PROJECT II :

Asymmetric Synthesis - Use of a Chiral Manganese Catalyst for the Asymmetric Epoxidation of Styrene

Introduction Chemists have discovered and developed many elegant and synthetically useful transformations of carbon-carbon double bonds. One important class of reactions involves oxidation to epoxides which serve as synthetic intermediates towards a wide variety of oxygen- bearing functionalities. Epoxides react with strong nucleophiles (e.g. RS- , RSi-) under basic conditions and even weak nucleophiles (e.g. H2O) will react under acidic conditions with opening of the epoxide ring.

R2C CR2 R2C CR2

O

R2C CR2

OH

Nu

H+ catalysis

H-Nu[O]

Hydrolysis in dilute mineral acid is a widely used method for the preparation of (trans-) 1,2-diols from alkenes.

R2C CR2 R2C CR2

O

R2C CR2

OH

OH

H+ catalysis

H2O[O]

Reactions with carbon nucleophiles such as Grignard reagents and organocuprates lead to ring opening and carbon- carbon bond formation.

R2C CR2 R2C CR2

O

R2C CR2

OH

R'

1. R'MgX2. H2O

[O]

2

Reductions using aluminum-hydride reagents afford alcohols.

R2C CR2 R2C CR2

O

R2C CR2

OH

H

1. LiAlH42. H2O

[O]

In addition, epoxides undergo Lewis acid-catalyzed rearrangements to carbonyls,

R2C CR2 R2C CR2

O

R2C CR

R O

[O] catalytic MgBr2

and base catalyzed rearrangements to allylic alcohols.

CH2R

R2C CR

O

R2C CR

OH

CHR

catalytic Li+[N(C2H5)2]-

Traditionally, olefin epoxidations have been accomplished by a variety of peroxy-acids. Since the early 1980's, however, a number of very effective transition metal-based catalyst systems have been developed which have significantly extended the scope of these reactions by allowing enantioselective oxygen transfer to form asymmetric epoxides. The most prevalent of these systems has been the Sharpless oxidation of prochiral allylic alcohols (which uses tert-butyl hydroperoxide in the presence of titanium tetra(isopropoxide) and either (+)- or (-)- diethyl tartrate) to give asymmetric epoxides in high optical yields.

R1R2

R3 OH

[O]

[O]

(-)-diethyl tartrate

(+)-diethyl tartrate The high enantioselectivity of this reaction is attributed to precoordination of the alcohol function to the titanium center, which serves to orient the face of the incoming double bond. In 1990, the Harvard chemist, Eric Jacobsen published the first of several important papers on the enantioselective epoxidation of unfunctionalized olefins catalyzed by chiral manganese complexes. In this system the stereoselectivity relies solely on nonbonded interactions, thus lifting the requirement for a precoordinating

3

pendant group. In fact, alkyl- and aryl-substituted olefins react with the highest enantioselectivity yet realized for nonenzymatic catalysts. This experiment is based upon some early work by Jacobsen, who employed a chiral (salen)MnIIICl catalyst to epoxidize trans-β-methylstyrene.

C C

H5C6 H

H CH3

C C

H5C6H

HCH3

C CH5C6 H

H CH3

O

O

[O]

or(salen*)MnCl

One of his original chiral salen ligands for the chiral manganese catalysts is prepared by treating the Shiff base of 5-methyl-3-tert- butylsalicylaldehyde with either (R,R)- or (S,S)-1,2-diamino-1,2-diphenylethane (sometimes abbreviated (R,R)- or (S,S)-stilbenediamine (stien) or (+)- or (-)-1,2-diphenylethylenediamine (DPEDA)). The second of these reagents has recently been made commercially available. The first is not readily available, and although it is required to realize high asymmetric induction in the epoxidation (see below), we will use commercial salicylaldehyde instead. The simplest catalyst, (salen*)MnIIICl, is then prepared in one step by reaction of the ligand with MnII(OAc)2.4H2O in air (to oxidize MnII to MnIII), followed by treatment of the solution with LiCl (Scheme I). The MnIII(salen) complexes are obtained in high yields, are thermally stable and can be stored as solids indefinitely without precautions to exclude light, air, or moisture. Although iodosylarenes have also been used, the epoxidation reactions are most conveniently carried out in undiluted, buffered commercial bleach solutions at pH 11.3. Enantioselectivities do not differ significantly in either case suggesting that both reactions have in common an oxo intermediate, e.g. (salen*)ClMnV=O, as the active oxidizing agent (in contrast to Ni(salen) and Co(salen) catalyzed epoxidations in which free ClO. has been implicated).

