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Simulation Study of Adrenaline Synthesis from Phenylalanine
Halla T. Mohammed, and Abbas A-Ali Drea
Chemistry Department, College of Science, Babylon University, Hilla, IRAQ
aadreab22@yahoo.com
ABSTRACT
Simulation study of Adrenaline synthesis from Phenylalanine has been carried out using semi-empirical methods (PM3)
and density functional theory (DFT) STO-3G level of theory . Geometrical properties and vibration mods have been
calculated for all structures. Different probable products have been suggested for each reaction and the most probable
products being selected depending upon the electronic properties to prove the pathway of reactions that’s needed to
synthesis adrenaline in the human body.
The calculations show the most probable product than other structurs due its energetic values of total energy,
energy barrier value, heat of formation, zero point energy, imaginary frequency and rate constant that’s equal to
(5.554*1012, 5.572*1012, 7.857*1012
, 1.331*1013,1.116*1013) respectively by s-1
units. Thermodynamic functions (?H, ?S,
?G) have been calculated for five steps reactions of Adrenaline synthesis . In reaction 1 equal to (-69.468, 1.37*10-4
, -
66.610), reaction 2 (-46.453, 3.044*10-3
, -64.710), reaction 3 (-63.734, 0.022, 138.900), reaction 4 (87.036, 8.631*10-3
, -
451.510) and reaction 5 (-6.722,-0.025, 346,800) respectively by kCal/mol, kCal/mol/deg, and kCal/mol respective units.
The chemical reactivity or energy gap has been calculated for the most probable products in the pathway of adrenaline
synthesis .
Keywords: Simulation Study; Semi-empirical method; DFT; Adrenaline.
Council for Innovative Research
Peer Review Research Publishing System
Journal: Journal of Advances in Chemistry
Vol. 12, No. 1
www.cirjac.com
editorjaconline@gmail.com, editor@cirjac.com
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1. INTRODUCTION
Adrenaline (Epinephrine or 4,5-?-trihydroxy phenethylamine) has formula chemical formula C6H13NO3. It,s a
hormone and a neurotransmitter secreted by the inner part of the adrenal gland, which produces in the heart of the
adrenal in response to physical or mental stress 1.
Adrenaline has one amino group that is associated with an
aromatic ring with a two-carbon chain, -CH2-CH2-). Epinephrine classified in the class of compounds
called catecholamine which is a monoamine derived from the amino acid tyrosine, and also the same case derived
from phenylalanine2
. Figure 1 shows the chemical structure of Adrenaline.
Figure 1: Chemical structure of Adrenaline.
Adrenaline was discovered as a substance produced from adrenal gland in 1886 by William Bates reported,
than was isolated and recognized in 1895 by Napoleon Cybulski3
, and synthesized of adrenaline for the first time
artificially in 1904 by Friedrich Stolz4
. Metabolic reactions that occur in Adrenaline synthesis in the human body
from Phenylalanine are Oxidation of Phenylalanine to Tyrosine, Oxidation of Tyrosine to L-DOPA, Decarboxylation
of L-DOPA to Dopamine, Oxidation of Dopamine to Noradrenaline, And at the last methylation of Noradrenaline to
Adrenaline 5
through the following steps:
The present study tends to prove the beast s path of Adrenaline synthesis from Phenylalanine theoretically
through the quantum calculations treatment of the electronic and geometrical structure by using PM3 of semiempirical
calculations and DFT minimal STO-3G. Different probables products will be suggested in each reaction to
find the most probable product.
2. COMPUTATIONAL DETAILS
Theoretical calculations were completed by using the computational implemented in the Hyperchem Version
8.0.9 program 6,7. Geometry optimization, electronic energies, heat of formation for all chemical compounds that’s
needed to Adrenaline synthesis from Phenylalanine have been optimized at semi empirical method and DFT- STO-
3G. The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) are studied
to calculate the Energy gap (?E) 8,9. Thermodynamic parameters (?G, ?H, ?S) were calculated at semi-empirical
method PM3 level10. Table 1 shows the chemical structures and abbreviations of all compounds.
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Table 1: List of chemical structures and abbreviations.
