The document summarizes a study that developed a free energy map for the co-oligomerization of HCN and NH3 in aqueous solution. Key findings include: 1) The majority of transition states favored an 8-centered, proton-transferring ring. Formamide was found to be the thermodynamic sink, while formic acid was second lowest. 2) The most thermodynamically and kinetically favorable routes from HCN to formamide coincided with HCN converting to formamidic acid and then formamide. 3) HCN, formamidic acid and formamide can produce stable 6-membered ring trimers, with formamide being the most stable product

1. HCN, Formamidic Acid and Formamide in Aqueous Solution:
A Free Energy Map
Kyra Thrush
Dr. Jeremy Kua, Dept. of Chemistry & Biochemistry
Project Background
• The purpose of the present study was to
develop a free energy map for co-
oligomerization of HCN and NH3 in aqueous
solution at 298 K, using water as both solvent
and reaction participant.
• HCN (1) and formamide (5) are significant
due to their implications in origin of life
chemistry and as constituents of simple
solutions necessary to develop amino acids. 1
• The relative free energies and reaction
barriers could inform us of the relative
stability of a variety of intermediates and
pathways to potential products.
Discussion/Future
Directions
• The 0.5 entropic correction factor is
insufficient for some reaction complexes.
The previous approximation (0.5T∆S) yields
good results for minima and most transition
states but significantly underestimates
barriers for tautomerizations of this system.
The scaled approach altering the 0.5 factor
resolves the artifact of a negative barrier.
• A prior project within the group investigated
the co-oligomerization of CH2O and NH3. We
are now moving towards analogous reactions
of C2 species by addition of formaldehyde
(CH2O) to the reaction solution—the results
appear to be consistent with the transition
states and energies of the C1 species map.
Results
• The majority of transition states favored an 8-
centered, proton-transferring ring.
• The barrier for HCN (1) hydration appears
consistent with results of Miyakawa et. al. 1
• Formamide (5) is the thermodynamic sink of
this free energy map, and formic acid (6) is
the second lowest.
• The most thermodynamically and kinetically
favorable routes from HCN to formamide
coincide with 1à3à8à5.
• HCN, formamidic acid and formamide can
produce trimers that are 6-membered rings.
These rings are sp2 hybridized, planar rings
(HCN (1)) or sp3 hybridized, non-planar rings
(formamidic acid (4) and formamide (5)).
Methods
• Jaguar 6.0 at the B3LYP flavor of density
functional theory with 6-311G** basis set.
• The Poisson-Boltzmann continuum was used
to approximate solvation energy associated
with calculations done in solution.
• Enthalpy and zero point energy corrections
were applied to account for a change to 298K
• The entropy in solution was approximated as
½ gas phase entropy (0.5T∆S) in accordance
with the methods of previous authors.2
• Previously compared this method to NMR
data and produced good agreement with
relative ∆G’s (diff.< 0.5 kcal/mol minima, and
approx. 1-3 kcal/mol transition states) for
oligomerization of glycoaldehyde.
Acknowledgements
The Camille & Henry Dreyfus Foundation
The University of San Diego
C1 species of HCN, NH3, H2O
Representative Transition State
Complexes
HC N
H2C N
OH
HC NH
HO
HC NH
H2N
HC O
H2N
CH NH2
H2N
H2N
CH OH
H2N
H2N
CH OH
H2N
HO
HC O
HO
CH OH
HO
HO
1
(0.00)
4
(-5.73)
5
(-21.21)
2
(34.63)
3
(-9.64)
8
(-2.96)
7
(0.46)
9
(-3.53)
6
(-16.27)
10
(-3.77)
ts1a
ts4b
ts4c
ts1b
ts4a
ts5a
ts3b
ts3a
ts5b
ts6b
H2O
H2O
H2O
H2O
H2O
H2O
NH3
NH3
NH3
NH3
ts3c
NH3
ts6a
ts6c
Unscaled ∆Gr
(kcal/mol)
Rescaled ∆Gr
(kcal/mol)
Entropy
Correc9on
Factor
ts1a 22.40 21.29 0.55
ts1b 28.14 28.74 0.48
ts3a 19.85 20.39 0.48
ts3b 6.51 6.81 0.45
ts3c -3.62 -0.34 0.36
ts4a 20.57 21.90 0.45
ts4b 16.62 17.25 0.48
ts4c -6.78 -3.00 0.34
ts5a 6.01 6.06 0.50
ts5b 9.78 10.88 0.46
ts6a 2.50 2.33 0.51
ts6b 8.47 10.88 0.41
ts6c -16.75 -11.73 0.28
HC N
HC NH
HO
HC O
H2N
1
(0.00)
4
(-5.73)
5
(-21.21)
ts4c
ts1t
ts4t
ts5t
N
N
N
H
N
HN NH
O
O O
HO OH
OH
H2N
NH2
NH2
11
(-29.44)
14
(-10.37)
15
(-7.82)
ts12b
N
HN NH
OH
OH
13
(-17.49)
N
N NH
OH
12
(-24.25)
ts13b
ts14b
3x
3x
3x
H2O
H2O
H2O
Trimerization of HCN, Formamidic
Acid, and Formamide
∆Gr
(kcal/mol)
ts1t 52.32
ts4t 38.00
ts5t 0.93
ts12b -6.25
ts13b -0.39
ts14b -0.73
References
1) Miyakawa, S.; Cleaves, H. J.; Miller, S. L. Orig Life Evol
Biosph 2002, 32 (3), 195-208.
2) Deubel, D. V.; Lau, J. K. Chem. Commun. 2006, (23),
2451-3.
*
* The ∆Gr values are
taken with reference to
free energies of HCN,
NH3 and H2O.