4

N N

PhPh

OHN N

PhPh

OH HO

O

H

H2N NH2

PhPh

O O

Mn

Cl

Scheme I.

(R,R)-(salen)MnIIICl

Salicylaldehyde

89-96%2. LiCl

1.Mn(OAc)2.4H2O

91-97%

EtOH

(R,R)-salen complex(R,R)-stien

+

Some of the more effective epoxidation catalysts developed in Jacobsen's laboratories are shown in Scheme II. Note that the synthesis of each family of catalyst involves the coupling of a salicylaldehyde derivative to a diamine of known stereochemical configuration. Modifications to the steric and electronic environments at the metal center can be obtained by merely by choosing an appropriately substituted salicylaldehyde during the ligand synthesis. The observed epoxidation enantioselection for these catalysts can be explained by analyzing key steric interactions for side-on perpendicular approach of the olefin to the manganese oxo bonds of the implicated MnV intermediates, as illustrated in structures A-C for the epoxidation of cis-β-methylstyrene by the 3-tert-butyl-5-methyl-salicylaldehyde salen derivative 1c (Figure 1). The most favored approach is seen in structure A in which the olefin is approaching from above the page. In B, the side of approach is the same but the opposite enantioface of the olefin is presented resulting in unfavorable interaction of the more bulky (phenyl) substituent with the ligand

5

N N

PhPh

OH

X

R

N N

PhPh

OHR

X

HO

X

R

O

H

H2N NH2

PhPh

OR

X

O

X

R

Mn

Cl

2. LiCl

1.Mn(OAc)2.4H2O

EtOH+

1a: X = H, R = H1b: X = CMe3, R = H1c: X = CMe3, R = CH3

1a-c

Scheme II.

tert-butyl groups. In structure C approach is from behind the page as depicted resulting in unfavorable interactions imposed as a consequence of the dissymmetery of the catalyst. Consistent with these arguments is that the highest ee's should be imparted to cis-olefins bearing one large and one small substituent.

6

CH3

CH3

CH3

Cl

O

N OMn

N O

CH3

CH3

Cl

O

N OMn

N O

CH3

CH3

CH3

Cl

O

N OMn

CH3

N O

A Favored

B Disfavored

C Disfavored

Figure 1. Proposed transition states for the epoxidation of cis-β-methylstyrene by 1c.

7

Experimental The following catalyst preparation and epoxidation procedures are general and may be scaled to the amount of starting compounds supplied by the TA's. All solvents may be used without further purification. All reactions should be carried out in a fume hood. Catalyst preparation

Salicylaldehyde (576 mg, 4.72 mmol, 2.0 equivalents) is weighed directly into a 50 mL single neck RB flask. (R,R)- or (S,S)-stien (500 mg, 2.36 mmol, 1.0 equivalent) is added followed by absolute ethanol (12 mL, to give a 0.2 M stien solution). The mixture is refluxed for 1 h (in air is O.K.) and allowed to cool to room temperature with continuous stirring. Water is then added dropwise (about 5-10 drops) to the stirred, cooled, bright yellow solution until product begins to crystallize (occasionally product begins to crystallize prior to addition of water). The resulting yellow crystalline solid is collected by filtration and washed with a small portion of cold 95% ethanol. The yields of analytically pure salen ligand obtained in this manner are typically in the range of 91-97%.