Phe Phenylalanine
4-HP 4-hydroxy phenylalanine
3-HP 3-hydroxy phenylalanine
2-HP 2-hydroxy phenylalanine
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THBP 5,6,7,8-Tetrahydrobiopterin
DHBP 7,8-Dihydrobiopterin
DOPA-3 3,4-Dihydroxyphenylalanine
DOPA-2 2.4-Dihydroxyphenylalanine
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DA Dopamine
Norepinephrine
4-[2-amino-1-
hydroxyethyl]benzene-1,2-
diol
2-A-1-
HEBDIOL
4-[2-aminoethyl]benzene-
2,3,4-triol
2-AEB-2.3,4-
TRIOL
4-[2-aminoethyl]benzene-
3,4,5-triol
2-AEB-3,4,5-
TRIOL
4-[2-amino-2-
hydroxyethyl]benzene-1,2-
diol
2-A-2-HEB-
1,2-DIOL
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A.A Ascorbic acid
DHA Dihydroascorbic acid
Epinephrine
4-(1-Hydroxy-2-
(methylamino)ethyl)benzene-
1,2-diol
4(1-H,2-
MAE)B1,2-
DIOL
4-(2-amino-1-methoxy
ethyl)benzene-1,2- diol
4(2-A-1-
ME)B-
1,2DIOL
5-(2-amino-1-hydroxy ethyl)-
2-methoxy phenol
5(2-A-1-HE)-
2-MP
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4-(2-amino-1-hydroxy ethyl)-
2-methoxy phenol
4(2-A-1-HE)-
2-MP
SAM S-adenosyl methionine
SAH S-adenosyl honocysteine
3. RESULTS AND DISCUSSION
The study included the adrenaline synthesis from phenylaniline in vacuum taking into account the factors of the
reaction at 25 C and 1M concentration for all chemical compounds by di ? fferent quantum calculation methods. The
energetic properties of Adrenaline synthesis were calculated by semi empirical PM3 method and listed in Table 2. Table 2
show that the rate constant of raction of aquired values is very high, thats mean these ractions are very fast, because the
values of the rate constant equal to the speed of the reaction at the concentrations used. These reactions are very fast
because they are nerve reactions 11. In very fast reactions that cannot control the value of the energy barrier which equal
to the value of activation energy is negative 12
. Thermodynamic parameters indicate that the reactions 1 and 3 are
exothermic and spontaneous, reaction 2 and 5 are exothermic and nonspontaneous while reaction 4 is endothermic and
spontaneous according to the concept of thermodynamic13,14
.
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Table 2: Energetic properties for synthetic reactions of Adrenaline.
k
(s-
1
)
?G
(kCal/mol)
?S
(kCal/mol/deg)
H?
(kCal/mo
l)
Energy
barrier
(kCal/mol)
Probabilities
Products Reactants
Steps
5.554*1012 1.37*10 -66.610 -4
69.469- -69.468 H2O+4-HP +
DHBP
O2+Phe+
THBP
Reaction 1
5.552*1012 4.63*10 -66.810 -4
-69.561 -69.560 H2O+3-HP +
DHBP
5.561*1012
-2.428*10 -65.810 -3
-69,427 -69.426 H2O+2-HP +
DHBP
5.572*1012
-3.044*10 -64.710 -3
-17880 -49.453 DOPA-3+H2O+
4-HP+O DHBP
2+
THBP
Reaction
2
5.558*1012
-2.5791*10 -66.110 -3
-17878.727 -48.18 DOPA-2+H2O+
DHBP
7.857*1012 DOPA-3 DA+CO2 131.563 -63.734 0.022 138.900
Reaction 3
1.331*1013 8.631*10 -451.510 -3
-461.941 87.036
2-A-1-
HEBDIOL
+DHA+H2O
DA+A.A+O2
Reaction 4
2.874*1012 6.864*10 -456.810 -3
-469.354 169.623
2-AEB-2.3,4-
TRIOL
+DHA+H2O
2.874*1012 4.247*10 -456.910 -3
-469.195 169.782
2-AEB-3,4,5-
TRIOL
+DHA+H2O
2.871*1012 6.543*10 -457.710 -3
-469.845 169.132
2-A-2-HEB-
1,2-DIOL
+DHA+H2O
1.116*1013
346.857 -6.722 -0.025 346.800
4(1-H,2-
MAE)B1,2-
DIOL +SAH
2-A-1-
HEBDIOL+S
AM
Reaction 5
1.125*1013 359.71 6.131 -0.026 351.900 4(2-A-1-ME)B-
1,2DIOL +SAH
1.135*1013 355.929 2.35 0.024- 356.800 5(2-A-1-HE)-2-
MP +SAH
1.127*1013 352.812 -0.768 -0.021 352.900 4(2-A-1-HE)-2-
MP +SAH
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Scheme 1 show the pathway of Adrenaline synthesis accourding to energetic properties . Scheme 1
. Pathway of Adrenaline synthesis within sevral steps.
