The Metolachlor Herbicide: An Exercise in Today's Stereochemistry

In the Classroom

The Metolachlor Herbicide: An Exercise in Today’s Stereochemistry Albrecht Mannschreck* Department of Organic Chemistry, University of Regensburg, D-93040 Regensburg, Germany; *[email protected] Erwin von Angerer Department of Pharmacy, University of Regensburg, D-93040 Regensburg, Germany

Many plants such as cereals are cultivated for the nutrition of humans and animals. The output of these crops would be considerably diminished if they were not protected against a variety of detrimental weeds. The latter compete successfully with the cultivated plants for space, sunlight, water, and nutrients in the soil. Chemicals used to selectively inactivate or kill weeds are called herbicides (1a). One of the most used representatives, (particularly in the United States) is metolachlor (Figure 1), an anilide registered for the protection of many different types of plants worldwide (2). This molecule forms stereoisomers1 that have been analyzed separately and as a mixture for their bioactivity in reference to weed extermination. Such experiments are required because of environmental aspects (2) and the necessity to optimize the agronomic use. The compositions of stereoisomeric mixtures must also be taken into account for the industrial preparation. The present article deals with the three-dimensional structures, the syntheses, and the bioactivities of metolachlor stereoisomers. An overview of the following topics is beneficial to the comprehension of this manuscript: racemic and chiral nonracemic (3a) samples; zigzag formulas (3b); the principle of NMR and chromatography with a nonracemic auxiliary or sorbent, respectively (4); crystallization of diastereomeric derivatives (5a, 6a); and the elements of enantioselective reactions (7a). The content of this article can be integrated into a lecture on advanced organic agrochemistry. The present manuscript describes facts related to metolachlor, such as its stereoisomers or its syntheses. These specific facts are proposed as examples to illustrate general stereochemical aspects, such as axial and central chirality or enantioselective hydrogenation of achiral substrates. These topics are often taught in the third (or a later) year of university chemistry curriculum. The general aspects will be summarized in the conclusion of the article.

O ClCH2C

O

CH2 OMe N

CHMe Et

Me

H O2C(CH2)2C

N

CH2Me Me

Me

Br Me metolachlor 1

a model anilide 2

Figure 1. Structures of metolachlor and a model anilide.

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Several Metolachlor Stereoisomers Two Elements of Chirality Metolachlor, 1, has a stereocenter in one of the N substituents but, in addition, it exhibits a second, less usual element of chirality, the axial one (3c, 7b). Before looking at metolachlor, we shall consider a similar molecule, the model anilide 2, showing this element exclusively. We focus for a moment on formulas (M)- and (P)-2 (Figure 2) representing the enantiomers; the descriptors (M) and (P) will be explained later. (M)-2 contains two planar π systems: the arene ring and the O=C−N fragment1 with O=C and C−N partial double bonds. When considering rotation about the aryl–nitrogen bond, one sees that conformations with noncoplanar π systems such as (M)-2 are sterically less hindered than coplanar ones. (M)-2 shows neither an internal plane of symmetry nor a center of symmetry; thus two enantiomers must exist (6b, 8). These stereoisomers were experimentally separated and characterized (9). The descriptors (M) and (P) will be briefly explained with the enantiomers of the model anilide 2 serving as an example: (i) look down the nitrogen–aryl bond, the axis of chirality (Figure 1) and (ii) determine the priorities (1) and (2) of the groups at the front and the priorities (3) and (4) of the substituents at the back. In the present case, the two ortho methyl groups have the same priority but the meta bromine and the meta hydrogen atoms differ. (iii) The substituent with higher priority in the front, that is, (1), and the one with higher priority in the rear, that is, (3), are used now. If the turn (1) → (3) is clockwise, we are dealing with the (P) enantiomer, otherwise the descriptor is (M) (3d, 10). An alternative nomenclature uses the notations (aR) and (aS); the correspondence of (M) with (aR) and (P) with (aS) is general (3d, 10). In the case of metolachlor, 1, we disregard its central chirality for a moment and see that the rotation and symmetry properties correspond to the ones discussed for the anilides (M)- and (P)-2. Therefore, 1 is also axially chiral, giving rise to (M) and (P) conformations. The latter combine with (R) and (S) configurations (due to the stereocenter in the side chain) to form the four stereoisomers in Scheme I. They show diastereomeric relationships, for example, (R,M)- and (R,P)-1, as well as enantiomeric ones, for example, (R,M)- and (S,P)-1. Separations of Stereoisomers Diastereomers usually exhibit unequal NMR shifts, whereas equal shifts are observed for enantiomers in an achiral medium (3e). The 1H NMR spectrum of a mixture of all stereo isomers of metolachlor shows the spectral superposition of two diastereomers (11) whereas the enantiomers are not separated. For instance, there are two OMe peaks, of which the δ values

