The Same and Not the Same: Chirality, Topicity, and Memory of

Research: Science and Education

The Same and Not the Same: Chirality, Topicity, and Memory of Chirality1 Wolfgang H. Kramer* Department of Chemistry, Millsaps College, Jackson, MS 39210; *[email protected] Axel G. Griesbeck Department of Chemistry, University of Cologne, D-50939 Köln, Germany

Stereochemistry is an important topic in chemical education. When thinking about biologically active molecules, either naturally derived or human-made, the three-dimensional structure—the configuration—is crucial and determines the biological effect. A tragic example of this chiral discrimination is the thalidomide catastrophe; appealing examples include the difference in the taste of terpene enantiomers, such as the (R)and (S)-limonenes. A whole universe of complexity is generated by the effect of chirality2 and precise teaching of it is therefore important.3 Before entering this topic, however, it might be worthwhile to discuss the principal problem in visualization and representation of objects—the problem of perspective. A clear understanding of chemical drawing conventions is necessary for any further teaching. Humans always seek to generate pictures of three-dimensional objects in order to create a memory and to pass the experience to the next generation. In Western art, perspective drawing was introduced during the ancient Roman times, vanished partly during the Middle Ages, and was rediscovered in the Renaissance. When teaching stereochemistry, it might be worthwhile to use some classical perspective drawings in order to explain the way chemists try to depict three-dimensional objects. Perspective drawing in art is often achieved by the combination of several “drawing tricks”, such as painting far-away objects smaller, lighter, or higher (with respect to a given baseline, see Figure 1A) or by using overlaying objects of identical size to differentiate depth perception. The latter trick is directly used in Newman projections of molecules in which one center is hidden behind another center (Figure 1B).

A

When trying to explain chirality using molecular structures, carbon as a chirality center (the stereogenic center4 on carbon) is the most obvious example with which to start. The tetrahedral arrangement at a tetra-substituted carbon atom can be visualized by drawings A–C in Figure 2. The most obvious way would be to use different sizes for the four substituents (A); however, this makes drawing inconvenient and difficult to perform by hand. The wedged and dashed lines (B) as implemented in most drawing software5 are more convenient. By logic, the dashed line should become narrow when departing from us (C). Using this drawing, the structurally simplest chiral α-amino acid, alanine, is now shown in the naturally predominant S-configuration (D). The Cahn–Ingold–Prelog (CIP) rules have to be introduced in the classroom and are presupposed here (1). Chirality, as apparent in alanine, is always introduced in the classroom using the tetrahedral carbon four different substituents concept. Shortly afterwards, this property is demonstrated by macroscopic objects such as the human hand (χειρ, Greek for “hand”) that are not superimposable with their mirror images. In a more advanced step, the criterion of non-superimposability is connected with the object’s symmetry, that is, the non-existence of certain symmetry elements like an internal mirror plane or rotational mirror axis. This might create the impression that it is complicated to immediately call an object (a molecule) chiral, yet some rules help to do that: four different substituents connected to a tetrahedral center, two pairs of different objects equally connected to a molecular axis, and so on. Next step is the introduction of topicity (τοποσ, Greek for “place”). Is this concept useful already in early stages of chemical

B

O

level I: constitution

O

CH3 HO

HO

Figure 1. Perspective drawing in chemistry.

B

B Y

A

X A

Y X

A

B

Y X

A

H COOH

H 2N

C

Figure 2. Representations of stereogenic centers.

D

level III: topicity

Leu CH3

HO

HO

NH2

(S)-Val

O

O H

HO

H NH2

(S)-Abu

HO

CH3

NH2

(S)-Abu CH3

H3C O

CH3 HO

NH2

CH3

B

O

CH3

CH3

NH2

Val

O

H3C O

CH3 HO NH2

NH2

Abu

level II: configuration

CH3

(S)-Leu

H3C CH3 O H C H3 HO NH2

(S)-Val

H

CH3 H H

NH2

(S)-Leu

Scheme I. Amino acids at different levels of drawing complexity.

© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 85 No. 5 May 2008 • Journal of Chemical Education

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education? Absolutely, because it links the abstract imagination of chirality to chemical properties and to chemical reactivity. Additionally, topicity helps to introduce terms like stereo-, enantio- and diastereoselectivity. Again, amino acids are helpful in making teaching and understanding of these concepts easier as explained subsequently.

19.7 ppm

22.4 ppm

18.9 ppm O

O CH3

HO

CH3

HO

O HO

CH3

NH2

CH3 CH3

NH2 20.2 ppm

Figure 3. 13C-NMR chemical shifts of alanine, valine, and 2-methylbutyric acid.

0.83 O

O H

HO H

H3C H CH3

HO

H

H

2.09

CH3

O

H

H

HO

H NH2

2.38

homotopic

0.73

enantiotopic

diastereotopic

Figure 4. Comparison of the 1H-NMR chemical shifts of homotopic, enantiotopic, and diastereotopic protons in acetic acid, propionic acid, and leucine.7

O H

HO

homotopic

H

O

O H

HO

H

H

H

HO D

D

H

identical

O

O CH3

HO

enantiotopic

H pro-(R)

H

H3C H O

H

pro-(S) CH3

H NH2

D

D

H

enantiomers

H

HO

(R) CH 3

HO

pro-(S)

pro-(R)

diastereotopic

HO

O (S) CH 3

H3C H O

(S)

H

HO

H NH2

D3C H

CD3

O

(R)

CH3 H

HO

H NH2

diastereomers

Scheme II. Homotopic, enantiotopic, and diastereotopic groups.

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Chirality, Topicity, Memory: A Pedagogical Approach Using Natural Amino Acids Structures and Definitions Discussing stereochemical structures (“stereostructures”) using the pool of naturally occurring amino acids achieves two goals. This is shown in Scheme I: three simple amino acids are depicted, one of them is non-proteinogenic6 (2-amino butyric acid, Abu) and two are proteinogenic, valine (Val) and leucine (Leu). In level I, only the constitution is drawn, and the difference in alkyl chain lengths and chain branching can be discussed. In level II, the three molecules are shown in their (S)-configuration, the absolute stereostructures predominant in nature. In level III, more details are shown with respect to groups that appear to be “the same” at first glance. The two hydrogens in the β-position to the carboxylic group in Abu and the two methyl groups in the β-position to the carboxylic acid group in Val are examples that demonstrate this quality. (The two methyl groups differing in chemical behavior can be shown by an intermolecular CH-activation reaction, which leads to a discussion of photochemistry, below.) In the three example molecules discussed, it appears to be simple to make the hydrogens and methyls different by connecting them with different lines (wedged and dashed) to carbons, however does this sufficiently indicate that they really are different? And what does the word different mean here? Structurally speaking, a methyl group is a methyl group, and this is true for every molecule of which it is a part. For example, the methyl groups in alanine and valine or in n-butane and isobutene are all structurally equivalent. Chemically speaking, methyl groups can behave quite differently depending on their structural environment, that is, in terms of the total molecular arrangement. This leads to fundamental chemical and physical consequences; for example, the methyl group in alanine can be easily distinguished from the methyl groups in valine by NMR spectroscopy.7 There is no need to understand the basics of NMR, just that the indicative number for the 13C chemical shifts of the two methyl carbons can be compared. Figure 3 illustrates this. The two methyl groups clearly do not act as the same groups when bound to the α-amino acid skeleton; therefore, they are not chemically equivalent. It is often difficult to sufficiently explain this fact. Strictly speaking, atoms, polyatomic groups, or substituents are chemically equivalent or homotopic if they can be superimposed by an internal symmetry operation. This is not the case for the two methyl groups in valine or for the two methyl groups in leucine. In expansion of the CIP system, these groups can be characterized by the pro-(R) and pro-(S) descriptors. These assignments are based on a simple “what would be” rule: one of two constitutionally identical groups is ranked with higher priority (this can be depicted by exchanging hydrogen with deuterium); if a new chirality center with an S-configuration results, the group is named pro-(S). This “trick” also allows the differentiation between homotopic (identical molecules are the result of the exchange as shown for acetic acid in Scheme II), enantiotopic (enantiomers are the result of the exchange process as shown for propionic acid), and diastereotopic groups8—diastereoisomers result from the exchange process as shown for (S)-leucine. The analytical consequences of the three different types of relationships can again be visualized by NMR spectroscopy, comparing the 1H chemical shifts of the three compounds in Figure 4. Homotopic and enantiotopic groups are chemically

