Jennifer Lin

TABLE OF CONTENTS

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 3

Background . . . . . . . . . . . . . . . . . . . . . . . . . 4-5

Materials and Procedures . . . . . . . . . . . . . . . . . . . . . 5-7

Table I: Predicted rotational constants, inertial defect, and structural conformations for 1-pentanal . 6

Discussion of the Data . . . . . . . . . . . . . . . . . . . . . . 7-10

Table II-A: Observed and predicted values along with error for 1-pentanal . . . . . . . . 8

Table II-B: Observed and predicted values along with error for 1-hexanal . . . . . . . . 9

Table II-C: Observed and predicted values along with error for 1-heptanal . . . . . . . . 9

Analysis and Synthesis . . . . . . . . . . . . . . . . . . . . . . 11

Works Cited . . . . . . . . . . . . . . . . . . . . . . . . . 12
 Jennifer Lin

ABSTRACT

This investigation tested the ability of computational chemistry to predict molecular

conformers. The rotational spectra of conformational isomers of 1-pentanal, 1-hexanal, and

1-heptanal were measured and assigned using a pulsed-molecular-beam Fourier-transform

microwave spectrometer. The results were compared against molecular modeling predictions.

The molecular modeling calculations predicted fifteen, fifty-eight, and one-hundred forty-eight

conformers for 1-pentanal, 1-hexanal, and 1-heptanal, respectively, of which four, five, and five

should have had sufficient population at room temperature to be detected in the molecular beam.

Experimentally, six, seven, and five conformers were observed for these aldehydes. The

rotational constants, which are sensitive probes of molecular structure, were predicted within

6% by the molecular modeling calculations, except for one case where they were in error by

24%.

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INTRODUCTION

The present investigation determines how effectively molecular modeling predicts

conformations of hydrocarbon chains with a polar terminating functional group. Specifically,

the rotational constants A, B, and C, which are the reciprocals of the three principal moments of

inertia are compared for each conformer characterized.

The rotational spectra of conformational isomers of 1-pentanal, 1-hexanal, and

1-heptanal are measured and assigned using a pulsed-molecular-beam Fourier-transform

microwave spectrometer and the results are compared against molecular modeling predictions

using the MM3 molecular mechanics force field. The long-chain aldehydes are chosen for study

because of their polarity and their possible potential to become more globular, similar to

proteins and other biological molecules important to intelligent drug design. The MM3 force

field, one of the current standards in molecular modeling, has not been previously tested with

experimental data of anything remotely close to the structure of a protein. Improved molecular

modeling would enhance predictions essential for better drug design.

The molecular modeling calculations predicted fifteen, fifty-eight, and one-hundred

forty-eight conformers for 1-pentanal, 1-hexanal, and 1-heptanal, respectively, of which four,

five, and five should have sufficient population at room temperature to be detected in the

molecular beam. Experimentally, six, seven, and five conformers have been observed in the

present study. The experimental rotational constants are sensitive probes of molecular structure

and agree to within 6% by the molecular modeling calculations, except for one case where they

are in error by 24%, and one where they are in error by 14%.

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BACKGROUND

In the past, drugs have been developed by trial-and-error. However, recent advances in

computer speed and graphics as well as in molecular modeling software and theory have

enabled the development of intelligent drug design [1]. In many cases, molecular modeling is

being applied to increasingly complex molecular systems to predict conformations of drugs and

their ability to attach to the receptor site of a protein. However, there is a need to further

evaluate the ability of molecular modeling to predict molecular conformations.

Rotational spectroscopy offers unambiguous determination of molecular conformations

[2]. The results of molecular spectroscopy can be used to evaluate molecular modeling

predictions. Of particular importance is the ability to test a system with a large number of

possible conformers such as hydrocarbon-based chains.

Previous research has been conducted on various types of molecules such as the alkanes

and the alkenes [3]. Both of these sets of molecules, however, contain highly non-polar

functional groups and have less significance as a biological molecule. Aldehydes, on the other

hand, are highly polar and more closely resemble the more conformationally complex molecules

found in biological systems. The current study was designed to determine the effect of this

polarity on the conformational structure and energy levels. Furthermore, this study looks to

advance towards the goal of testing the validity of molecular modeling predictions for a

molecule in a biological system.

Previously, only hydrocarbon chains were examined, testing the sensitivity of molecular

modeling to carbon and hydrogen containing molecules. Aldehydes contain a carbonyl group,

which possess an oxygen atom and places more demand on the molecular modeling force field.

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Hence, the sensitivity of molecular modeling on oxygen in addition to hydrogen and carbon can

be assessed.

MATERIALS AND METHODS

Preparation of the Samples

The rotational spectra was examined and recorded using pulsed molecular-beam

Fourier-transform microwave spectrometers. The molecules, obtained from Aldrich, were

purified by distillation by using the freeze-pump-thaw method. A sample was then prepared by

mixing the molecule with an inert carrier gas, consisting of twenty-percent helium in neon by

volume. A molecular beam was formed by expanding the gas adiabatically through a 1.2-mm

nozzle into a vacuum chamber.

