1
2013, 113, 7402
Through the Looking Glass
(and What Alice Found There)
“Perhaps Looking-glass milk isn’t good to drink…”
3
Chiral Objects
4
R-Carvone
S-Carvone
5
Homochiral Object
6
Carbohydrates – D-form in nature
D-Glucose
L-Glucose
7
Amino Acids – L form in nature
D-Amino acid
L-Amino acid
8
Phospholipids – sn-3 in nature
3
1
sn-1-Phospholipid
1
3
sn-3-Phospholipid
9
Homochirality – required for evolution of life
• predictable and reproducible molecular and
supramolecular structure
- eff...
“Perhaps Looking-glass milk isn’t good to drink…”
D-carbohydrates
L-amino acids
D-ribose DNA & RNA
sn-3 phospholipid
L-c...
Polymorphism influences the physical
properties of many foods
Butter
β′
Margarine
β′
Chocolate
βV and βVI
12
(2002), Science, 295, 2410-2413
“The fundamental difficulty for this field is that
molecular crystals are held together b...
Free
Energy
Local Minimum
Local Minimum
Local Minimum
Local Minimum
Global Minimum
14
Typical thermodynamic stability:
α < β′< β
DSC melting
curve for three
polymorphs of
Tripalmitin
(5°C/min)
time
α
β′
β
...
16
Subcell Concept
17
18
Polymorph assignments based on XRD
short spacings
Short spacings (Å)
Subcell
TAG
1,3-DAG
1-MAG
Hexagonal
H
4.15
α
...
20
10:0
10:0
10:0
16:0
E
16:0
10:0
E′
21
Melting point of mixtures
If the clothes peg model is true then when we
combine E and E′ TAG – nothing happens!
22
Phase diagram for enantiomers of
10:0-10:0-16:0
β′
β
β′
E
R
Craven, R. J.; Lencki, R. W. Crystal Growth and Design 20...
24
So far…
in biology...
in crystallization…
Stereochemistry matters!
25
building blocks:
D-Carbohydrates
D-Ribose → RNA, DNA
L-Amino Acids → Proteins
Phospholipids
homochiral
molecules:
arch...
Enantiopure phosphatidylcholine
produces right-handed helical tubules
*
Spector, M. S.; Selinger, J. V.; Schnur, J. M. In...
Chiral
building blocks
Chiral
molecular architectures
1. Design Ideas Daily, http://dornob.com/spinal-staircase-bare-bon...
Assembly of chiral sub-units produces chiral
architectures with predictable handedness
Design Ideas Daily, http://dornob....
Nandi, N. (2012) Chirality in Biological Nanospaces: Reactions in Active Sites,
CRC Press, Boca Raton FL
30
Nandi, N. (2012) Chirality in Biological Nanospaces: Reactions in Active Sites,
CRC Press, Boca Raton FL
31
building blocks:
homochiral
heterochiral
molecules:
architectures:
space groups:
achiral
phase
behavior: solid solu...
Binary Phase Behavior for
Enantiomeric Mixtures
E-E = E-E′ = E′-E′
Solid Solution
E-E > E-E′ < E′-E′
Conglomerate
E-E ...
Binary Phase Behavior for
Enantiomeric Mixtures
E-E = E-E′ = E′-E′
Solid Solution
E-E > E-E′ < E′-E′
Conglomerate
E-E ...
Racemic membrane lipids appear to
form racemic compounds
• >35 enantiopure membrane lipids, analogues,
and associated mole...
Enantiopure TAG β′-tending
Racemic TAG β-tending
Positional
Isomer
12:0-16:0-16:0
16:0-18:1-18:0
18:0-16:0-16:0
12:0-12:0-...
Triacylglycerols - Configurations
Chair
Asymmetric Tuning Fork
37
Triacylglycerols
18:0-16:0-16:0
β′
β′ 10:0-10:0-16:0
β
β
12:0-16:0-16:0
Schlenk, W., Jr Journal of the American Oil C...
