1. Aza Cope Rearrangement of Propargyl Enammonium
Cations Catalyzed By a Self-Assembled “Nanozyme”

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. The Cope Rearrangement
• 3,3 sigmatropic rearrangement
• Aza Cope rearrangement

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. Enammonium synthesis

6. Basic Cope rearrangement of
enammonium

7. 1
H NMR
• NMR in D2O
• Hi-res ES-TOF MS in H2O

9. 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].

10. • 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
∆
+





+
∆−
=






11. 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

12. 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

13. 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

14. Methodology
• Lowest energy conformers of neutral
amino acid
• Geometry in Gaussian
• Charge = +1; Multiplicity = 2 (ionization)
• Run CPMD simulation to test

15. “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
+
+

16. Amino Acids
• Arginine
• Asparigine
• Aspartic Acid
• Threonine
• Tryptophan

17. Radical-Cationic Arginine (Arg+•
)

18. Arg+•
0
2
4
6
8
10
12
0 100 200 300 400 500 600 700 800
Time (fs)
C-CBondLength(Angstroms)

19. 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)

20. Radical-Cationic Asparigine (Asn+•
)

21. 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)

22. Asn+•
0
1
2
3
4
5
6
7
0 100 200 300 400 500 600 700 800
Time (fs)
C-CBondDistance(Angstroms)

23. Radical-Cationic Aspartic Acid
(Asp+•
)

24. Asp+•
0
1
2
3
4
5
6
7
0 100 200 300 400 500
Time (fs)
C-CBondDistance(Angstroms)

25. Asp+•
0
1
2
3
4
5
6
0 100 200 300 400 500
Time (fs)
O-HBondDistance(Angstroms)
~124 fs

26. Radical-Cationic Threonine (Thr+•
)

27. Radical-Cationic Tryptophan (Trp+•
)

28. 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