Journal of Chemical Education • Vol. 85 No. 5 May 2008 • www.JCE.DivCHED.org • © Division of Chemical Education


equivalent and appear at the same chemical shift in the NMR spectrum (acetic acid and propionic acid), while diastereotopic groups have different chemical environments and are thus recorded at different chemical shift values (leucine). In general, achiral molecules can only contain homotopic and enantiotopic groups, while chiral molecules can contain diastereotopic and also homotopic groups (molecules with an internal axis of symmetry, for example 2,4-diaminoglutaric acid). Pedagogically, it is sometimes appropriate to introduce common terms from daily life that are used in a different context when applied to science or chemistry in particular, such as the word “memory”. In chemistry, especially in stereochemistry, this word can be used for different purposes. If a chemical reaction is conducted in such a way that a specific property is conserved during the process, one might be tempted to use the word “memory” to describe the conservation. This, however, is clearly not correct; instead, consider the meaning of computer memory. Computers have a hard drive that can “memorize” what we type into it, which enables us to leave and come back later to retrieve exactly what we have stored on the drive. So, in actuality, memory is connected with a given time of storage and cannot or should not be used for processes where information is directly converted into new information (such as RAM, a kind of volatile—i.e., requiring power to maintain the stored information—computer data storage, although the term memory is also used here to indicate a short storage time). Chemically speaking, a concerted process like a cycloaddition reaction or a SN2-type substitution often proceeds with a high degree of stereoselectivity (either retention of given stereochemical properties or the inversion), yet not with a stereochemical memory (3) (see Scheme III). However, in early organic chemistry lessons, we learn that SN1-type substitutions can show some degree of stereoselectivity as well. Complete racemization from a given enantiomerically pure starting material is more an exception than a rule. In these cases, a molecular arrangement composed of the substrate and its environment generates the basis for molecular memory. However, this memory—comparable to computer memory or storing data on a CD—fades away after a certain time; the time domain is an important feature here although not in concerted reactions. A classical SN2-type reaction trajectory therefore includes a reaction in which the absolute configuration is inverted with respect to the chirality center involved. Memory of Chirality At this point we want to introduce the concept of a “memory of chirality” (MOC) effect or reaction and consequently terms have to be discussed even more carefully: the property of chirality does not depend on the absolute configuration of a molecule and also not on the degree of enantiomerical purity—it is entirely a molecular or object-linked term. Thus, the phenomenon of chirality exists in the case of pure (S)-alanine or a racemic mixture of (S)- and (R)-alanine. In contrast to that, the term memory of chirality is connected with the degree of macroscopic excess of one enantiomer over the other in a nonconcerted reaction. Complicating the situation more, this very reaction must proceed by a mechanism that, in principle, leads to a 1:1 stereochemical scrambling. If this does not occur, some memory of the preceding configuration of the starting material must have survived the reaction. The SN1 reaction can proceed with some

degree of memory of chirality as proven by the careful, thorough investigations in the 1940s and1950s, especially by the research groups of Cram, Winstein, W. v. E. Doering, and others. In one highly instructive experiment, Doering studied the methanolysis of a chiral phthalic acid monoester. By carefully analyzing the racemization rate of the product (a process that obviously distorts the results of the stereochemical analysis) and the results of the substitution reaction with methanol, a higher preference of inversion was detected (see Scheme IV) (4). The original publication is a masterpiece that discusses the multiple possibilities of experimental errors and their exclusion, as well as the mechanistic possibilities for such an unusually high degree of “memory”. One possible explanation is that tight ion pairs are formed after primary bond cleavage to the leaving group, generating a chiral global (trigonal bipyramidal) environment. The traditional way to accomplish a stereoselective synthesis is by asymmetric induction, in which the “preferential formation in a chemical reaction of one enantiomer or diastereomer over the other” takes place “as a result of the influence of a chiral feature in the substrate, reagent, catalyst, or environment” (5). An alternative way to accomplish a stereoselective synthesis is with the help of a “memory of chirality” effect or reaction, which originally was defined by Fuji and Kawabata as a process in which “the chirality of the starting material is preserved in a reactive intermediate for a limited time” (6). A more recent definition by Carlier (8) describes a MOC reaction as a [F]ormal substitution at a sp3 stereogenic center that proceeds stereospecifically, even though the reaction proceeds by trigonalization of that center, and despite the fact that no other permanently chiral elements are present.

