Stereochemistry of reactions

Reading

Section A

1. You are going to read the texts about Stereochemistry. Scan the texts and find the definitions of the following words:

optical activity,chiral,achiral,plane of symmetry,enantiomers,Fischer projections,diastereomers,meso compounds,racemic mixtures

When a beam of plane-polarized light is passed through a solution of certain organic molecules, the plane of polarization is rotated. Compounds that exhibit this behavior are called optically active. Optical activity is due to the asymmetric structure of the molecules themselves.

An object or molecule that is not superimposable on its mirror image is said to be chiral, meaning "handed". For example, a glove is chiral but a coffee cup is nonchiral, or achiral. A chiral molecule is one that does not contain a plane of symmetry - an imaginary plane that cuts through the molecule so that one half is a mirror image of the other half. The most common cause of chirality in organic molecules is the presence of a tetrahedral, sp³-hybridized carbon atom bonded to four different groups. Compounds that contain such chiral carbon atoms exist as a pair of non-superimposable, mirror-image stereoisomers called enantiomers. Enantiomers are identical in all physical properties except for the direction in which they rotate plane-polarized light.

The stereochemical configuration of a chiral carbon atom can be depicted using Fischer projections, in which horizontal lines (bonds) are understood to come out of the plane of the paper and vertical bonds are understood to go back into the plane of the paper. The configuration can be specified as either R (rectus) or S (sinister) by using the Cahn-Ingold-Preloe sequence rules. This is done by first assigning priorities to the four substituents on the chiral carbon atom and then orienting the molecule so that the lowest-priority group points directly back away from the viewer. We then look at the remaining three substituents and let the eye travel from the group having the highest priority to second highest to third highest. If the direction of travel is clockwise, the configuration is labeled R; if the direction of travel is counterclockwise, the configuration is labeled S.

Some molecules possess more than one chiral center. Enantiomers have opposite configuration at all chiral centers, whereas diastereomers have the same configuration in at least one center but opposite configurations at the others. Epimers are diastereomers that differ in configuration at onlyone chirality center. A compound with n chiral centers can have 2ⁿ stereoisomers.

Meso compounds contain chiral centers, but are achiral overall because they contain a plane of symmetry. Racemic mixtures, or race-mates are 50:50 mixtures of (+) and (-) enantiomers. Racemic mixtures and individual diastereomers differ from each other in their physical properties such as solubility, melting point, and boiling point.

Most reactions give chiral products. If the starting materials are optically inactive, the products must also be optically inactive—either meso or racemic. If one or both of the starting materials is optically active, however, the product will also be optically active if the original chiral center remains.

A molecule is prochiral if can be converted from achiral to chiral in a single chemical step. A prochiral sp²-hybridized atom has two faces, described as either Re or Si. An sp^3-hybridized atom is a prochirality center if, by changing one of its attached atoms, a chirality center results. The atom whose replacement leads to an R chirality center is pro-R, and the atom whose replacement leads to an S chirality center is pro-S.

2. There are some more terms dealing with stereochemistry, try to explain them:

plane-polarized light, stereochemical configuration, absolute configuration, chiral environment, chirality center, configuration, dextrorotatory, epimers, levorotatory, pro-R configuration, pro-S configuration, prochiral, prochirality center, Re face, resolution, S configuration, Siface, specific rotation.

3. Read the text again, divide it into logical parts and write possible titles for them.

4. Choose any part of the text and present it as a separate topic. Give as much information on it as possible.

5. Render the text.

Section B

1. The title of the text in this section is Chiral molecules with two stereogenic centers. What is the likely content of the article?

You are going to read a text about chiral molecules. Four paragraphs have been removed from the text. Choose from the paragraphs A-E the one which fits each gap (1-4). There is one extra paragraph which you do not need to use.

When a molecule contains two stereogenic centers, as does 2,3-dihydroxybutanoic acid, how many stereoisomers are possible?

1__________________________________________________________

The four possible combinations of these two stereogenic centers are (2R,3R) (stereoisomer I); (2S,3S)(stereoisomer II); (2R,3S)(stereoisomer III); (2S,3R) (stereoisomer IV).

Stereoisomer I is not a mirror image of III or IV, so is not an enantiomer of either one. Stereoisomers that are not related as an object and its mirror image are called diastereomers; diastereomers are stereoisomers that are not enantiomers. Thus, stereoisomer I is a diastereomer of III and a diastereomer of IV. Similarly, II is a diastereomer of III and IV.

2____________________________________________________________

Enantiomers must have equal and opposite specific rotations. Diastereomeric sub­stances can have different rotations, with respect to both sign and magnitude. The (2R,3R)and (2S,3S)enantiomers (I and II) have specific rotations that are equal in magnitude but opposite in sign. The (2R,3S)and (2S,3R)enantiomers (III and IV) likewise have specific rotations that are equal to each other but opposite in sign. The magnitudes of rotation of I and II are different, however, from those of their diastereomers III and IV.

3___________________________________________________________

Organic chemists use an informal nomenclature system based on Fischer projec­tions to distinguish between diastereomers. When the carbon chain is vertical and like substituents are on the same side of the Fischer projection, the molecule is described as the erythrodiastereomer. When alike substituents are on opposite sides of the Fischer projection, the molecule is described as the threo diastereomer.

