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Aza Cope Rearrangement of Propargyl Enammonium
Cations Catalyzed By a Self-Assembled “Nanozyme”
Dr. Kenneth Raymond
Born 1942; B. A. Reed College (1964); Ph. D. Northwestern
University (1968); Alfred P. Sloan Research ...
The Cope Rearrangement
• 3,3 sigmatropic rearrangement
• Aza Cope rearrangement
The Catalyst
• M4L6
12-
assembly
• M = Ga3+
(Al3+
, Fe3+
); L = N,N’-bis(2,3-dihydroxybenzoyl)-
1,5-diaminonaphthalene
• R...
Enammonium synthesis
Basic Cope rearrangement of
enammonium
1
H NMR
• NMR in D2O
• Hi-res ES-TOF MS in H2O
Rate constants
Compound R kfree=(10-8
s-1
) kencaps=(10-8
s-1
) kencaps/kfree
2 H 62.4 237 4
3 Me 62.3 6200 100
4 Et 20.0 ...
• Catalyzed reaction on the left; uncatalyzed on
the right. ΔH‡
is more negative for the catalyzed
reaction
• Entropy for ...
Michaelis-Menten in the house
Vmax = 1.2 x 10-4
mM.s-1
Km = 0.67 mM
kcat = 7.0 x 10-5
s-1
Vmax = ~1.05 x 10-4
mM.s-1
Km = ...
The Emergence of a New Radical-Cationic
Amino Acid Dynamics:
The Proton Patches Model
Matthew MacLennan
1 J. Mol. Struct. ...
Dr. Galina Orlova
Rostov University, Russia, 1981-1998
(R. Minyaev)
Southern Illinois University at
Carbondale 1996/97 (S....
Methodology
• Lowest energy conformers of neutral
amino acid
• Geometry in Gaussian
• Charge = +1; Multiplicity = 2 (ioniz...
“Proton Scissors”
12 AWFULLY
COMPLICATED
STEPS
This fragmentation of C-N bond to give
oxazolone cation and neutral fragmen...
Amino Acids
• Arginine
• Asparigine
• Aspartic Acid
• Threonine
• Tryptophan
Radical-Cationic Arginine (Arg+•
)
Arg+•
0
2
4
6
8
10
12
0 100 200 300 400 500 600 700 800
Time (fs)
C-CBondLength(Angstroms)
Arg+•
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0 100 200 300 400 500 600 700 800
Time (fs)
N-HBondDistance(Angstroms)
Radical-Cationic Asparigine (Asn+•
)
Asn+•
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
2.2
0 100 200 300 400 500 600 700 800
Time (fs)
O-HBondDistance(Angstroms)
Asn+•
0
1
2
3
4
5
6
7
0 100 200 300 400 500 600 700 800
Time (fs)
C-CBondDistance(Angstroms)
Radical-Cationic Aspartic Acid
(Asp+•
)
Asp+•
0
1
2
3
4
5
6
7
0 100 200 300 400 500
Time (fs)
C-CBondDistance(Angstroms)
Asp+•
0
1
2
3
4
5
6
0 100 200 300 400 500
Time (fs)
O-HBondDistance(Angstroms)
~124 fs
Radical-Cationic Threonine (Thr+•
)
Radical-Cationic Tryptophan (Trp+•
)
Summary
• Radical-cationic amino acids do not obey the
“proton scissors” motif (Proton transfer before C-
C bond cleavage)...
Aza Cope Rearrangement of Propargyl Enammonium Cations Catalyzed by a Self-Assembled "Nanozyme"
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Aza Cope Rearrangement of Propargyl Enammonium Cations Catalyzed by a Self-Assembled "Nanozyme"

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Aza Cope Rearrangement of Propargyl Enammonium Cations Catalyzed by a Self-Assembled "Nanozyme"