Journal of Chemical Education • Vol. 86 No. 9 September 2009 • www.JCE.DivCHED.org • © Division of Chemical Education

In the Classroom O

O

HO2 C(CH2)2C

CH2Me

N

Me

HO2C(CH2)2C Me

CH2Me

N

Me

Me

H

Br Br

Me Figure 2. Model anilide, 2: (top) axial chirality and (bottom) determination of the (M) and (P) descriptors of the enantiomers.

Me

(M)-2

O (1) HO2 C(CH2)2C

(11) are given in Scheme I. However, in the presence of a chiral nonracemic additive, unequal shifts are usually observed for diastereomers as well as for enantiomers (4, 12). Diastereomeric association complexes with the auxiliary are the reasons for the latter splitting. As expected, the 1H NMR spectrum of a mixture of all stereoisomers of metolachlor (1) exhibits four OMe peaks (13) with a nonracemic additive, a europium(III) compound. In agreement with NMR, HPLC on a chiral nonracemic sorbent usually shows separate peaks for diastereomers and for enantiomers (4, 14). Diastereomeric sorption complexes with the stationary phase are responsible for the splitting. Indeed, HPLC of a mixture containing the isomers of metolachlor, 1, exhibited up to four peaks on cellulose derivatives under different conditions (15–18). Tris(3,5-dimethylphenylcarbamoyl) cellulose/SiO2 (Chiralcel OD−H) with hexane/diethyl ether was the most useful and resulted in the assignment of all peaks (19). Stereoisomers of 1 were also separated successfully by gas chromatography on chiral nonracemic sorbents (15, 16, 20). Depending upon the temperatures applied, a partial thermal isomerization may occur; possible consequences for the analysis of 1 were discussed in ref 16. The methods mentioned above were used to determine the compositions of metolachlor batches including samples relevant to environmental investigations. Preparative separations were accomplished by HPLC (15, 16, 19) or by a combination with HPLC on an achiral sorbent (16). In addition, the classical crystallization of diastereomeric derivatives (5a, 6a) of 1 was successful (13). Noncrystalline samples of the four species were characterized by polarimetry, 1H NMR, HPLC, and gas chromatography (13, 15, 16, 19). Interconversion of Diastereomers by Rotation About the Aryl–Nitrogen Bond When dealing with axial chirality, isomers are present that owe their existence to steric hindrance of rotation. This process occurs with a rate depending on the extent of hindrance and the temperature. The rate of interconversion of two diastereomers

H

(P)-2

(4)

(3)

Me(H)

Me(Br)

N

O (1) HO2 C(CH2)2C

CH2Me (2)

N

CH2Me (2)

Me(Br)

Me(H)

(3)

(4)

(M)

(P)

A and B is measured by means of a thermal equilibration (3f, 16, 21), that is, starting from A, an equilibrium mixture A and B is formed. When one of the separated isomers of metolachlor is heated at 128 °C, its 1H NMR spectrum gradually changes to the spectral superposition of two diastereomers. An equilibrium, for example, (R,M)-1 (R,P)-1 (Scheme I), is established by aryl–nitrogen rotation. In the present case, the final concentrations of the two species are accidentally equal (13)