4___________________________________________________________

The situation is the same when the two stereogenic centers are present in a ring. There are four stereoisomers I-bromo-2-chlorocyclopropanes: a pair of enantiomers in which the halogens are trans and a pair in which they are cis. The cis compounds are diastereomers of the trans.

A) In writing Fischer projections of molecules with two stereogenic centers, the mol­ecule is arranged in an eclipsedconformation for projection onto the page. Again, horizontal lines in the projection represent bonds coming toward you; vertical bonds point away.  

B) We can use straightforward reasoning to come up with the answer. The absolute config­uration at C-2may be R or S. Likewise, C-3 may have either the R or the Sconfigura­tion.  

C) Because diastereomers are not mirror images of each other, they can have quite different physical and chemical properties. For example, the (2R,3R)stereoisomer of 3-amino-2-butanol is a liquid, but the (2R,3S)diastereomer is a crystalline solid.  

D) When using Fischer projections for this purpose, however, be sure to remember what three-dimensional objects they stand for. One should not, for example, test for superpo­sition of the two chiral stereoisomers by a procedure that involves moving any part of a Fischer projection out of the plane of the paper in any step.

E) To convert a molecule with two stereogenic centers to its enantiomer, the config­uration at both centers must be changed. Reversing the configuration at only one stereo­genic center converts it to a diastereomeric structure.  

3. Build a step-by-step picture of the text using a Flow Chart. Look at Appendix 4-6 for help.

Using your Flow Chart retell the text.

5. Give any additional information on the topic.

Speaking

1. EVASIVE PARTNERS: There is an article about chiral drugs presented below. Work in pairs. Imagine thatyou are representative of the British pharmaceutical company produced thalidomide that caused over 2000 cases of seri­ous birth defects in children born to women who took it while pregnant. You are giving an interview.You area little evasive and provide one- or two-word replies to questions. Interviewer has to dig deeper in trying to find out more about the causes of the incident. Use the following exponents to get more information:

· Could you tell me more?

· Would you like to expand on that?

· Could you add to that?

· That only answers half the question.

· You’re being a little evasive here. Could you add more?

· A little more explanation would be nice.

Chiral Drug

A recent estimate places the number of prescrip­tion and over-the-counter drugs marketed throughout the world at about 2000. Approx­imately one-third of these are either naturally occur­ring substances themselves or are prepared by chemi­cal modification of natural products. Most of the drugs derived from natural sources are chiral and are almost always obtained as a single enantiomer rather than as a racemic mixture. Not so with the over 500 chiral substances represented among the more than 1300 drugs that are the products of synthetic organic chemistry. Until recently such substances were, with few exceptions, prepared, sold, and administered as racemic mixtures even though the desired "therapeutic activity resided in only one of the enantiomers. Spurred by a number of factors ranging from safety and efficacy to synthetic methodology and econom­ics, this practice is undergoing rapid change as more and more chiral synthetic drugs become available in enantiomerically pure form.

Because of the high degree of chiral recogni­tion inherent in most biological processes, it is unlikely that both enantiomers of a chiral drug will exhibit the same level, or even the same kind, of effect. At one extreme, one enantiomer has the desired effect, and the other exhibits no biologi­cal activity at all. In this case, which is relatively rare, the racemic form is simply a drug that is 50% pure and contains 50% "inert ingredients." Real cases are more complicated. For example, it is the S enantiomer that is responsible for the pain-relieving properties of ibuprofen, normally sold as a racemic mix­ture. The 50% of racemic ibuprofen that is the R enantiomer is not completely wasted, however, be­cause enzyme-catalyzed reactions in our body con­vert much of it to active (S)- ibuprofen.

A much more serious drawback to using chiral drugs as racemic mixtures is illustrated by thalidomide, briefly employed as a sedative and antinausea drug in Europe and Great Britain during the period 1959 - 1962. The desired properties are those of (R)-thalidomide. S-Thalidomide, however, has a very different spectrum of biological activity and was shown to be responsible for over 2000 cases of seri­ous birth defects in children born to women who took it while pregnant.

Basic research directed toward understanding the factors that control the stereochemistry of chem­ical reactions has led to new synthetic methods that make it practical to prepare chiral molecules in enan­tiomerically pure form. Recognizing this, most major pharmaceutical companies are examining their exist­ing drugs to see which ones are the best candidates for synthesis as single enantiomers and, when prepar­ing a new drug, design its synthesis so as to provide only the desired enantiomer. In 1992, the United States Food and Drug Administration (FDA) issued guidelines that encouraged such an approach, but left open the door for approval of new drugs as racemic mixtures when special circumstances war­rant. One incentive to developing enantiomerically pure versions of existing drugs is that the novel pro­duction methods they require may make them eligi­ble for patent protection separate from that of the original drugs. Thus the temporary monopoly posi­tion that patent law views as essential to fostering in­novation can be extended by transforming a success­ful chiral, but racemic, drug into an enantiomerically pure version.

2. Render the text from the exercise 1.

3. Write down ten questions starting with “How?” to the text above and put them to your partner. Compare your questions.

4. Find five things in the article to finish the sentence: “It reminds me of…”

5. Think of all the positive and negative sides of the information in the text above. Make a speech. Share and compare ideas with your group mates. Start your speech with “On the one hand… but on the other hand…”

Listening

1.Presentation: questions.

At the end of your presentation, you may wish to open the floor to questions – to ask if anyone has any questions about your presentation. What phrases might you use or hear?

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