rate of I* substitution

=

I

rate of racemization I

NaI* acetone

SN 2

NaI acetone

SN 2

I*

I

Scheme III. Graphic results of the 1935 experiments show that the SN2 mechanism leads to inversion of configuration; no memory of chirality effect is involved (I* indicates radioactive iodine) (3).

Me

Et O

O

MeOH

Ar

Et OMe

% (36 h)

SN1

enantiomerically pure

Me

77% inversion 23% retention

54% ee

Scheme IV. Memory of chirality in an SN1 reaction (4). Enantiomeric excess is indicated by “ee”.


703


OK CO2Et

Ph N

MOM

KHMDS 78 °C

Boc

OEt

Ph MOM

chiral B-amino acid

N

retention of configuration 96% yield, 81% ee

KO EtO

N

CO2 t-Bu N

N Bn

Me

CH2OMe

CH2OMe

Scheme V. Memory of chirality in carbanion chemistry (7). MOM indicates methoxymethyl; KHMDS is potassium hexamethyldisilazade.

EtO2C

CO2 t-Bu

CO2 t-Bu

H

CO2Et

Me N MOM Boc

78 °C

Boc

"achiral" enolate

EtO2C

Ph

MeI

CH2OMe Bn

Bn

chirality transfer

static chirality

conformational chirality (axial chiral enolate)

chirality transfer

static chirality

Scheme VI. The reaction from Scheme V with emphasis on the chirality transfer. t-Butyloxycarbonyl is referred to in the text as BOC.

One of the classical examples by Fuji and Kawabata of the memory of chirality effect is discussed here and illustrated in Scheme V (7). In this simple deprotonation–methylation sequence, starting with the (S)-enantiomer of a phenylalanine derivative, a large excess of just one enantiomeric product—here also (S) is produced—although the chirality is formally destroyed in the carbanion–enolate intermediate. The different substituents on the nitrogen make the intermediate axially chiral (transient conformational chirality, the different sides of the double bond being occupied by the MOM and the larger BOC substituent), conserving the chirality and thus enabling the subsequent stereoselective methylation step

A substrate*

fast

very slow

B (P)-intermediate very slow

(M )-intermediate

C fast

(S)-product

very slow

(R)-product fast

A

Conformationally chiral intermediate must form with high stereoselectivity at chirality center

B

Conformationally chiral intermediate must not racemize on the timescale of the reaction

C

Reaction must occur with high stereospecificity

Scheme VII. The essential requirements for a MOC reaction are illustrated for a hypothetical reaction that produces a helically chiral intermediate (8).

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from the less hindered side. Chirality transfer takes place from the statically chiral starting material to the conformationally chiral intermediate and finally to the again statically chiral product (Scheme VI). The authors show in a control experiment that identical substituents (two BOC groups) on the nitrogen make the intermediate nonchiral and thus destroy the MOC effect, yielding a near-racemic product mixture (9). This leads to one of the requirements for a memory of chirality effect to occur: the chiral information is stored (memorized) in a transient chiral conformation at the intermediate state without the help of external chiral controllers. This transient chirality is usually conserved with the help of a rotational barrier around a single bond that has a large activation energy at the reaction temperature. In the example in Schemes V and VI, an activation barrier of about 16 kcal mol–1 leads to a half-life of epimerization of about 20 h at ‒78 °C, enough to retain all chiral information. At 0 °C the half-life of epimerization is shorter than a second and consequently the memory of chirality effect is destroyed at that temperature, the reaction giving an almost equal ratio of the enantiomers (9). In general, there are three requirements for a memory of chirality effect to occur, which are indicated in Scheme VII (8) for a hypothetical reaction. First, the enantiopure substrate must convert into a conformationally chiral intermediate with high enantioselectivity. The chirality of the intermediate is indicated by the arbitrary assignation of the helical descriptor (P)-, the mirror image is designated with a (M)- descriptor. Second, the racemization in the intermediate state—equilibrium between the (P)- and (M)-intermediate—must not occur on the timescale of the subsequent reaction. Third, this subsequent reaction, in addition, must occur with equally high enantioselectivity to produce (S)-product—configuration again arbitrarily assigned, it could also only solely form the (R)-product. All three requirements (formation of a chiral intermediate with high enantioselectivity, slow racemization in the intermediate state,