OMe X N

Me

OMe

3.20

Me

3.23

X k1

Et

Me

N

Et

Me

k2

(R,M)-1

(R,P)-1

OMe

OMe 3.23

X Me

N

Me Et

(S,M)-1

3.20

X k2

Et

Me

N

Me

k1

(S,P)-1

Scheme I. Axial and central chirality of metolachlor,1. X is chloroacetyl. The 1H NMR shifts δ at 300 MHz in CDCl3 at 20 °C are given below the OMe groups. Rotations about the aryl–nitrogen bond proceed with the rate constants k1 and k2.

© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 86 No. 9 September 2009 • Journal of Chemical Education

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In the Classroom OMe

O

Me + NH2

Me

Et OMe H

∙H2O

H2SO4

N

Me

Me

Cl

O Cl

Et

OMe

O N Me

Cl

Me Et

H2

OMe

N Me

(i)

(RS)-3

(RS)-1

Me Et OMe

H2 (ii)

H

4

N

Me

Me Et

(S)-3 ee = 79%

OMe

O Cl

O Cl

Cl

N Me

Me Et

(S)-1 ee = 79%

Scheme II. Two metolachlor syntheses on industrial scales. The non-enantioselective preparation (via imine 4 that is not isolated); (i) 5 bar, Pt/C, H2O, trace of H2SO4, 50 °C. The enantioselective preparation (via imine 4 that is isolated); (ii) 80 bar, a catalysis mixture containing a chiral nonracemic component, HOAc, NBu4I, 50 °C, 4 h.

and, therefore, k1 = k2 in Scheme I. The experimental half-life is as long as 50.6 h at 128 °C (13). The substituents hindering rotation in metolachlor, 1, are roughly similar to the ones in the model anilides (M)- and (P)-2. In the latter case, enantiomers, not diastereomers, equilibrate; the half-life is of the same order of magnitude (9) as the one for 1. According to these findings, the thermal interconversion of the diastereomers in Scheme I is practically absent at room temperature, a result that will be of interest when bioactivities are described. Two Metolachlor Syntheses on Industrial Scales The Non-Enantioselective Preparation 2-Ethyl-6-methylaniline is subjected to a reductive alkylation (6c) with methoxyacetone, using Pt/C as an achiral catalyst (Scheme II). The amine (RS)-3 is formed via imine 4 without isolation of the latter. Chloroacetylation of (RS)-3 results in the desired 1 (22, 23). This product is sometimes designated (RS) -metolachlor, although all four stereoisomers are present (in the equilibrium ratio of 1:1:1:1); information on axial chirality is not included. The reason is that the latter is less important for the agricultural application of 1 than its central chirality.

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The (M) and the (P) isomers show similar activity, whereas the (R) and the (S) species exhibit highly different herbicidal effectiveness; these observations will be described when bio activities are considered. The non-enantioselective preparation, according to Scheme II, yielded more than 20,000 tons per year, until the enantioselective synthesis started to successfully compete in 1997. The Enantioselective Preparation Upon the catalytic hydrogenation of a double bond in an achiral substrate, enantiomers of the product can result, depending upon the substitution pattern of the starting material. With an achiral catalyst, equal amounts of these enantiomers are formed. This happens when imine 4 (without its isolation) is hydrogenated with the achiral catalyst Pt/C (Scheme II), yielding the amine (RS)-3. However, with a chiral nonracemic catalyst, unequal amounts of the enantiomers are usually formed (7a, 24). This takes place upon the homogeneous hydrogenation of imine 4 (Scheme II), the result being the amine (S)-3 with 79% enantiomeric excess (22). This selectivity is qualitatively explained on the basis of the required reaction conditions of kinetic


In the Classroom Me

Table 1. The Metolachlor Stereoisomers as Herbicides Herbicidal Materiala

PR2 Fe

PPh2

5

Ir

Cl Cl

(S,M)-1

Ir

6

Relative Activity (%)b 100

(S,P )-1

96

1:1:1:1 Mixture

93

(R,P )-1

53

(R,M)-1

34

Figure 3. Components of the catalysis mixture used for the enantioselective hydrogenation of imine 4 (Scheme II). R is 3,5-dimethylphenyl.

