I also express my sincere gratitude to all the faculty members, Department of Chemistry, IIT Guwahati for their help and encouragement. I am grateful to all the research scientists and M.Sc students of Department of Chemistry, IIT Guwahati for their help.
Separation of Biogenic amino alcohols
The results in this chapter highlighted the complex nature of crystallization separation, where a subtle change in the host can alter the crystallization pathway (Figure 4).
Few more examples and identification of the factors
Schematic representation of observations on chiral enhancement of amine and amino alcohols by two binuclear hosts. The amino alcohols were chosen to have a chiral center either near the amine or near the alcohol group.
Chapter-1
Introduction
The model explains the differential binding of the two enantiomers at a three-point chiral site in the selector. The small molecular weight and rigidity of the metal complexes can produce a structurally characterized host-guest adduct, which in turn can contribute to the understanding of the chiral recognition mechanism.
Chapter- 2
Crystallinity vs. Solution equilibrium
Material and Methods .1 Solvents and reagents
- Measurements
Solid state magnetic susceptibility of the complexes at room temperature was recorded using Sherwood Scientific Magnetic balance MSB-1. Most of the hydrogen atoms attached to the solvent molecules could not be detected or fixed, so the molecular weight may not match.
Syntheses
Crystallographic data and details of refinements are listed in Table 2.1, and selected bond distances and angles for are listed in Table 2.2a,b.
Estimation of enantiomeric separation through HPLC
- Procedure of recovery of amine from metal complexes as crystal
- Procedure of recovery of amine from amorphous metal complexes
- Derivatization of chiral amine With Benzoyl Chloride
The free amine was extracted from Na2CO3 in water-ethyl acetate and the organic fraction was separated, dried and evaporated to dryness. Guest amines from the crystals were also recovered by decomposition of the metal complex with dil.
Result and Discussion
- Syntheses and isolation host-guest complexes
- X-ray Structure of ((rac)-1-phenylethylammonium)[Ni 2 (L L-his ) 2 (OAc)]
- Thermogravimetric analysis of complexes
- Powder X-ray diffraction analysis of complexes
- Recovery of the chiral guest amine and determination of enantiomeric enhancement through HPLC
- Effect of the solubility and crystalization on chiral enahancement
The molecular structure of the dinuclear Ni(II) anion is almost identical to that in R-2. The phase purity of the complexes was further checked by the powder X-ray diffraction (PXRD) pattern (Figure 2.6). Structural data of rac-4 host-guest adducts showed that, in the crystal, the (S)-isomer of the amine was preferentially recognized (∼10% ee).
S amine in the bulk of the crystals, the free amine was isolated by releasing the gas from the host-guest adducts.
Conclusions
This is perhaps the reason for significant chiral enhancement present in solution for 1-amino-2-propanol. Participation of polar solvent caused further difficulties in assigning their relative contributions to chiral enhancement. This and the participation of solvent molecules in the H-bonding caused difficulties in determining the relative contribution of individual interactions to chiral enhancement.
The chiral enhancement of S-isomer could be attributed to a combination of lower solubility and channel structures in the lattice.
Change in crystallization pathway by modifying cavity
Material and Methods .1 Solvents and reagents
- Measurements
All geometric and intensity data for the crystals were collected at room temperature using a Bruker SMART APEX CCD diffractometer equipped with a fine focus 1.75 kW sealed tube Mo-Ka Å) X-ray source with increasing ω (width of 0.3º per frame) at a scanning speed of either 3 or 5 s/frame. The SMART software was used for data acquisition and the SAINT software for data extraction. Crystallographic data and details of refinements are given in Table 3.1, and selected bond distances and angles for are listed in Table 3.2a.
Syntheses
After 3 hours, the solution is stirred, concentrated with a rotary evaporator and 10 ml of acetonitrile is added for complete precipitation. The sticky green mass was dissolved in 6 ml of acetonitrile and methanol (v/v, 1:1) in a beaker and kept for slow evaporation at room temperature. After 1 h, the stirred solution was concentrated to 5 mL with a rotary evaporator and kept for slow evaporation at room temperature.
Estimation of enantiomeric separation through HPLC
- Procedure of recovery of amine from metal complexes as crystal
- Procedure of recovery of amine from amorphous metal complexes
The guest amines from the crystals were also obtained by decomposition of the metal complex with dil.HCl, followed by extraction of the amine from the aqueous solution with ethyl acetate. However, the acidification method produces fragments of the ligand, giving additional peaks in the HPLC trace. Add 2 equivalents of the racemic mixture of 1-phenylethylamine to the resulting solution and stir for 4 hours.