The ligand is redissolved in hot absolute ethanol to give a 0.1 molar solution. Solid MnII(OAc)2.4H2O (2.0 equivalents) is added in one portion and the solution is refluxed for 1 h. Approximately 3 equivalents of solid LiCl are then added and the mixture is heated to reflux for an additional 0.5 h. The product is purified by evaporating the reaction mixture to dryness, redissolving the crude product in methylene chloride, and filtering to remove excess MnII(OAc)2.4H2O. The solution is then concentrated on a rotovap. Cooling this mixture to 0 oC affords the MnIII(salen) complex as dark brown needles which are washed with a small amount of cold ethanol and isolated by filtration in ~75% yield. An additional crop of material can be obtained from the mother liquor.

Epoxidation

To 25.0 mL of undiluted household bleach in a 250 mL Erlenmeyer flask is added

10.0 mL of 0.05 M Na2HPO4. The pH of the resulting buffered solution (~0.55 M in NaOCl) is adjusted to pH = 11.3 by addition of a few drops of 2 M NaOH. To this solution is added a solution of catalyst (509 mg, 1.0 mmol) and trans-β-methylstyrene (1.18 g, 10 mmol) in 10 mL of CH2Cl2. The two-phase mixture is stirred at room temperature, and the progress of the reaction is monitored by TLC (20% CH2Cl2: 80% hexane). After 3 hours, 100 mL of hexane is added to the mixture, and the brown organic phase is separated, washed twice with 100 mL of saturated NaCl solution, and then dried (Na2SO4). Filtration and solvent removal affords the crude epoxide.

8

Purification

A flash chromatography column is wet packed with silica gel (75 g) using 20% CH2Cl2: 80% hexane. The crude epoxide is first eluted with 20% CH2Cl2: 80% hexane (200 mL) followed by 30% CH2Cl2: 70% hexane (200 mL) and finally with 40% CH2Cl2: 60% hexane (ca. 300 mL). The fractions are collected in ca, 40 mL portions and evaluated by analytic TLC. The epoxide containing fractions are combined into a pre-weighed flask, and the solvent is removed by rotovap.

Optional Carry out an epoxidation on another prochiral olefin which you think will be more

or less suited to this catalyst system. Compare your results with those for trans-β-methylstyrene and discuss the results in the context of the arguments above with regard to steric effects on enantioface selection. Are your results consistent with expectations based on these arguments?

NMR analysis

The ee (enantiomeric excess) of the epoxide was determined by 1H NMR analysis in the presence of the NMR shift reagent tris-(3-heptafluorobutyryl-d-camphorato)-europium (III), Eu(hfc)3. This is a paramagnetic complex that will shift the NMR signals of molecules that coordinate to it. Since Eu(hfc)3 is chiral the signals of the two enantiomers of your epoxide will shift to a different degree. Run an NMR using 25- 35 mg of your product in 700 mg CDCl3. Now add 15 mg of Eu(hfc)3 and rerun the spectrum. Notice how some of the signals have been shifted downfield. Continue adding Eu(hfc)3 in 15 mg aliquots until the fastest moving signal has shifted by about 2 ppm. You should now be able to resolve shoulders on the sides of your main peaks which correspond to the minor isomer. Expand the scale and carefully integrate the signals using the whole width of the paper. Using this information, approximate the % ee obtained in your epoxidation reaction.

EPR analysis

You will be provided an opportunity to characterize the manganese catalyst, its precursor, and, for comparison, yet another, di-nuclear manganese complex, using electron paramagnetic resonance spectroscopy (EPR). Introductory Remarks In most ions and molecules, electrons are paired so that the spin and orbital angular momenta cancel and the substance is diamagnetic. If the substance contains unpaired electrons, it is paramagnetic. Some examples of paramagnetic species are: a. Atoms for which a shell inside the valence shell is not filled, so that unpaired electrons are present (by Hund's rules). These are the transition elements. The first transition group is the iron group in which electrons start filling the 3d shell after the 4s

9

valence shell is filled. Another transition group is the rare earth group in which the 4f shell is unfilled. b. Molecules containing unpaired electrons. Examples are O2, NO, NO2, and diphenylpicrylhydrazyl (DPPH). The latter is routinely used as a standard in EPR measurements.