39
Triacylglycerols –
Space Group Assignments
Compound
β′ forms
8 / 13 compounds
β forms
33 / 34 compounds
Space group
S# a...
1-Monoacylglycerols (18:0-OH-OH)
β
β′
β′
Iwahashi, M.; Watanabe, Y.; Watanabe, T.; Muramatsu, M. Bulletin of the Chemic...
1-Monoacylglycerols Space Group Assignments
Compound
Enantiomer
sn-C11Br:0-OH-OH
sn-HO-HO-18:0
Racemic Mixture
rac-18:0-OH...
“It has thus been proved that the crystal form earlier known as the β′
form is optically active, and that the racemic form...
1,2-Diacylglycerol (16:0-16:0-OH)
β′
α
Iwahashi, M.; Ashizawa, K.; Ashizawa, M.; Kaneko, Y.; Muramatsu, M. Bulletin of t...
1,2-Diacylglycerol (18:0-18:0-OH)
β′
α
Iwahashi, M.; Ashizawa, K.; Ashizawa, M.; Kaneko, Y.; Muramatsu, M. Bulletin of t...
1,2-Diacylglycerols Space Group Assignments
Form
Space group
Z
E# a
Reference
sn-HO-12:0-12:0
β′
P21
2
one
1
sn...
“The respective IR spectra of both the α- and β′-polymorphic forms of
rac-PP(OH) are indistinguishable from the spectra of...
2-Monoacylglycerol
• is the only achiral class of acylglycerols
• crystallizes in a symmetric configuration
• no reported ...
*
Bredikhin, A. A.; Bredikhina, Z. A.; Zakharychev, D. V. Mendeleev Communications 2012, 22, 171
49
*
“The fact that the secondary
hydroxyl is directly bound to
the chiral centre ensures the
sensitivity of the crystal pac...
*
*
solid solution
*
racemic compound
conglomerate
Bredikhin, A. A.; Bredikhina, Z. A.; Zakharychev, D. V. Mendeleev ...
Exact same behavior is seen for acylglycerols
1,2-DAG
1,3-DAG
α
TAG and 1-MAG
*
*
solid solution
*
conglomerate
rac...
Free
Energy
Local Minimum
Local Minimum
Local Minimum
Local Minimum
Global Minimum
53
Free
Energy
Subcell
α
β′
Stereo
chemistry
β
54
Free
Energy
Solid Solution
Conglomerate
Racemic Compound
55
(2013) 85, 1852-1859
hazelnut oil
human blood
plasma
56
cellulose-tris-(3,5-dimethylphenylcarbamate)
Scalemic Mixture
10%
90%
57
Tm
α
E
Tmα
R
XE′
58
β′
Tmβ′
Tm
E
R
XE′
59
β
β′
Tmβ
Tm
E
R
XE′
60
β
β′
Tmβ′ Tmβ
Tm
α
E
Tmα
R
XE′
61
Observations / Conclusions / Future Work
• Absolutely no way stereochemistry is not
involved in the polymorphism of acylgl...
Observations / Conclusions / Future Work
• Acylglycerols (fats & oils / metabolism)
– scalemic mixtures occur in nature
• ...
Observations / Conclusions / Future Work
• encapsulated bioactives / drug delivery /
sensor technologies
– homochiral bioa...