O

H CH

OH

hO

C

HO

O O

H

HO NH2

CH3

O

H

MeO CH3 CH3

Scheme VIII. The photochemical Norrish–Yang cyclization reaction.

H

hO

NH

O

H3 C

H NH

O

O

HO NH2

CH3

O CH3

MeO

H N

O

HN O

O

O

CH3

MeO N

O

OH

O

H

HO NH2

CH3 CH3

CH2

MeO

CH3

hO

85%

O

CH2 N

OH

Va

IIa O

CH2 H CH2 OH

IVa H

CH3 CH3

91%

CH2

MeO

OH

O H

O

CH3

MeO

Ia

O

CH3

CH3

H CH3

Ph

H CH3

OH

CH3

hO

H NHAc

IIIa

CH2

Ph

H NHAc

74%

HO

H

Ph

CH3 NHAc

VIa

Scheme IX. Photochemistry of valine derivatives.

and stereospecific subsequent reaction) must be met to obtain any kind of stereoselectivity. The chirality transfer from static to conformational and back to static chirality is common for all memory of chirality effects (see Scheme VI), although the mode of conformational chirality (axial, helical, etc.) is unique in each example of MOC reaction. We provide some classic examples below. Using Photochemistry In principle, many reactions are applicable for demonstrating the difference in chemical properties of two diastereotopic groups, mostly hydrogen atoms or alkyl groups in organic molecules. The most convincing way, however, to map these differences is homolytic hydrogen transfer, a process that can be initiated by absorption of light. When the most important functional group in organic chemistry, the carbonyl group, is activated by the absorption of ultraviolet light, it can abstract a hydrogen atom from a remote CH position. This hydrogen is preferentially located at the γ-carbon with respect to the excited C=O group. Such a transfer has the lowest activation barrier due to a favorable chair-like, six-membered transition structure. If favored, the resulting 1,4-biradical can form a new carbon– carbon bond and generate a cyclobutanol. The former reaction is known as the Norrish-II process, the latter as the Yang reaction (10) (see Scheme VIII).

Scheme IX shows three derivatives (Ia, IIa, and IIIa) of the same amino acid, (S)-valine; all of these derivatives can undergo photochemical hydrogen transfer as described. The reactive carbonyl oxygen atoms in the starting materials are shown in bold type; these atoms can be followed through the reaction sequences. In Ia, the N terminus of valine is converted into a pyruvamide with concomitant protection of the C terminus as a methyl ester. In IIa, the N terminus of valine is converted into a phthalimide, again with concomitant protection of the C terminus. In IIIa, eventually, the C terminus of valine is converted into a phenylketone, and the N terminus is protected as acetamide. When irradiated, these compounds are converted into the products IVa-VIa in high yields (11–13). The transfer of a γ-hydrogen atom to the carbonyl oxygen is, in all three cases, the primary step (all intermediate 1,4-biradicals are shown). Note that additional chirality centers are formed during all photochemical processes: one center each in IVa and Va, and two new centers in VIa. To complicate the process even further, product IVa is formed as a racemic mixture, whereas the other two products formed are enantiomerically pure. This is because hydrogen abstraction from Ia destroys the initial stereogenic center and there is also no memory of chirality. From the standpoint of topicity, the reaction of substrate IIIa shows a stereochemical differentiation: only the pro-(R) methyl group participates in the hydrogen transfer step!