Other examples are molecules in which bonds have been broken by radiation damage, or by one-electron oxidation or reduction. The most appropriate method for detecting these unpaired electrons is by EPR. Single Electron in a Magnetic Field An electron has its intrinsic spin and hence a spin angular momentum. In an external field, say in the z direction, the component of the spin angular momentum in the direction of the field is quantized and has magnitude msh where ms = ±½. In zero magnetic field, the spins and magnetic moments are all of equal energy. The energy levels of an electron spin in a magnetic field B are

Ems = geµΒmsB, ms = ±½,

where µΒ = eh/4πmc is Bohr magneton, 9.27×10-28J/G. The separation of the levels is

ΔE = geµΒ B

Due to their different energies, these two states, α and β, are differently populated, the difference being subject of Boltzmann distribution

Nα = Nβ exp(-ΔE/kT) Electromagnetic radiation of frequency ν= ΔE/h stimulates transitions between these two levels, with the same probability up and down. However, since the lower level is more populated, the number of electrons going up is higher than those going down. As a result, net resonant absorption occurs at the resonance condition:

hν = geµΒ B For many species, g !2.0023, the free electron value. At a frequency of 9.5 GHz, this gives a field of about 3300 gauss. In most often applied X-band spectrometers, those are regular values of frequency (which is kept constant), and magnetic field (which is sweeping around 3300 G).

There are relaxation mechanisms, such as spin-lattice interaction, that restore the difference in populations reduced by the resonance absorption. However, at high enough microwave power, saturation effects do occur, i.e. most of electrons are at the upper level and further absorption of microwave energy can not take place.

N N NO2

NO2

NO2

10

Hyperfine Interaction

Most nuclei also have an intrinsic spin characterized by a nuclear spin quantum number I (examples, 13C, 16O, 32S have I = 0; 1H, 13C, 19F, 31P have I=1/2; 2H, 14N have I=1; 53Cr, 63Cu, 35Cl, 37Cl have I=3/2; 55Mn, 95,97Mo have I=5/2; 51V, 59Co have I=7/2, etc.) If the orbit of the unpaired electron embraces a nucleus with a non-zero spin, the energy levels of the electron will be split due to their so called hyperfine interaction resulting in the hyperfine splitting (hfs). If I = 1/2, the local magnetic field acting on the electron can be presented as Bloc = B + amI, where mI = ±½, and a is hyperfine coupling constant, i.e. the line splits into a doublet separated by a gauss. In general (2I+1) lines are observed from splittings due to one nucleus. For I = 1, as in 14,15N, the number of possible orientations of the nuclear momentum is 2I+1 =3, i.e. triplets are observed, for copper, chlorine (I=3/2) quadruplets, for manganese, molybdenum (I = 5/2) sextets, for cobalt, vanadium octets can be observed. Often not one, but two or more nuclei contribute to hfs, e.g. in bis-salicylaldimine copper EPR spectrum consist of a quadruplet due to splitting on copper nucleus (I = 3/2), where each line is further split on two equivalent nitrogens and two equivalent protons. Overall, one would expect (2×1+1) (2×1/2+1) = 15 lines in each of the four groups, although only 11 are observed due to some overlaps.

Cu

ON

O N

H

H

Characteristic shape of conventional EPR spectra is due to the fact that not the absorption, but its derivative is recorded.