2013, 113, 7402
Copy of slides available at:
http://snthesis.com
65
66
of 66

Polymorphism of Acylglycerols: A Stereochemical Perspective

The underlying cause for polymorphism in acyglycerols has puzzled researchers for more than 150 years. For the last 50 years or so, the subcell concept has been used to describe and understand this phenomenon. In general, there is a correlation between the crystal structure of the various polymorphs and the packing of the polymethylene chains (reflected in the subcell). This occurs because, for acylglcyerols, higher-melting polymorphs form due to an increase in packing efficiency for the polymethylene chains (i.e. packing efficiency increases α < β′ < β) . These same concepts are used to understand polymorphism in waxes and alkanes, and when applied to acylglycerols, they work reasonably well (i.e. as a rule of thumb). They are, however, of limited use in understanding more complex or exceptional polymorphic behaviors. In fact, progress in answering more difficult research problems is hindered, rather than helped, by the current reliance on the subcell concept. In this work we provide a more fundamental understanding for polymorphism in acylglycerols. Using a stereochemical approach, we are able to provide solutions and mechanisms for research questions that have challenged (and remained unanswered) by many previous workers.
Published on: Mar 4, 2016
Published in: Technology      Business      
Source: www.slideshare.net


Transcripts - Polymorphism of Acylglycerols: A Stereochemical Perspective

  • 1. 1
  • 2. 2013, 113, 7402
  • 3. Through the Looking Glass (and What Alice Found There) “Perhaps Looking-glass milk isn’t good to drink…” 3
  • 4. Chiral Objects 4
  • 5. R-Carvone S-Carvone 5
  • 6. Homochiral Object 6
  • 7. Carbohydrates – D-form in nature D-Glucose L-Glucose 7
  • 8. Amino Acids – L form in nature D-Amino acid L-Amino acid 8
  • 9. Phospholipids – sn-3 in nature 3 1 sn-1-Phospholipid 1 3 sn-3-Phospholipid 9
  • 10. Homochirality – required for evolution of life • predictable and reproducible molecular and supramolecular structure - efficient function of natural enzymes, transfer and storage of genetic information in nucleic acids • “… a detailed knowledge of the stereochemistry of intermolecular and interionic organization is ultimately required for understanding the molecular processes that characterize life.” Stewart, M. V.; Arnett, E. M. In Topics in Stereochemistry; Allinger, N. L., Eliel, E. L., Wilen, S. H., Eds.; John Wiley & Sons: New York, 1982; Vol. 13. 10
  • 11. “Perhaps Looking-glass milk isn’t good to drink…” D-carbohydrates L-amino acids D-ribose DNA & RNA sn-3 phospholipid L-carbohydrates D-amino acids L-ribose DNA & RNA sn-1 phospholipid 11
  • 12. Polymorphism influences the physical properties of many foods Butter β′ Margarine β′ Chocolate βV and βVI 12
  • 13. (2002), Science, 295, 2410-2413 “The fundamental difficulty for this field is that molecular crystals are held together by a multitude of weak interactions, a huge number of free energy minima (polymorphs) exist within a few kilojoules/mol of the global minimum.” 13
  • 14. Free Energy Local Minimum Local Minimum Local Minimum Local Minimum Global Minimum 14
  • 15. Typical thermodynamic stability: α < β′< β DSC melting curve for three polymorphs of Tripalmitin (5°C/min) time α β′ β 15
  • 16. 16
  • 17. Subcell Concept 17
  • 18. 18
  • 19. Polymorph assignments based on XRD short spacings Short spacings (Å) Subcell TAG 1,3-DAG 1-MAG Hexagonal H 4.15 α Triclinic parallel T∥ 4.6, 3.8 β Orthorhombic perpendicular O 4.20, 3.80 β′ O′ 4.27, 3.97, 3.71 Monoclinic parallel M∥ 4.57, 4.35, 3.85 β1, β2 Orthorhombic parallel O∥ 4.61, 4.12, 3.75 branched-chain PUFA O∥′ 4.71, 4.05, 3.78 Larsson, K. Acta Chemica Scandinavica, 1966, 20, 2255 β1, β2 β′1, β′2 cis 18:1 19