See Scheme I for the stereoformulas. b Relative activity of 1000 g of herbicidal material applied per hectare of agricultural area; from ref 13, diagram II.

control (6d), that is, control via the energies of the two possible transition states. One of them contains the catalyst, symbolized by Rcat, and leads to (R)-3 (not depicted); the other one also contains the Rcat catalyst but leads to (S)-3 (Scheme II). The diastereomeric Rcat–R and Rcat–S transition states generate unequal reaction rates and, therefore, unequal amounts of amines (R)- and (S)-3. More detailed descriptions, including schematic diagrams of energy versus reaction coordinate, are available (7a, 25, 26). The hydrogenation reaction is performed with a catalysis mixture (Figure 3), from which the proper catalytic molecule of unknown structure originates in situ. One component of this mixture, the ferrocenyldiphosphane 5, is a chiral nonracemic ligand. Different complexes with the iridium compound 6 or its monomer are formed (22, 27). In spite of considerable effort (28), the mechanism of the hydrogenation is not known. The catalysis mixture and the reaction conditions took 13 years to be developed and were optimized by the group of Blaser (22, 27, 29). For the present step of the synthesis, there were many ligands to choose from; many screening capabilities, many experienced people, and, finally, rapid analytical techniques were the key to the success (30). Chloroacetylation of (S)-3 yields the desired highly enriched 1 (22, 23, 27), commonly designated (S)-metolachlor (Scheme II). The whole synthesis is carried out by the Syngenta Company (formerly Ciba–Geigy and Novartis) on a scale of more than 10,000 tons per year with 76–79% enantiomeric excess and represents one of the enantioselective catalytic processes utilized on largest scale.

The Four Separated Metolachlor Species as Herbicides

Bioactivities of Metolachlor Stereoisomers (RS)-Metolachlor as a Herbicide In 1975, the 1:1:1:1 mixture, designated (RS)-metolachlor (Scheme II), was introduced into the market by the former Ciba–Geigy company as an antiweed agent, for instance, in cereals such as maize, under the trade name Dual (2). To assess whether the constitution of metolachlor was suitable for this purpose, the effect of (RS)-metolachlor was compared with the activities of compounds with similar structures. A molecule devoid of the C methyl group in the side chain of 1 is one example. In another model herbicide, the ethyl group in the ortho position has been replaced by a methyl group. Further molecules have been checked by screening (31) for bioactivity.

a

Distinct NMR and chromatography peaks for enantio mers in the presence of a chiral nonracemic additive or sorbent were found. The reason for the two separate peaks is that there are two diastereomeric-association complexes in which many noncovalent interactions (32) differ. Similar species occur upon the uptake of two enantiomers by the organism, the complexation partner being, for instance, an enzyme. Since the latter as a protein contains amino acids of one configuration, the enzyme is a chiral molecule. Two diastereomeric complexes give rise to unequal bioactivities (5b, 33). This is also true for diastereomeric molecules (6e), that is, in the case of more than two stereoisomers entering the organism; all of them usually show different behavior. The herbicidal effects (13) of the four separated species of metolachlor (Table 1) are in line with this expectation. The diastereomers, for example, (S,M)- and (S,P)-1, differ as well as the enantiomers, for example, (S,M)- and (R,P)-1. The (S) configuration generates much higher activity than the (R) configuration (13). As far as axial chirality is concerned, there are smaller differences between the effects of the (M) and the (P) stereoisomers (Table 1). Even so, isomers such as (S,M)- and (S,P)-1 do not interconvert at room temperature and show clearly unequal biological behavior. (S)-Metolachlor as a Herbicide The marketing of one enantiomer instead of the racemate is frequently called a chiral switch (20, 34, 35), which is common for both herbicides and drugs (33a, 36). Among the reasons for effecting a chiral switch, an important one is a higher bioactivity of one enantiomer compared with the racemate. When dealing with herbicides, we shall use the notion of dosage, which means the mass of material applied per agricultural area. The enantioselective preparation of 1 (Scheme II) yielded a highly enriched product, commonly designated (S)-metolachlor. It exerts the same effect as (RS)-metolachlor at only about 65% of the dosage (2, 22, 29, 35). This reduction is advantageous because of the savings with respect to storage, package, shipping, and selling when (RS)-metolachlor is replaced by (S)-meto lachlor. In addition, the load of herbicide to the environment diminishes considerably by the chiral switch (37, 38). An additional qualitative explanation for the dosage reduction is available. If (S,M)- and (S,P)-1 are not considered