Hfs is often considered as a fingerprint that helps to identify species present in a sample. However, since magnitude of the splitting depends on the distribution of the unpaired electron near the magnetic nuclei, the spectrum can also be used to map the molecular orbital occupied by that electron. There are two contributions to hyperfine interactions. An electron on p-orbital does not approach the nucleus, so it experiences a field that appears to arise from a point magnetic dipole. This is dipole-dipole interaction. This interaction is anisotropic, i.e. it depends on the orientation of the radical in respect to the magnetic field. When the radical is free to tumble (in liquid) dipole-dipole interaction averages to zero. An s electron has a spherically symmetric distribution, hence does not experience dipole-dipole interaction. However, it has a non-zero probability of being at nucleus and is subject of Fermi contact interaction, which is isotropic and shows up even in liquid phase. To give a well-resolved EPR spectrum, the sample must be paramagnetically diluted. Otherwise spin coupling between unpaired electrons broadens spectrum in a way that only a non-characteristic single line may be observed. To avoid concentrational broadening, solutions should be diluted down to at least 0.01 M. Broadening may occur on other paramagnetic species present, such as dissolved dioxygen. Therefore, in many cases, the solutions should be degassed or saturated by nitrogen, argon.

B

11

Yet another complication comes from the heavy dielectric losts when a polar solvent is present. To avoid those, either a non-polar solvent should be used, or solution may be frozen, or a special, very thin (capillary or flat) cell is applied.

You are encouraged to record, compare and discuss EPR spectra of your catalyst, manganese(II) acetate, and a dinuclear manganese complex (frozen solution in acetonitryl). The latter is a representative of the mixed valence compounds with clusters of transition metals, which have received attention, prompted in part by interest in synthesis of new catalysts, and the occurrence of mixed valence compounds in biology, such as iron in ferredoxins and manganese in some bacterial catalases or photosynthesis catalyst of water oxidation. EPR proved to be most efficient approach to characterization of such systems, applicable to both those for which comprehensive structural information is available (such as numerous synthetic complexes), and to those which could not be isolated or crystallized so far (as photosynthetic catalyst of water oxidation). One of the earliest systems, which served kind of a landmark in these studies, were mixed-valence di-manganese complexes with 2,2'-dipyridyl and o-phenanthroline [1]. In this part of the lab, EPR spectrum may be obtained of the [(bpy)2MnO2Mn(bpy)2]3+ ion, where bpy stands for 2,2'-dipyridyl, perchlorate serves as counter-ion and the entire structure may be presented as

assuming bpy planes are nearly mutually perpendicular in this chelate structure around manganese ions:

NNNNMnMnONNNNO

3+

- 3 ClO4

.2 H2O F. W. 988.5

12

The complex has been prepared from manganese(II) acetate and 2,2'-bipyridyl by careful oxidation with stoichiometric amount of potassium permanganate [2], and recrystallized from dipyridyl-nitrate buffer pH 4.5.

This complex contains two non-equivalent manganese ions, Mn(III) and Mn(IV), and so called µ-oxo bridge typical for some important biological complexes of manganese , with substantial delocalization of unpaired electron between both of them,

To get a well-resolved hyperfine structure of the EPR spectrum, approx. 0.001 M solution in acetonitryl is recommended, and spectra may be recorded using cylindrical cells below the freezing point of the solution to avoid dielectric losses due to the high dielectric constant of the solvent.

The predominant features of the EPR spectra are accounted for by the spin-Hamiltonian

H = g||βHzSz + g⊥β(HxSx + HySy) + (A1I1 + A2I2)S -2JS1S2

where S1 and I1 are the electron spin and nuclear spin operators, respectively, and A1 is the hyperfine coupling tensor for the Mn(III) ion, while terms with subscript 2 refer to the Mn(IV) ion. The total spin S = S1 + S2 , g|| and g⊥ are the principal g tensor components for axial symmetry, and J is the isotropic spin-exchange energy between Mn(III) and Mn(IV). The EPR spectra demonstrate that the largest term in spin-Hamiltonian is the exchange interaction: the spectrum is free of the forbidden hyperfine transitions Δm = +1, +2 common to d3 and d5 systems such as Mn(IV) and Mn(II). Their absence in this case is consistent with the ground spin state S = 1/2.