  • 20. 20
  • 21. 10:0 10:0 10:0 16:0 E 16:0 10:0 E′ 21
  • 22. Melting point of mixtures If the clothes peg model is true then when we combine E and E′ TAG – nothing happens! 22
  • 23. Phase diagram for enantiomers of 10:0-10:0-16:0 β′ β β′ E R Craven, R. J.; Lencki, R. W. Crystal Growth and Design 2011, 11, 1723. E′ 23
  • 24. 24
  • 25. So far… in biology... in crystallization… Stereochemistry matters! 25
  • 26. building blocks: D-Carbohydrates D-Ribose → RNA, DNA L-Amino Acids → Proteins Phospholipids homochiral molecules: architectures: space groups: chiral 26
  • 27. Enantiopure phosphatidylcholine produces right-handed helical tubules * Spector, M. S.; Selinger, J. V.; Schnur, J. M. In Materials-Chirality; Topics in Stereochemistry, Vol. 24. 27
  • 28. Chiral building blocks Chiral molecular architectures 1. Design Ideas Daily, http://dornob.com/spinal-staircase-bare-bones-steps-inspired-byvertebrae/ accessed Feb 2, 2013 28
  • 29. Assembly of chiral sub-units produces chiral architectures with predictable handedness Design Ideas Daily, http://dornob.com/spinal-staircase-bare-bones-steps-inspired-by-vertebrae/ accessed Feb 2, 2013 29
  • 30. Nandi, N. (2012) Chirality in Biological Nanospaces: Reactions in Active Sites, CRC Press, Boca Raton FL 30
  • 31. Nandi, N. (2012) Chirality in Biological Nanospaces: Reactions in Active Sites, CRC Press, Boca Raton FL 31
  • 32. building blocks: homochiral heterochiral molecules: architectures: space groups: achiral phase behavior: solid solution racemic compound chiral conglomerate 32
  • 33. Binary Phase Behavior for Enantiomeric Mixtures E-E = E-E′ = E′-E′ Solid Solution E-E > E-E′ < E′-E′ Conglomerate E-E ≈ E-E′ ≈ E′-E′ near R, E-E′ > RC-E near E, E-E > RC-E Racemic Compound Roozeboom, H. W. B. (1899) Z. Phys. Chem., 28, 494 cited in Jacques, Collet and Wilen (1981) Enantiomers, Racemates, and Resolutions. 33
  • 34. Binary Phase Behavior for Enantiomeric Mixtures E-E = E-E′ = E′-E′ Solid Solution E-E > E-E′ < E′-E′ Conglomerate E-E ≈ E-E′ ≈ E′-E′ near R, E-E′ > RC-E near E, E-E > RC-E Racemic Compound Roozeboom, H. W. B. (1899) Z. Phys. Chem., 28, 494 cited in Jacques, Collet and Wilen (1981) Enantiomers, Racemates, and Resolutions. 34
  • 35. Racemic membrane lipids appear to form racemic compounds • >35 enantiopure membrane lipids, analogues, and associated molecules1 – mostly P21 • racemic mixtures (which must be at least 50% synthetic)1,2 – P1 or P21/a 1. Pascher et al. (1992) Biophys. Acta, 1113, 339 2. Dorset (1990) Biophys. J., 58, 1077 35
  • 36. Enantiopure TAG β′-tending Racemic TAG β-tending Positional Isomer 12:0-16:0-16:0 16:0-18:1-18:0 18:0-16:0-16:0 12:0-12:0-18:0 12:0-12:0-14:0 16:0-16:0-14:0 10:0-10:0-16:0 Enantiomer Tm(°C) Polymorph 53.9 β′ 34.5 β′ 64.0 β′ 60 β′ 45 β′ 43 β′ 54.8 β′ 32.90 β′ Racemic mixture Tm(°C) Polymorph 55.8 β 38 β 62.9 β 61 β 45 β 42 β β 33.38 β reference Schlenk Jr, 1965 Stahl, Persmark, Herslof, 1976 Sato et al., 2001 Craven, Lencki, 2011 36
  • 37. Triacylglycerols - Configurations Chair Asymmetric Tuning Fork 37
  • 38. Triacylglycerols 18:0-16:0-16:0 β′ β′ 10:0-10:0-16:0 β β 12:0-16:0-16:0 Schlenk, W., Jr Journal of the American Oil Chemist's Society 1965, 42, 945. Craven, R. J.; Lencki, R. W. Crystal Growth and Design 2011, 11, 1723. β′ 38
  • 39. 39
  • 40. Triacylglycerols – Space Group Assignments Compound β′ forms 8 / 13 compounds β forms 33 / 34 compounds Space group S# a C2 / I2 one P1 both a. S# ≡ number of stereoisomers in the unit cell determined by the lack or presence of a reflective symmetry operation for the designated space group. 40
  • 41. 1-Monoacylglycerols (18:0-OH-OH) β β′ β′ Iwahashi, M.; Watanabe, Y.; Watanabe, T.; Muramatsu, M. Bulletin of the Chemical Society of Japan 41 1984, 57, 1446.
