prebiotic synthesis of adenine. hydrogen atom tunneling in the virtual [1,7]-sigmatropic...
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Prebiotic Synthesis of Adenine. Hydrogen Atom Tunneling in the Virtual
[1,7]-Sigmatropic Rearrangement of Monocyclic HCN-Pentamer
Rainer Glaser,a,* Jian Yin,a Jingjing Zheng,b and Donald G. Truhlarb,*
(a) Department of Chemistry, University of Missouri, Columbia, Missouri 65211, and
(b) Department of Chemistry and Supercomputer Institute, University of Minnesota,
207 Pleasant Street S.E., Minneapolis, Minnesota 55455
Adenine from HCN
Ponnamperuma was well known for his work on the chemical basis for the origin of life, and for showing that the basic building blocks of DNA and RNA molecules could be synthesized outside living cells. His interest in this subject area goes back to his student days, when as an undergraduate at Birbeck College, University of London, England (B.S. 1959), he studied under the guidance of J. D. Bernal, followed by a doctorate (1962) under Nobel laureate Melvin Calvin at the University of California, Berkeley. A native of Sri Lanka, Ponnamperuma also received a bachelor's degree in philosophy from the University of Madras, India, in 1948. After receiving his Ph.D., Ponnamperuma was associated with several institutions in the United States and abroad, coming to UMCP in 1971.
The Scientist 9[2]:3, Jan. 23, 1995.
CYRILPONNAMPERUMA
1924 - 1995
HCN Pentamerization: The Ponnamperuma Experiment
In one of the first experiments we found adenine. Adenine to the biochemist is the single most important biochemical. It is found in DNA, in RNA, in ATP, and in the coenzymes.
When we take a very dilute solution of hydrogen cyanide and expose it to ultraviolet light, adenine, guanine, and urea were synthesized. If we look at this mixture very carefully, a hundred different organic compounds may be detected arising from the single carbon-containing compound HCN.
Adenine is the pentamer of hydrogen cyanide. If we have a process of generating hydrogen cyanide, we can come up with adenine.
HCN Pentamerization
Ponnamperuma Mechanism
NH
N
N
H2NC
N
H
NH
N
NH
HNC
N
H
5-(N'-formamidinyl)-1H-imidazole-
4-carbonitrile, 6
5-(N-formamidinyl)-1H-imidazole-
4-carbonitrile, 5
HN
N NH
N
N
H
H
9H-adenine (E)-imino-form, (E)-2
HN
N NH
N
N
H
H
9H-adenine (Z)-imino-form, (Z)-2
NH
N
N
HN
H
CHN
(E)-N-(4-(iminomethylene)-1H-imidazol-5(4H)
-ylidene)formamidine, 7
N
N NH
N
NH2
9H-adenineamino form, 1
NH2C
H2N C
N
N
NH2C
C NH2
N
N
NH
N
H2N
4-amino-1H-imidazole-
4-carbonitrile, 3
CN
N
HN
H2N
5-amino-1H-imidazole-
4-carbonitrile, 4
CN
diaminofumaronitrileDAFN
diaminomalonitrileDAMN
h
h
h
+HCN
ProtonCatalysis
No BarrierNo Catalysis
Adenine Synthesis in Interstellar Space: Mechanisms of Prebiotic Pyrimidine-Ring Formation of Monocyclic HCN-Pentamers. Glaser, R.; Hodgen, B.; Farrelly, D.; and McKee, E. Astrobiology 2007, 7, 455-470.
NH
N
N
H2NC
N
H
NH
N
NH
HNC
N
H
5-(N'-formamidinyl)-1H-imidazole-
4-carbonitrile, 6
5-(N-formamidinyl)-1H-imidazole-
4-carbonitrile, 5
HN
N NH
N
N
H
H
9H-adenine (E)-imino-form, (E)-2
HN
N NH
N
N
H
H
9H-adenine (Z)-imino-form, (Z)-2
NH
N
N
HN
H
CHN
(E)-N-(4-(iminomethylene)-1H-imidazol-5(4H)
-ylidene)formamidine, 7
N
N NH
N
NH2
9H-adenineamino form, 1
NH2C
H2N C
N
N
NH2C
C NH2
N
N
NH
N
H2N
4-amino-1H-imidazole-
4-carbonitrile, 3
CN
N
HN
H2N
5-amino-1H-imidazole-
4-carbonitrile, 4
CN
diaminofumaronitrileDAFN
diaminomalonitrileDAMN
h
h
h
+HCN
ProtonCatalysis
No BarrierNo Catalysis
?