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In the Classroom

separately as in Table 1 but as a 1:1 mixture called (S,MP)-1, the relative activity of the 1:1:1:1 mixture of stereoisomers, that is, (RS)-metolachlor, at 1000 g/hectare is achieved by (S,MP)-1 at a much lower dosage. Comparison of the relative activities at a dosage of 250 g/hectare reveals the increased activity of (S,MP)-1 (77% of the maximum effect) over the 1:1:1:1 mixture (63%). These results are taken, as examples, from the measurements in ref 13, diagram I. Prior to their approval, biological agents are run through a series of thorough examinations with respect to degradation in the environment, possible accumulation in living organisms, and potential toxicity (1a, 1b, 33). It is reported that herbicides sometimes appear in surface or ground water (2, 37, 39); corresponding risk assessments of (S)-metolachlor resulted in positive registrations in the United States (in 1997) and other countries. This agent and several materials containing (S)-metolachlor and some additives have been marketed by the Syngenta company under the trade names Dual Gold, Dual Magnum, Gardo Gold, Primextra Gold, and others. They protect maize, soybeans, and peanuts against various kinds of weeds (2). The production of (S)-metolachlor is expensive but pays off because it is used in large amounts to benefit the nutrition of humans and animals. Conclusion The present article describes specific facts concerning metolachlor. Some of these facts can be chosen as examples to illustrate the following general stereochemical aspects: axial and central chirality; NMR and chromatography with a chiral nonracemic additive or sorbent; steric hindrance of rotation; enantioselective hydrogenation of achiral substrates; unequal biological effects of stereoisomers; and chiral switch from a racemate to an enantiomer. These aspects are often taught in the third (or a later) year of university chemistry curriculum. Metolachlor is an attractive molecule for the use in chemical education because this herbicide is tightly connected with the application of analytical methods, the industrial synthesis, and the agricultural practice. Acknowledgments Thanks are due to H.-U. Blaser, G. Diriwaechter, and A. Michel, Basel, Switzerland; to S. Toma. Bratislava, Slovakia; and to J. Daub, G. Hauska, and J. Sauer, Regensburg, Germany, for valuable information. The authors are grateful to N. KastnerPustet, Regensburg, for help with the graphics. Note 1. The structures of metolachlor, 1 (Figure 1 and Scheme II), represent one of the (E) or (Z) species with respect to the carbonyl– nitrogen partial double bond. The other isomer is not shown. These isomers are interesting but undergo fast interconversion at room temperature (15) and are, therefore, not important in the present context. Similarly, the structures of the model anilide, 2, only represent the (E) species.

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http://www.jce.divched.org/Journal/Issues/2009/Sep/abs1054.html Abstract and keywords Full text (PDF) Links to cited URL and JCE articles JCE Featured Molecules for September 2009 (see p 1104 for details) Structures of some of the molecules in this article are available in fully manipulable Jmol format in the JCE Digital Library at http://www.JCE.DivCHED.org/JCEWWW/Features/ MonthlyMolecules/2009/Sep/.


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The Metolachlor Herbicide: An Exercise in Today's Stereochemistry

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