  1. 1. Aza Cope Rearrangement of Propargyl Enammonium Cations Catalyzed By a Self-Assembled “Nanozyme”
  2. 2. Dr. Kenneth Raymond Born 1942; B. A. Reed College (1964); Ph. D. Northwestern University (1968); Alfred P. Sloan Research Fellow (1971- 1973); Miller Research Professor (1977-1978, 1996, 2004); Guggenheim Fellow (1980-1981); Selected as one of the "Technology 100, 1981" by Technology Magazine; American Association for the Advancement of Science Fellow (1984); DOE Ernest O. Lawrence Award (1984); Lawrence Berkeley Laboratory Technology Transfer award (1988, 1991); Humboldt Research Award for Senior U.S. Scientists (1992); American Chemical Society Alfred Bader Award in Bioinorganic or Bioorganic Chemistry (1994); Erskine Fellow, University of Canterbury, New Zealand (1997); Elected to National Academy of Sciences (1997); Basolo Medal, Northwestern University (1997); Max-Planck-Institut fur Strahlenchemie "Frontiers in Biological Chemistry" Award (1997); Elected to the American Academy of Arts and Sciences (2001); Reed College Howard Vollum Award (2002); ACS Auburn Section G. M. Kosolapoff Award (2004); Izatt-Christensen Award in Macrocyclic Chemistry (2005); Joe L. Franklin Memorial Lectureship (2006); Paulo Fasella Lectureship (2006); UC Berkeley Chancellor's Professor, (2007-). 426 Pubs 126 Inorg Chem 113 JACS 21 Angew
  3. 3. The Cope Rearrangement • 3,3 sigmatropic rearrangement • Aza Cope rearrangement
  4. 4. The Catalyst • M4L6 12- assembly • M = Ga3+ (Al3+ , Fe3+ ); L = N,N’-bis(2,3-dihydroxybenzoyl)- 1,5-diaminonaphthalene • Racemic mixture of homochiral ΔΔΔΔ and ΛΛΛΛ enantiomers • Anionic nature makes soluble in H2O, with hydrophobic core • Water-labile cations (ketone-derived iminium ions, diazonium, tropylium, phosphine-acetone adducts) are encapsulated
  5. 5. Enammonium synthesis
  6. 6. Basic Cope rearrangement of enammonium
  7. 7. 1 H NMR • NMR in D2O • Hi-res ES-TOF MS in H2O
  8. 8. Rate constants Compound R kfree=(10-8 s-1 ) kencaps=(10-8 s-1 ) kencaps/kfree 2 H 62.4 237 4 3 Me 62.3 6200 100 4 Et 20.0 3670 184 5 n-Pr 19.5 1920 98 6 i-Pr 6.7 870 129 7 n-Bu 15.1 73 5 8 i-Bu 17.0 477 28 9 s-Bu 50.0 1150 23 R=Me has fastest encapsulation rate; zeroth order when >3 eq substrate; RLS = rearrangementrate depends on [host-bound substrate].
  9. 9. • Catalyzed reaction on the left; uncatalyzed on the right. ΔH‡ is more negative for the catalyzed reaction • Entropy for catalyzed reaction is >20 J/mol more positive than for uncatalyzed • Entropy-based rate increase R S h k RT H T k Brate ‡‡ lnln ∆ +      + ∆− =     
  10. 10. Michaelis-Menten in the house Vmax = 1.2 x 10-4 mM.s-1 Km = 0.67 mM kcat = 7.0 x 10-5 s-1 Vmax = ~1.05 x 10-4 mM.s-1 Km = >1.7 mM kcat = ? x 10-5 s-1
  11. 11. The Emergence of a New Radical-Cationic Amino Acid Dynamics: The Proton Patches Model Matthew MacLennan 1 J. Mol. Struct. THEOCHEM 0 Angew. Chem. 0 JACS
  12. 12. Dr. Galina Orlova Rostov University, Russia, 1981-1998 (R. Minyaev) Southern Illinois University at Carbondale 1996/97 (S. Scheiner) University at Guelph 1998/2002 (J. D. Goddard) York University 2002/2004 (K.W.M. Siu, D.K. Bohme, A.C. Hopkinson) 42 Pubs 10 J Phys Chem A 5 JACS
  13. 13. Methodology • Lowest energy conformers of neutral amino acid • Geometry in Gaussian • Charge = +1; Multiplicity = 2 (ionization) • Run CPMD simulation to test
  14. 14. “Proton Scissors” 12 AWFULLY COMPLICATED STEPS This fragmentation of C-N bond to give oxazolone cation and neutral fragment occurs at 31.3 kcal/mol. This size barrier is common with protonated species (between 30 and 40 kcal/mol). The fragmentation of any C-N or C-C bond in GGG is always preceded by proton transfer. Fragments + +
  15. 15. Amino Acids • Arginine • Asparigine • Aspartic Acid • Threonine • Tryptophan
  16. 16. Radical-Cationic Arginine (Arg+• )
  17. 17. Arg+• 0 2 4 6 8 10 12 0 100 200 300 400 500 600 700 800 Time (fs) C-CBondLength(Angstroms)
  18. 18. Arg+• 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 0 100 200 300 400 500 600 700 800 Time (fs) N-HBondDistance(Angstroms)
  19. 19. Radical-Cationic Asparigine (Asn+• )
  20. 20. Asn+• 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 0 100 200 300 400 500 600 700 800 Time (fs) O-HBondDistance(Angstroms)
  21. 21. Asn+• 0 1 2 3 4 5 6 7 0 100 200 300 400 500 600 700 800 Time (fs) C-CBondDistance(Angstroms)
  22. 22. Radical-Cationic Aspartic Acid (Asp+• )
  23. 23. Asp+• 0 1 2 3 4 5 6 7 0 100 200 300 400 500 Time (fs) C-CBondDistance(Angstroms)
  24. 24. Asp+• 0 1 2 3 4 5 6 0 100 200 300 400 500 Time (fs) O-HBondDistance(Angstroms) ~124 fs
  25. 25. Radical-Cationic Threonine (Thr+• )
  26. 26. Radical-Cationic Tryptophan (Trp+• )
  27. 27. Summary • Radical-cationic amino acids do not obey the “proton scissors” motif (Proton transfer before C- C bond cleavage); we see variety • Arg+• , Asp+• , and Thr+• (conformer 2) show C-C bond cleavage before proton transfer • Asn+• shows C-C bond cleavage and proton transfer occurring almost simultaneously • Thr+• , Trp+• show C-C bond cleavage without any proton transfer • Explanation for lack of IE potentials of amino acids

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