Topic of the Present Study
HCH3C
HO
R
H2C
HO
R
CH2
Previtamin D
Vitamin D3; R = C8H17 25-Hydroxyvit. D3; R = C8H16OVitamin D2; R = C9H17
CH2
Me2CCH3
CMe2
7-methylocta-1,3(Z),5(Z)-triene 2-methylocta-2,4(Z),6(Z)-triene
60-120 oC
80 oC
H
Vitamin D
CH2
CH3CH3
CH2
MeO MeO
thermal
CHMe
OCH3
CH2Me
OCH2
HCCH3 COOMe H2C
CH2 COOMethermal
in GCMillar, 1997
Houk, 2004
Ramage, 1970
Baldwin, 1987
Okamura, 1991
thermal
NH
N
N
H2NC
N
H
6
NH
N
N
HN
H
CN
7a (Z)-2
NH
N
N
HN
H
C
NHH
N
H2NC
N
H
M1S
N
HN
H
CN
M1P (Z)-M1PC
N
HN
H
C
NHH
H2NC
N
H
M2S
HN
H
CN
M2P (Z)-M2PC
HN
H
C
NHH
H HH
M1TS1
M2TS1
(E)-2
NH
N
N
HN
H
C
N
(E)-M1PC
N
HN
H
C
N
(E)-M2PC
HN
H
C
N
H
TS(6a,"7a") TS(6a,(Z)-2)
H
H
H
H
H
H
H
H
H
H
HITS(M1PC)
ITS(M2PC)
ITS(2)
M1TS2
M2TS2
H
H
H
H
H
H
H
H
[1,7]-Sigmatropic Rearrangement
Electrocyclization E/Z-Isomerization
Tandem Pericyclic Reactions
Electronic Structure TheoryPotential energy hypersurface analysis employed Density Functional Theory (DFT; B3LYP, M06-type), second-order Perturbation Theory (MP2), and Coupled Cluster Theory (CCSD(T)).
[1] Locate stationary structures and perform thermochemical analysis.
[2] Determine intrinsic reaction paths (IRC).
[3] Analyze stereoelectronic properties.
Pericyclic Reactions: Pericyclic Reactions - A Textbook: Reactions, Applications and Theory. Sankararaman, S.; Hoffmann, R. Wiley: New York, NY, 2005.
General Reference: Essentials of Computational Chemistry. Cramer, C. J. Wiley: New York, NY, 2004.
Advanced DFT Methods: (a) Density Functionals with Broad Applicability in Chemistry. Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157-167. (b) The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Zhao, Y.; Truhlar, D. G. Theo. Chem. Acc. 2008, xx, xxx-xxx (Online First section of SpringerLink at http://dx.doi.org/10.1007/s00214-007-0310-x).
Tandem Pericyclic Reaction ChemistryLeads to (Z)-Isomers of Imino-Form of Adenine
• In contrast, the anticipated two-step reaction 6a 7a (Z)-2 is found to be a one-step process 6a “7a” ―(no barrier) (Z)-2. A minimum of type 7a does not exist. The product “7a” of the virtual [1,7]-sigmatropic rearrangement collapses without any hindrance to (Z)-2. • Even though M1P and M2P correspond to high-energy minima, M1P and M2P are not reaction intermediates in a mechanistic sense because there is virtually no barrier (< 1.5 kcal/mol) to prevent the subsequent electrocyclization. • Mechanistically, all three systems de facto feature the same tandem pericyclic reaction chemistry, that is, a rate-limiting [1,7]-sigmatropic rearrangement followed by inevitable electrocyclization.
• Essential features of the potential energy surface analysis are confirmed by higher-level coupled cluster computations (structures and energies).
MO6-2X/6-311+G(2df,2p): Activation energy 44.5 kcal/mol.
CCSD(T)/6-311+G(d,f)//CCSD/6-31G(d): Activation energy 44.1 kcal/mol.
The barrier for 6 is about 15 kcal/mol higher than for the parent model M1S due to the presence of
-- (a) the imidazole (reduction of aromaticity, constraint on helical twisting)
-- (b) the imine-N within the -system.
Conclusion: This reaction cannot occur in the cold ISM.
New Question: Could Hydrogen Atom Tunneling accomplish the reaction?
Result of Potential Energy Surface Analysis
Molecular Dynamics: CVT-SCT TheoryThe direct dynamics calculations are based on canonical variational theory (CVT) and small-curvature tunneling (SCT) approximation.
[1] Compute MEP by steepest decent in isoinertial coordinates. The path determined in this way is independent of the coordinate system and it is the intrinsic reaction coordinate (IRC).
[2] Determine the generalized reaction rate via kCVT(T) = min[kGT(T,s)].
[3] Quantum effects along the reaction coordinate are considered via the ground-state transmission coefficient kCVT/G(T) and the final quantized rate constant kCVT/G(T) becomes kCVT/G(T) = kCVT/G(T) · kCVT(T).
Leading Reference: Variational transition state theory with multidimensional tunneling. Fernandez-Ramos, A.; Ellingson, B. A.; Garrett, B. C.; Truhlar, D. G. Rev. Comp. Chem. 2007, 23, 125-232.
For an application to a [1,5]-Sigmatropic Rearrangement, see: Molecular Modeling of the Kinetic Isotope Effect for the [1,5] Sigmatropic Rearrangement of cis- 1,3-Pentadiene. Liu, Y.-P.; Lynch, G. C.; Truong, T. N.; Lu, D.; Truhlar, D. C.; Garrett, B. C. J. Am. Chem. Soc. 1993, 115, 2408-2415.