705


This situation changes for the 2-aminobutyric acid (Abu) derivatives Ib–IIIb (Scheme X): there are two diastereotopic methylene hydrogens instead of the two methyl groups in valine. Again, in the three derivatives, different hydrogens (indicated by a γ) migrate because of the position of the reactive carbonyl group. In compound IIb, the γ-hydrogen transfer originates from one of the two diastereotopic hydrogens followed by a second hydrogen transfer onto one of the diastereotopic faces of the carbonyl group. This photochemical process leads to a derivative of vinylglycine and is a straightforward synthetic approach to this unusual unsaturated amino acid. The reactions of the starting materials Ib and IIIb proceed in a fashion similar to that of the valine analogs and result in the racemic ß-lactam IVb and the enantiopure cyclobutanol VIb (via inductive effect of the substituted amine). Thus, the reliable rule of γ-hydrogen transfer permits the prediction of the chemical process initiated by absorption of light. When combined with the structurally rich family of α-amino acids, a multitude of starting materials can be designed that allow the discussion of stereochemical terms (such as chirotopic groups, a group that is located within a chiral environment) as well as the description of stereoselective processes (such as diastereoselective hydrogen transfer).

element of chirality is conserved in the intermediate for a given time and this prevents a total loss of chiral information. The first examples of MOC phenomena were reported in the field of enolate chemistry (carbanions). One of the classical examples by Fuji and Kawabata has been discussed earlier (Schemes V and VI). Schmalz and coworkers (15) used a MOC effect to perform a stereospecific Umpolung reaction of arene-tricarbonylchromium complexes. One electron reduction and fragmentation transforms the initial chiral 1-phenyl-1-ethoxyethane tricarbonyl chromium complex into a 17-valence electron complex with an exocyclic double bond. This planar chiral species is further reduced and alkylated to yield the desired products with a high degree of retention (Scheme XI). A photochemically initiated radical cyclization reaction with a memory of chirality effect was reported by Giese and coworkers, as shown in Scheme XII (16). Using an alanine derivative, the cyclization proceeded through a helically chiral singlet biradical. Without a triplet quencher, the longer-lived triplet biradical has been shown to racemize and destroy the memory of chirality effect. In a more rigid system, even a long-lived triplet biradical can exhibit a memory of chirality effect, as shown by Griesbeck and coworkers (17). The axially chiral triplet 1,7-biradical in Scheme XIII needs to fulfill certain conformational requirements according to the Salem–Rowland rules (18) to undergo intersystem crossing and subsequent radical combination. The rotational barrier established by the ortho-substituted benzene ring is large enough to overcome racemization attempts during the lifetime of the triplet biradical. Replacing the ortho-substituted benzene ring with two simple methylene spacers destroys the memory of chirality effect (19).

Memory of Chirality—More Examples of a Useful Concept In recent years, a collection of MOC effects has been reported involving different reactive intermediates: carbanions, monoradicals, biradicals of different electronic configuration (singlet, triplet), and carbocations (for recent reviews see refs 8 and 14). The key mechanistic feature in all examples is that some

O O

CH3 H

HO

H

CH3 H

MeO

O H

H

O

hO

NH

CH3

O H

MeO

MeO

H

O

91%

NH2

O H3C

O

OH

Ib

IVb

O O

CH3 H

CH3

H N

O

H

O H

MeO H

HO

CH3 OH

HN

NH

CH3

MeO

H

hO

O

O

N

O

MeO

OH

NH2

85%

O

IIb

N

OH

Vb H

O

CH3

O H

HO

H NH2

CH3

OH H

Ph

H NHAc IIIb

CH2

hO

HO H

Ph

H NHAc

74%

Ph NHAc VIb

Scheme X. Photochemistry of 2-aminobutyric acid derivatives.

706



OEt

Bn

CH3

Scheme XI. Memory of chirality in benzyl radical chemistry (15). LiDBB indicates lithium 4,4’-di-tbutylbiphenyl.