The mixture was evaporated to dryness and 6 ml of mixture of diethyl ether and acetonitrile (5:1) was added, a blue precipitate was obtained and filtered.
Schematic representation of recovery of the bounded amine from host- guest complexes as either crystals or precipitations
- Derivatization of chiral amine With Benzoyl Chloride
- Result and Discussion
- Synthesis and characterization of monomer as chiral monobasic acid
- Syntheses and isolation of host-guest complexes
- Crystal Structure of complex 2 and complex 3
From the graph (Figure 3.1), the pKa of the acidic proton was determined to be 6.7, which is comparable to the 6.6 of the histidine analog. Crystals isolated from the first two syntheses, complex 2 and complex 3, respectively, were purely diastereomeric to each other. The third reaction with racemic amine showed that although the isolated crystals were visually similar (Figure 3.2), upon structural characterization they contained both 4 and 5.
The complex 6 is obtained from the metathesis reaction between host-guest complex and KNO3, carried out for the recovery of bound amine in host-guest adduct (Scheme 3.1).
Both 2 and 3, synthesized using enantiopure amine, were crystallized in identical space group P3 2 (Table 3.1) and quite similar in terms of molecular structure
- Crystal Structure of complexes 4 and 5
- Crystal Structure of complexes 6
- Chiral enahancement determined by the HPLC analysis
- Powder X-Ray Diffraction analysis of 2 and 3
- Thermogravimetric analysis of 2 and 3
- Conclusion
- References
Compared to this, chiral amino alcohols with histidine analogue show an improvement even in the amorphous state. This lower difference in solubility and crystal lattice similarity between two pure diastereomers in the present case probably promoted the formation of individual crystals of both pure diastereomers in a mixture (Scheme 3.2). The diffraction pattern observed for the mixture of 4 and 5 appears to be a combination of patterns from both 2 and 3, indicating that both are present in the crystals from the racemic amine reaction.
However, elemental analysis on the crystals supports the formula as observed in the crystal structure (two waters in each case).
Chapter - 4
Enantiomeric Separation of Biogenic Amino alcohols
Material and Methods .1 Solvents and reagents
- Measurements
Details of the solvent purification and analytical measurements have already been discussed in Chapter 2. Dihydroxy-phenethylamine hydrochloride was purchased from Aldrich Chemical Co. and L-Metheonine was purchased from Sisco Research Laboratories Pvt. SRL), India, and used as received. Some solvent molecules, methanol and water in some complexes were isotropically refined to avoid alert level A at checkcif. Where possible, the hydrogen atoms were located based on the difference Fourier maps and have been isotropically refined.
Crystallographic data and details of refinements are given in Table 4.1, and selected bond distances and angles for are given in Table 4.2a, b.
Syntheses
The complex was synthesized following the same procedure as in 1L using the ligand H2LD-met (0.150 g, 0.40 mmol) instead of ligand H2LL-met from 2-amino-1-phenylethanol. The complex was synthesized following the same procedure as in 1L using the ligand H2LD-met (0.150 g, 0.40 mmol) instead of ligand H2LL-met from pure (R)-(-)-2-amino- 1-phenylethanol. Because the complex was soluble in both methanol and acetonitrile, the complex was isolated as a light blue solid by precipitation with a mixture of acetonitrile and diethyl ether (1:3) and dried in a vacuum desiccator.
The complex was synthesized by following the same procedure as in 2L using the ligand H2LD-met (0.150 g, 0.40mmol) instead of ligand H2LL-met from 3, - dihydroxyphenethylamine hydrogen chloride.
Estimation of enantiomeric separation through HPLC
- Procedure of recovery of amine from metal complexes as crystal
- Procedure of recovery of amine from amorphous metal complexes
- Derivatization of chiral amine with Benzoyl Chloride
Result and Discussion
- Syntheses and isolation host-guest complexes
- X-Ray crystal structure of 1L and 1D
- X-Ray crystal structure of 2L and 2D
- Thermogravimetric analysis of complexes
- Powder X-Ray diffraction analysis of complexes
- Enantiomeric separation of amino alcohols estimated by HPLC analysis From the Chapter 2, recovery and isolation of the recognized guest amine has
- General motif of recognition between host and guest
- Utility of this method
Although 1L and 2L are enantiomers to each other, due to the different position of the solvent molecule in the lattice, a small difference in the number and type of intermolecular non-covalent interactions is present between two enantiomers (Figure 4.2c & d, Table 4.3). Structural analysis of the complexes, 2L and 2D shows that both enantiomers are resolved in the same space group P21 (Table 4.1), leaving a similar structure for the different number of solvent molecules, i.e. two methanol and six water molecules respectively (Figure 4.3a and b). It shows a similar diffraction pattern to crystal of 1D, which also confirms the microcrystalline nature of host-guest adduct in solution (Figure 4.6a).