Hydrogen Atom Tunneling increases the reaction rate of the [1,7]-sigmatropic rearrangement by a • factor of 1.7 at 300 K• factor of 4.4 at 200 K• factor of 380 at 100 K The tunneling contribution is not sufficiently high for the reaction to become productive, and this remains true even when one allows for cosmological reaction times (i.e. hundreds of millions of years; 32.5E+12 s/MY).
Conclusion: This reaction cannot occur in the cold ISM even when accounting for tunneling.
Result of Molecular Dynamics Study
Pericyclic Reaction Theory
The reactions fit the criteria for [1,7]-sigmatropic rearrangement regarding structural topology (connectivity). But there are marked differences regarding the electronic topology (Scheme).
The Carbon Prototype: Fundamental to the Woodward-Hoffmann rules for [1,7]-sigmatropic rearrangements of substrates with methyl H-donors is the idea that hyperconjugation of the C–H bond becomes conjugation as the C–H bond breaks; A and B in the Scheme.
The Nitrogen Analog: The analogous case for the pyramidal (about sp3-hybridized) amine H-donor is illustrated by C and D and, to be explicit, the N–H bond aligns with the -system and the N-lone pair merely adjusts from sp3-like to sp2-like as the N–H bond breaks.
The Nitrogen Alternative: In reality, however, the reaction 6a → 7a features a near-planar (about sp2-hybridized) amine H-donor and the p-AO-like N-lone pair aligns far better with the -system than the N–H bond, and this scenario is illustrated by E and F.The two scenarios are clearly distinct by the orientation of the retained N–H bond. The analogous scenario invokes “negative hyperconjugation” and the notion of a hydride shift, whereas the alternative scenario invokes (positive) hyperconjugation and the notion of a proton transfer that turns the N–H bond density into the imine’s N-lone pair. The analogous scenario overall is an antarafacial process in an 8-electron system; all p-AOs are in phase, the H-atom orbital is symmetric and connects to the ends of the -system from top and bottom, respectively, and overall one phase change results. In the alternative scenario, again all p-AOs are in phase and the H-atom is symmetric. However, in this case the H-atom connects only to one end of the -system and to an incipient lone pair. Irrespective of the electron count, the very notion of cyclic stabilization or destabilization of the transition state no longer makes any sense because of the involvements of two orthogonal electron pairs at the NH donor.
C
HH
H
C H
H
H
N
H
H
N
H
H
N
H
H
N
H
H
H
H
H
H
A B
C D
E F
A [1.7]-Sigmatropic
Rearrangement, really?
Hmmm…
The geometries along the MEP of reaction 6a → “7a” clearly support the alternative scenario. The orbital symmetry rules do not apply and the similarity of reaction 6a → “7a” and of [1,7]-sigmatropic rearrangements is limited to connectivity. To think of the reaction 6a → “7a” as a [1,7]-sigmatropic rearrangement only obfuscates the true nature of the reaction. The reaction is best described as a privileged proton transfer, that is, the proton transfer and concomitant reorganization of the -system avoid charge separation as much as possible. The Nitrogen Knockout Effect. The activation barrier for the reaction M1S M1TS1 is higher than for M2S M2TS1. The privileged proton transfer mechanism provides a simple explanation because 6a-II and its analog M1S-II are important contributors whereas the importance of the respective resonance form M2S-II clearly is diminished. The decreased importance of II increases contributions from III and IV and thereby assists the proton transfer. Preferential Formation of (Z)-2. The product stereochemistry depends on the mechanism of the ring-closure of the 7a-type structures irrespective as to whether 7a exists as a local minimum or not. This process formally qualifies as an electrocyclic reaction or as a dative bond formation. We favor the description as a privileged dative bond formation and this concept offers a simple explanation for the preferential formation of (Z)-2: Dative bond formation to the keteneimine carbon occurs with polarization of the C=C and C=N bonds. The polarization of the C=C bond allows for electron delocalization in the -system to offset the electron loss in the -system as the imine N-lone pair engages in dative bond formation and significant charge separation can be avoided during the course of the reaction. The increase of electron density at the ketenimine’s N-atom and incipient N-lone pair formation cause electron-electron repulsion as the new NC bond is formed, and the rotational motion leading to (Z)-2 formation moderates.
CH
N
C N
N
NH
N
H
H
C
N
N
N
NH
N
H
H
Htarget atom
double-bondedtarget atom is triple-bonded
N-lone pairp-AO-like
& aligned toconjugate
N-lone pairsp2-HAO-like
CH
N
C N
N
NH
N
H
H
CH
N
C N
N
NH
N
H
H
CH
N
C N
N
NH
N
H
H
6a-I
6a-II 6a-III 6a-IV
Result of the Stereoelectronic Analysis
Comets Meteor, Park Forest, 2003Meteorite Newspaper Archive
Why not? [And let’s look for more evidence.]