CH3

1) 2.1 eq LiDBB 2) PhCH2Br

Cr(CO)3

Cr(CO)3 87% ee H

CH3

CH3

Cr(CO)3

CH3 H

Cr(CO)3 Cr(CO)3

"achiral" radical

chiral complex

O

Me

MeO2C

CO2Me OH

hO

OEt

N

planar chiral radical

Me CO2Et

N

Ts

O

Ts 40%, 96% ee

Scheme XII. Memory of chirality in singlet biradical chemistry (16). CO2Me

CO2Me

OH Me

Me N

CO2Et

N Ts

"achiral" biradical

O

CO2Et

OH

Ts helically chiral 1,5 singlet biradical

N

O

O

N HO

CO2K hO

N

N

O

O 86% ee (> 98% de)

Scheme XIII. Memory of chirality in triplet biradical chemistr y (17). Diastereomeric excess is indicated by “de”.

O

3

N HO

O

N

3

N

HO

N

O

O "achiral" triplet biradical

axial chiral triplet biradical


707


O

O

H3C

CO2H

N

H3 C O

2 Faraday/mol NaOMe 10 eq

H3C

OCH3

O

Pt cathode Pt anode MeOH, 30 °C

Ph

N

H3C

Ph 80% ee

Scheme XIV. Memory of chirality in carbocation chemistry (20). Me

O H3C N

H3C

á

N O

O

á

O

Me

Ph "achiral" carbenium ion

A memory of chirality effect involving a carbocation intermediate has been reported by Matsumura and coworkers (20). The N-(o-phenylbenzoylated) cyclic serine derivative in Scheme XIV was electrochemically oxidized and decarboxylated to yield a conformationally chiral iminium ion. The o-phenyl group shields one side of the iminium ion from the attack of nucleophiles. Racemization of the conformationally chiral iminium ion is slow because of the hindered rotation around the amide bond. Conclusion In 1875, Jacobus Henricus van’t Hoff wrote (21): Dans le cas où les affinités d’un atome de carbone sont saturées par quatre groupes différents entre eux, on peut obtenir deux tétraèdres différents, lesquels sont l’image spéculaire l’un de l’autre et ne peuvent jamais être superposés, c’est-àdire qu’on a affaire à deux isomères dans l’espace.

The title of this seminal paper is Sur les Formules de Structure dans l’Espace. van’t Hoff received the first Nobel Prize in chemistry in 1901 in “recognition of the extraordinary services he has rendered by the discovery of the laws of chemical dynamics and osmotic pressure in solutions” (22). His work of what we now call stereochemistry of organic molecules was also mentioned in the justification for his Nobel Prize although it was not recognized as “revolutionary” as his work on chemical dynamics was. If we talk about space structures (structure dans l’espace) today, we are aware of the extremely important role in chemistry, biochemistry, biology and pharmacy and thus can appreciate the impact of the ideas originating from the end of the 19th century. It took a long time to find methods to make molecules with defined stereochemistry reproducible and predictable. Understanding three-dimensional structures and the synthetic way to these products is thus essential for modern chemistry. New discoveries such as the memory of chirality effect have to be integrated into the chemical curriculum today, the same way as earlier discoveries were added over the last century. 708

chiral iminium ion

Notes 1. The Same and Not the Same is the title of a 1995 book by Roald Hoffmann, winner of the Nobel Prize in chemistry in 1981. In this acclaimed book Hoffmann describes the beauty of chemistry, chemical structures, and chemical language. 2. In 1884 Lord Kelvin introduced the term chirality in the discourse of chemistry. 3. The state-of-the-art textbook for this topic is Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen ( John Wiley and Sons, Inc.: New York, 1994). 4. IUPAC recommends “chirality center”, older textbooks use the “chiral center” or even the “chiral carbon”, the latter of course being nonsense (2). 5. Such as ChemDraw, Isis Draw, or others. 6. Proteinogenic amino acids are coded for in the genetic code. 7. From the Aldrich Library of 13C and 1H FT–NMR Spectra, Pouchert, C., Behnke, J., Eds.; Aldrich Chemical: Milwaukee, WI, 1993. 8. In general, “chirotopic” groups.