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The energetic properties for all chemical compounds were calculated by the DFT- STO-3G level of theory as
show in Table 3.
Table 3: The properties of energy for all chemical compounds.
Molecular orbital energy
ZPE
kCal/mol
Total energy
kCal/mol Reactions ?Egab
(eV)
LUMO
(eV) HOMO (eV)
Phe -296103.504 85.94813 14.062 14.932 0.870
Reaction 1
4-HP -331815.725 -795.942 15.546 16.334 0.787
3-HP -337296.732 76.934 14.336 15.205 0.868
2-HP -313882.509 69.241 19.857 20.422 0.564
THBP -347533.704 -404.734 42.418 43.648 1.229
DHBP -431753.039 -1795.760 16.393 16.784 0.390
L-DOPA-3 -342495.390 -118.740 19.614 19.715 0.101
Reaction
2
L-DOPA-2 -378502.277 79.769 14.515 15.343 0.827
DA -218124.785 -992.327 15.566 15.686 0.119
Reaction
3
A.A -33256.054 -842.535 16.201 17.123 0.922
Reaction 4
DHA -368366.966 -225.570 18.587 18.897 0.310
-317459.957 91.849 8.232 10.207 1.915 2-A-1-HEBDIOL
-306639.698 -993.124 13.978 15.015 1.037 2-AEB-2.3,4-
TRIOL
-314215.161 -617.481 9.999 10.117 0.117 2-AEB-3,4,5-
TRIOL
-317442.890 91.312 8.870 10.367 1.497 2-A-2-HEB-1,2-
DIOL
SAM -799039.175 -3448.226 -0.205 6.474 6.680
Reaction 5
SAH -722545.307 -2988.044 65.772 65.871 0.065
-267243.197 -96.147 29.879 30.473 0.593 4(1-H,2-
MAE)B1,2-DIOL
-289960.017 -299.302 5.573 7.312 1.738 4(2-A-1-ME)B-
1,2DIOL
-338039.050 108.338 8.242 10.158 1.915 5(2-A-1-HE)-2-
MP
-338033.276 104.902 8.794 10.523 1.728 4(2-A-1-HE)-2-
MP
The energy band gap of all compounds through the adrenaline synthesis pathway was calculated15 and showed as below:
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Phe 4-HP L-DOPA-3 DA

2-A-1-HEBDIOL 4(1-H, 2-MAE)B1,2-DIOL
The energy gap value for all chemical compounds in the pathway of Adrenaline synthesis indicates they are good
conductors 16, this enables to transfer electrical signals in the nervous system. The HOMO and LUMO orbitals were
calculated by the DFT- STO-3G level of theory, they showed in Table 3.
Table 3: The molecular properties of chemical meoties calculated by the DFT- STO-3G level of theory.
Probabilitie HOMO at 2D contours LUMO at 2D contours
s Products Reactants
4-HP
O2+Phe+
THBP
Reaction 1
3-HP
2-HP
DOPA-3
4-HP+O2
+ THBP
Reaction 2
(0.870 eV) (0.787 eV) (0.101 eV)
(1.915 eV)
(0.119 eV)
(0.593 eV)
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DOPA-2
DOPA-3 DA
Reaction 3
2-A-1-
HEBDIOL
DA+A.A+O
2
Reaction 4
2-AEB-
2.3,4-
TRIOL
2-AEB-
3,4,5-
TRIOL
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2-A-2-HEB-
1,2-DIOL
+DHA+H2O
4(1-H,2-
MAE)B1,2-
DIOL
2-A-1-
HEBDIOL
+SAM
Reaction 5
4(2-A-1-
ME)B-
1,2DIOL
5(2-A-1-
HE)-2-MP
4(2-A-1-
HE)-2-MP
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4. CONCLUSIONS
? The pathway of Adrenaline synthesis have been investigated accourding to theoretical calculations.
? Comparitive of chemical recations are achevied dependiong on the energetic phenomena for every stepwise reaction.
? Molecular orbital behavoure have been estimated through DFT calculation and the reactivity been determinated for all
chemical mioties of chemical synthesis in vaccum.
? The reactions of synthesis are spontinously takeplaces due the biological signal transfer in brine.
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