  • 42. 1-Monoacylglycerols Space Group Assignments Compound Enantiomer sn-C11Br:0-OH-OH sn-HO-HO-18:0 Racemic Mixture rac-18:0-OH-OH rac-16:0-OH-OH Form Space group Z Z′ E# a Reference β′ β′ P21 P212121 4 8 2 2 one one 1 2 β1 β2 P21/m Am 8 8 both 3 both 3 a. E# ≡ number of enantiomers in the unit cell determined by the lack or presence of a reflective symmetry operation for the designated space group. 1. Larsson, K. Acta Crystallographica 1966, 21, 267. 2. Goto, M.; Kozawa, K.; Uchida, T. Bulletin of the Chemical Society of Japan 1988, 61, 1434. 3. Larsson, K. Arkiv fur Kemi 1964, Band 32, 29. 42
  • 43. “It has thus been proved that the crystal form earlier known as the β′ form is optically active, and that the racemic form is separated into antipode crystals on rapid crystallization. … A single-crystal analysis of the β1 form, earlier known as the β form, has shown that it is a racemic form. “ [Larsson, 1964, Arkiv for Kemi, 23, 35] “The β′ form of a racemic mixture, however, is isomorphous with the β′ form of optically active 1-monoglyceride, so obviously the two antipodes separate into D- and L-crystals.” [Hernquist in Garti and Sato, 1988] “Single-crystal analysis of the β1 form of racemic monostearin shows that this form contains both enantiomers in the same crystal.” [Hernquist in Garti and Sato, 1988] For racemic mixtures of 1(3)-MAG in the β form “… alternative distribution of D- and L- molecules in the unit cell.” “… mirror symmetry relating the associated molecules.” [Larsson, 1964, Arkiv for Kemi, 23, 35] 43
  • 44. 1,2-Diacylglycerol (16:0-16:0-OH) β′ α Iwahashi, M.; Ashizawa, K.; Ashizawa, M.; Kaneko, Y.; Muramatsu, M. Bulletin of the Chemical Society44 of Japan 1984, 57, 956.
  • 45. 1,2-Diacylglycerol (18:0-18:0-OH) β′ α Iwahashi, M.; Ashizawa, K.; Ashizawa, M.; Kaneko, Y.; Muramatsu, M. Bulletin of the Chemical Society45 of Japan 1984, 57, 956.