O Mn

Mn

O

13

The hyperfine structure is accounted for by coupling to two non-equivalent 55Mn nuclei (I = 5/2) with A1 = (167 + 3) G and A2 = (79 + 3) G. The hyperfine pattern with |A1| = 2|A2| and the small g anisotropy are consistent with high-spin Mn(III) anti-ferromagnetically coupled to Mn(IV), producing S = 2 - 3/2 = 1/2 ground state. Absence of substantial temperature dependence of the EPR spectra in a broad range of temperature is in good agreement with the isotropic Heisenberg exchange Hamiltonian H = -2JS2S2, yielding J = (-150 + 7)cm-1. The increase in separation between lines and the resolution of additional line at the high-field end of the spectrum are a consequence of the second-order corrections to the hyperfine energy. This asymmetric hyperfine structure arises because the hyperfine interaction is not small compared to the Zeeman interaction. A stick spectrum and a computer simulation predicted from the hyperfine terms in the expression for the transition energies are shown in the figure above, while the transition energies for the allowed transitions ΔM = +1, Δm1 = Δm2 = 0 within the ground doublet (obtained through second-order perturbation theory [3]) is:

EM - EM-1 = = gβH + (A1m1 + A2m2) + (2gβH)-1 {A1

2 [I1(I1+1) - m12] + A2

2 [I2(I2+1) - m22]}

where g2 = g||2 cos2θ + g⊥

2 sin2θ, θ is the angle between the symmetry axis and the external magnetic field, and m1 and m2 are the nuclear spin quantum numbers. Anisotropic hyperfine structure is not accounted for in this expression.

Di-manganese EPR References

Mixed valence interactions in di-µ-oxo-bridged manganese complexes. Electron paramagnetic resonance and magnetic susceptibility studies. S. R. Cooper, G. Ch. Dismukes, M. P. Klein, M. Calvin, J. Am. Chem. Soc. 100, 7248-7252 (1978). Mixed valence interactions in di-µ-oxo bridged manganese complexes. S. R. Cooper, M. Calvin, ibid, 99, 6623-6630 (1977). EPR of oxidized binuclear manganese cluster: a possible model of the oxygen-evolving system of photosynthesis. S. V. Khangulov, M. G. Goldfeld, et al. J. Chem. Soc. Chem Communs. 1989, 1755-1756.

EPR Spectrum of Mn(III,IV) dipyridyl complex. a - recorded at 18 K as a 0.001 M solution in acetonitryl. b - Computer simulation and stick diagram.

a

b

14

Questions

1. Elaborate on the statement that the highest ee's should be imparted to cis-olefins bearing one large and one small substituent.

2. Would you expect (R,R)- catalyst to give the same or a different enantiomer as the (S,S)- catalyst for a given olefin? Why? What can you expect for the ee's?

3. How should the ee for the epoxidation performed in this experiment (using the salen catalyst (R,R)- or (S,S)- 1a) compare to those for epoxidations performed on the same substrate but using catalysts derived from 3-alkyl substituted salicylaldehydes (such as (R,R)- or (S,S)- 1c)?

4. Give a definition of each of the following terms: i. prochiral ii. enantiotopic and diasteriotopic iii. pro-R and pro-S iv. re face and se face v. erythro and threo REFERENCES

1. Carruthers, W. Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, New York, NY, section 6.3: "Oxidation of Carbon-Carbon Double Bonds".

2. Zhang, W.; Loebach; J. L.; Wilson, S. R.; Jacobsen, E. N. J. Amer. Chem. Soc. 1990, 112, 2801-2803, and references cited therein.

3. Larrow, J. L.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J. Org. Chem., 1994, 59, 1939-1942, and references cited therein.