Other analyzes of 1Da support complex formation, PXRD shows the nature of the solid as amorphous (Figure 4.6a).
Conclusions
Considering the simplicity of the reaction from a relatively cheaper component, this method is not impractical. The use of di-O-p-toluoyl-tartaric acid needs the partial crystallization method, which is not necessary for the present method since the other diastereomer does not crystallize.
Chapter - 5
Few more examples and identification of the factors
Material and Methods .1 Solvents and reagents
- Measurements
Where possible, the hydrogen atoms were located from the various Fourier maps and refined isotropically. Crystallographic data and details of refinements are given in Table 5.1, and selected bond distances and angles are listed in Table 5.2.
Syntheses
This was synthesized following the same procedure as 2 using pure ( R )-2-amino-1-propanol instead of racemic 2-amino-1-propanol. Blue diamond-shaped crystals were obtained from the methanolic solution after several days at room temperature. This was synthesized following the same procedure as 4 using pure ( S )-2-amino-1-butanol instead of racemic 2-amino-1-butanol.
It was synthesized following the same procedure as 4 using pure ( R )-2-amino-1-butanol instead of racemic 2-amino-1-butanol.
Estimation of enantiomeric separation through HPLC
Result and Discussion
- Syntheses and isolation host-guest complexes
- Molecular Structure of complex 1
- Molecular structure of complexes 2 and 3
- Molecular structure of complexes 4 and 5
- Powder X-Ray diffraction analysis
- Chiral enahancement determined by the HPLC
- Comparison of crystal lattice and the solubility difference
The alcoholic O6 is H-bonded to another terminal carboxylate O2 (Figure 5.2a) and solvent molecules to form a H-bonded network. Within the crystal lattice, one water molecule exhibits tetrahedral H-bonding with two water and two terminal carboxylate oxygens participating in the formation of one pseudo-water chain intercalated by gasamine (Figure 5.2c). Diffraction pattern of complex 4, crystals isolated from racemic Am5, differs from complexes 5 and 6, but matches simulated pattern reasonably (Figure 5.5b).
The structural analysis of both diastereomers reveals a small difference in crystal lattice between two diastereomers (Figure 5.6), resulting in a small difference in solubility between complex 2 and 3.
Conclusions
Other results in this section are that (a) in the case of 1-amino-2-propanol, S-isomer is recognized with comparable % of resolution (98% ee) to the previous result (100% ee) that remains similar recognition site with anionic host (b) by changing the host, from racemic 2-amino-1-propanol, S-isomer is recognized over R-isomer with 70% ee. In histidine-derived host, R-isomer guest amino alcohol was recognized over S-isomer from racemic mixture by H-bonding through -NH3+. However, in the case of methionine-derived host, the spatial orientation of the guest is such that the -NH 3+ and the -OH group are not H-bonded with the same host.
These differences may have influenced the recognition of the S isomer compared to the R isomer from a racemic mixture (Figure 5.8). (c) Although 2-amino-1-butanol is a higher carbon analog of 2-amino-1-propanol, its recognition behavior through noncovalent interactions is most likely significantly altered due to the presence of a bulkier –Et- group instead of -Me group attached to chiral carbon.
FINDINGS OF THE THESIS
In the stepwise progress, we establish some factors in the recognition process which are mainly attributed to different percentage chiral resolution of amine and amino alcohols. Curiously, two amino alcohols with phenyl ring showed much higher dissolution enhancement (70% ee) than the three amino alcohols without phenyl ring (15–25% ee). When tested with racemic gas, the isolated host-gas adduct showed chiral enhancement of the diastereomer with the lower solubility.
In amino alcohols substituted with phenyl ring, due to the presence of an additional intermolecular non-covalent C(H)..interaction between aromatic ring and neighboring host, chiral enhancement (70% ee) is in solution equilibrium.