  • 46. 1,2-Diacylglycerols Space Group Assignments Form Space group Z E# a Reference sn-HO-12:0-12:0 β′ P21 2 one 1 sn-16:0-16:0-OH β′ P21 2 one 2-5 Compound Enantiomers Racemic Mixture rac-16:0-16:0-OH α subcell plane group: p6m — 6 electron diffraction a. E# ≡ number of enantiomers in the unit cell determined by the lack or presence of a reflective symmetry operation for the designated space group. 1. 2. 3. 4. 5. 6. Pascher, I.; Sundell, S.; Hauser, H. Journal of Molecular Biology 1981, 791. Albon, N.; Baret, J. F. Journal of Physical Chemistry 1984, 88, 6333. Dorset, D. L.; Pangborn, W. A. Chemistry and Physics of Lipids 1988, 48, 19. Mo, F.; Hauback, B. C.; Albon, N. Journal of Physical Chemistry 1993, 97, 6083. Han, G. W.; Ruble, J. R.; Craven, B. M. Chemistry and Physics of Lipids 1994, 71, 219. Dorset, D. L. Chemistry and Physics of Lipids 1974, 13, 133. 46
  • 47. “The respective IR spectra of both the α- and β′-polymorphic forms of rac-PP(OH) are indistinguishable from the spectra of the corresponding polymorphs of sn-PP(OH). This is indicative of identical structure and environment between the sn- and rac-PP(OH) in their respective polymorphic forms. ”[Shannon et al. 1992] “However, both X-ray diffraction patterns (including X-ray small angle diffraction) and the infrared absorption spectra were almost the same between (R)- and (RS)-forms irrespective of their crystalline forms. ” [Iwahashi et al, 1984] “Melting temperatures for the racemic 1,2-DGs are systematically 6°C lower than those for the corresponding [enantiopure] 1,2DGs.” [Kodali et al 1990] 47
  • 48. 2-Monoacylglycerol • is the only achiral class of acylglycerols • crystallizes in a symmetric configuration • no reported polymorphism 48
  • 49. * Bredikhin, A. A.; Bredikhina, Z. A.; Zakharychev, D. V. Mendeleev Communications 2012, 22, 171 49
  • 50. * “The fact that the secondary hydroxyl is directly bound to the chiral centre ensures the sensitivity of the crystal packing to chirality effects.” Bredikhin, A. A.; Bredikhina, Z. A.; Zakharychev, D. V. Mendeleev Communications 2012, 22, 171 50
  • 51. * * solid solution * racemic compound conglomerate Bredikhin, A. A.; Bredikhina, Z. A.; Zakharychev, D. V. Mendeleev Communications 2012, 22, 171 51
  • 52. Exact same behavior is seen for acylglycerols 1,2-DAG 1,3-DAG α TAG and 1-MAG * * solid solution * conglomerate racemic compound Bredikhin, A. A.; Bredikhina, Z. A.; Zakharychev, D. V. Mendeleev Communications 2012, 22, 171 52
  • 53. Free Energy Local Minimum Local Minimum Local Minimum Local Minimum Global Minimum 53
  • 54. Free Energy Subcell α β′ Stereo chemistry β 54
  • 55. Free Energy Solid Solution Conglomerate Racemic Compound 55
  • 56. (2013) 85, 1852-1859 hazelnut oil human blood plasma 56 cellulose-tris-(3,5-dimethylphenylcarbamate)
  • 57. Scalemic Mixture 10% 90% 57
  • 58. Tm α E Tmα R XE′ 58
  • 59. β′ Tmβ′ Tm E R XE′ 59
  • 60. β β′ Tmβ Tm E R XE′ 60
  • 61. β β′ Tmβ′ Tmβ Tm α E Tmα R XE′ 61
  • 62. Observations / Conclusions / Future Work • Absolutely no way stereochemistry is not involved in the polymorphism of acylglycerols – suggesting that acylglycerols behave like all other molecules with a stereocenter – the most important factor (?) 62
  • 63. Observations / Conclusions / Future Work • Acylglycerols (fats & oils / metabolism) – scalemic mixtures occur in nature • frequently <—> rarely ? – crystallization POS in cocoa butter / POO in palm 63
  • 64. Observations / Conclusions / Future Work • encapsulated bioactives / drug delivery / sensor technologies – homochiral bioactives / homochiral membranes / homochiral enzymes / homochiral active sites 64
  • 65. 2013, 113, 7402 Copy of slides available at: http://snthesis.com 65
  • 66. 66

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