Literature Cited 1. (a) Cahn, R. S.; Ingold, C.; Prelog, V. Angew. Chem. Int. Ed. Engl. 1966, 5, 385–415. (b) Seebach, D.; Prelog, V. Angew. Chem. Int. Ed. Engl. 1982, 21, 654–660. 2. IUPAC recommendations: Pure Appl. Chem. 1996, 68, 2193– 2222. For a detailed discussion of recommended, unacceptable, and problematic terms in stereochemistry, see: Helmchen, G. Nomenclature and Vocabulary of Organic Stereochemistry. In Methods in Organic Chemistry (Houben–Weyl); Thieme: Stuttgart, Germany, 1996; E21a (Stereoselective Synthesis), 1–74. 3. Hughes, E. D.; Juliusburger, F.; Masterman, S.; Topley, B.; Weiss, J. J. Chem. Soc. 1935, 1525–1529. 4. Doering, W. v. E.; Zeiss, H. H. J. Am. Chem. Soc. 1953, 75, 4733–4738. 5. IUPAC Compendium of Chemical Terminology. http://www.iupac.org/publications/compendium/index.html (accessed Feb 2008).


Research: Science and Education 6. Fuji, K.; Kawabata, T. Chem. Eur. J. 1998, 4, 373–376. 7. Kawabata, T.; Suzuki, H.; Nagae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155–2157. 8. Zhao, H.; Hsu, D. C.; Carlier, P. R. Synthesis 2005, 1–16. 9. Kawabata, T.; Chen, J.; Suzuki, H.; Fuji, K. Synthesis 2005, 1368–1377. 10. First report of cyclobutanol products in type II photochemistry: Yang, N. C.; Yang, D. H. J. Am. Chem. Soc. 1958, 80, 2913–2914. Reviews of Norrish–Yang reactions: Wagner, P.; Park, B.-S. In Organic Photochemistry, Padwa, A., Ed.; Marcel Dekker: New York, 1991; Vol. 11, Chapter 4. Wagner, P. J. In Molecular Rearrangements in Ground and Excited States, de Mayo, P., Ed.; Academic Press: New York, 1980; Chapter 20. Wagner, P. J. Acc. Chem. Res. 1971, 4, 168–177. 11. Griesbeck, A. G.; Heckroth, H. Synlett 2002, 131–133. 12. Griesbeck, A. G.; Mauder, H.; Müller, I. Chem. Ber. 1992, 125, 2467–2475. 13. Griesbeck, A. G.; Heckroth, H. J. Am. Chem. Soc. 2002, 124, 396–403. 14. Kawabata, T.; Fuji, K. Memory of Chirality: Asymmetric Induction Based on the Dynamic Chirality of Enolates. In Topics in Stereochemistry, Denmark, S. E., Eliel, E. L., Wilen, S. H., Allinger, N. L., Eds.; John Wiley: New York, 2003; Vol. 23, pp 175–205. 15. Schmalz, H.-G.; de Koning, C. B.; Bernicke, D.; Siegel, S.; Pf-

letschinger, A. Angew. Chem. Int. Ed. 1999, 38, 1620–1623. 16. Giese, B.; Wettstein, P.; Stähelin, C.; Barbosa, F.; Neuburger, M.; Zehnder, M.; Wessig, P. Angew. Chem. Int. Ed. Engl. 1999, 38, 2586–2587. 17. Griesbeck, A. G.; Kramer, W.; Lex, J. Angew. Chem. Int. Ed. 2001, 40, 577–579. 18. Salem, L.; Rowland, C. Angew. Chem. Int. Ed. Engl. 1972, 11, 92–94. 19. Griesbeck, A. G.; Kramer, W.; Bartoschek, A.; Schmickler, H. Org. Lett. 2001, 3, 537–539. 20. Ng’ang’a Wanyoike, G.; Onomura, O.; Maki, T.; Matsumura, Y. Org. Lett. 2002, 4, 1875–1877. 21. van’t Hoff, J.-H. Bull. Soc. Chim. Fr. 1875, 23, 295–301. 22. The Nobel Prize in Chemistry 1901, Presentation Speech for Jacobus Henricus van’t Hoff. http://nobelprize.org/chemistry/ laureates/1901/press.html (accessed Feb 2008)

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The Same and Not the Same: Chirality, Topicity, and Memory of

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