properties Epimers اپیمر are diastereomers different at only 1 chiral center 19
ترکیبات مزو 9.7 Meso Compounds Tartaric acid has two chiral centers and two diastereomeric forms One form is chiral and one is achiral, but both have two chiral centers An achiral compound with chiral centers is called a meso compound it has a plane of symmetry The two structures on the right in the figure are identical so the compound (2R, 3S) is achiral Identical substitution on both chiral centers 20
9.8 Racemic Mixtures and The تفکیک انانتیومرها Resolution of Enantiomers A 50:50 mixture of two chiral compounds that are mirror images does not rotate light called a racemic mixture (named for racemic acid that was the double salt of (+) and (-) tartaric acid The pure compounds need to be separated or resolved from the mixture (called a racemate) To separate components of a racemate (reversibly) we make a derivative of each with a chiral substance that is free of its enantiomer (resolving agent) This gives diastereomers that are separated by their differing solubility The resolving agent is then removed 21
Using an Achiral amine doesn t change the relationship of the products Still can t separate the Enantiomeric Salts 22
Using a Chiral amine changes the relationship of the products Now we can separate the Diastereomeric Salts 23
9.9 A Review of Isomerism The flowchart summarizes the types of isomers we have seen
Constitutional Isomers ایزومرهای ساختمانی Different order of connections gives different carbon backbone and/or different functional groups 25
استریوایزومرها Stereoisomers Same connections, different spatial arrangement of atoms Enantiomers (nonsuperimposable mirror images) Diastereomers (all other stereoisomers) Includes cis, trans and configurational diastereomers 26
9.10 Stereochemistry of Reactions: Addition of H 2 O to Alkenes Many reactions can produce new chiral centers from compounds without them What is the stereochemistry of the chiral product? What relative amounts of stereoisomers form? Example addition of H 2 O to 1-butene 27
Achiral Intermediate Gives Racemic Product Addition via carbocation Top and bottom are equally accessible Achiral reactant + Achiral reactant = Optically Inactive Product Optical Activity doesn t come from nowhere فعالیت نوری از ناکجاآباد نمی آید 28
Addition of H 2 O to a Chiral Alkene What is the sterochemical result of the addition of H 2 O to a chiral alkene R-4-methyl-1-hexene Product has 2 chiral centers -Chiral + Achiral = Optically Active -Chiral Intermediate has different top and bottom sides -Amounts of the two products will be different -Product will have optical activity 29
9.12 Chirality at Nitrogen, Phosphorus, and Sulfur N, P, S commonly found in organic compounds, and can have chiral centers Trivalent nitrogen is tetrahedral Does not form a chiral center since it rapidly flips Individual enantiomers cannot be isolated = Achiral 30
Also applies to phosphorus but it flips more slowly Can isolate individual enantiomers = Chiral Trivalent Sulfur Cations are also Chiral 31
پروکایرالیته 9.13 Prochirality A molecule that is achiral but that can become chiral by a single alteration is a prochiral molecule مولکولی که طی یک شیمیایی از ناکایرال به تبدیل شود پروکایرال می شود. مرحله کایرال نامیده Re and Si are used to describe the faces of the prochiral sp 2 reactant رخی که درآن پیکان خمیده در جهت عقربه ساعت می چرخد در اینجا افزایش H منجر به انانتیومر (S) شده است و اینجا انانتیومر (R) تولید شده است رخی که درآن پیکان خمیده در خالف جهت عقربه ساعت می چرخد 32
Prochiral distinctions, paired atoms or groups شود An sp 3 carbon with two groups the same is also a prochiral center The two identical groups are distinguished by considering either and seeing if it was increased in priority in comparison with the other If the center becomes R the group is pro-r and pro-s if the center becomes S اتمی که جایگزینی آن منجر به مرکز کایرالیته R اتمی که جایگزینی آن منجر به مرکز کایرالیته S شود pro-r pro-s 33
Prochiral Distinctions in Nature Biological reactions often involve making distinctions between prochiral faces or or groups Chiral entities (such as enzymes) can always make such a distinction Example: addition of water to fumarate مرحله ای از چرخه سیتریک اسید در متابولیسم غذا 34
Chirality in Nature and Chiral Environments Enantiomers have same physical properties, different biological ones Stereoisomers are readily distinguished by chiral receptors in nature Properties of drugs depend on stereochemistry Think of biological recognition as equivalent to 3-point interaction Enzymes can make only one enantiomer from an achiral reactant In the chiral environment, pro-r and pro-s are chemically different 35
Biological Molecules RULE - Enzymes are chiral reagents because their binding site is chiral