Low-Resolution Analysis

The rotational spectra consisted of discrete resonance of ~10 kHz linewidth. The

resonance structure is well predicted by quantum mechanics, and is primarily sensitive to the

moments of inertia of the molecule. Initially, several gigahertz (GHz) wide low-resolution

spectra were recorded. Predictions of rotational assignments and energy levels were given by

molecular modeling calculations using from the MM3 force field, a standard in molecular

modeling. An example of such a calculation can be found in Table I as shown on page 6.

High-Resolution Analysis

Using survey scans, the a-type electric dipole spectral patterns were first identified.

Individual transitions with its corresponding quantum numbers were placed into a least-squares

fit to the spectroscopic Hamiltonian. When necessary, the Stark effect was examined to

determine the rotational quantum numbers of a transition. To utilize the Stark effect, an

electronic field was induced in the Fabry-Perot cavity within the spectrometer. This caused a

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<see gaussian_modeling_summary.xls>

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resonance to split, allowing the determination of angular momentum states. Eventually as the fit

was improved and the number of assigned a-type transitions increase, b- and c-type transitions

were also measured and recorded at high-resolution to use in fitting the spectra.

Rotational Constants

With the assignments, the observed rotational constants A, B, and C as well as the

inertial defect were compared to those from the predictions. The inertial defect was calculated

with the formula:

∆ I = IC – IB – IA,

where IA, IB, and IC are components of the inertia tensor of the molecule in the principal axis

system and are related to A, B, and C where:

2 2 2
A= B= C=
2IA 2IB 2IC
After comparing the constants and the inertial defect with the predictions, the errors

were compared to those found in other molecules observed in previous research performed on

alkanes and alkenes.

DISCUSSION OF THE DATA

Predictions of the A, B, and C rotational constants were made using the MM3 molecular

mechanics force field. These calculations also led to information regarding the relative minima

to be expected and the relative energies (Erel) of the minima.

Using the MM3 predictions as a guide, six of the fifteen conformers predicted to be

relative minima were found for 1-pentanal. For 1-hexanal, it was expected the five lowest

energy conformers would be found from the fifty-eight total possible conformers. Instead, seven

were found. Out of the one hundred forty-eight possible conformers of 1-heptanal, the five

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lowest-energy conformers were identified. The constants and inertial defects of each conformer

can be found in Table II as shown in three parts on pages 8 and 9.

Conformers differ by a value for the dihedral angles. In all molecules, there is a planar

conformer, which is the extended form of the molecule. This is always the lowest-energy

conformer. As in the normal (unbranched) alkanes, this conformer usually forms around a

backbone of carbons as shown:

C C C C

C C C C

As the number of carbons increase, so do the number of possible conformers for the molecule

because of more possible changes in dihedral angles. The lower-energy conformers have fewer

twists in comparison to the higher-energy conformers, which are found to be more globular.

Table II-A: Observed and predicted values along with error for 1-pentanal.
1-Pentanal: CH3(CH2)3CHO
Observed
I II III IV V VI
A 10361 9718 6897 14877 7963 6245
B 1467 1566 1905 1248 1639 2023
C 1328 1476 1647 1218 1471 1912
∆I -12.6 -32.3 -31.7 -24.0 -28.1 -66.4

Predicted
I II III IV V VI
A 10138 9616 6766 14682 7811 5891
B 1457 1547 1897 1231 1629 2069
C 1317 1458 1633 1203 1458 1939
∆I -12.9 -32.6 -31.6 -24.8 -28.4 -69.4

Error
I II III IV V VI
A 0.022 0.011 0.019 0.013 0.019 0.057
B 0.007 0.012 0.004 0.014 0.006 -0.022
C 0.008 0.012 0.009 0.013 0.009 -0.014
∆I -0.024 -0.012 0.004 -0.034 -0.007 -0.046
Note: Conformer I is the planar conformer. Also, Conformer IV experienced internal rotation tunneling of the
terminal methyl group.

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Table II-B: Observed and predicted values along with error for 1-hexanal.
1-Hexanal: CH3(CH2)4CHO
Observed
I II III IV V VI VII
A 9770 5995 5400 8974 12500 5456 5362
B 869 1047 1143 933 785 1056 1110
C 819 946 1029 898 612 937 1063
∆I -16.0 -32.9 -44.5 -35.0 ? -32.1 -74.1

Predicted
I II III IV V VI VII
A 9545 5877 5289 8862 12696 5350 5410
B 863 1040 1140 923 767 1050 1128
C 812 938 1021 889 755 930 1085
∆I -16.2 -33.4 -43.9 -35.9 -29.2 -32.3 -75.8

Error
I II III IV V VI VII
A 0.023 0.020 0.021 0.012 -0.016 0.019 -0.009
B 0.006 0.007 0.003 0.011 0.023 0.005 -0.016
C 0.007 0.008 0.008 0.010 -0.234 0.008 -0.021
∆I -0.013 -0.015 0.013 -0.026 N/A -0.006 -0.023
Note: Conformer I was once again the planar molecule. Conformer V was very prolate and proved hard to assign,
accounting for the inability to calculate the internal defect.

Table II-C: Observed and predicted values along with error for 1-heptanal.
1-Heptanal: CH3(CH2)5CHO
Observed
I II III IV V
A 7883 6679 5098 4999 6335
B 572 621 659 706 632
C 545 596 610 659 606
∆I -19.2 -41.6 -37.6 -50.3 -45.9

Predicted
I II III IV V
A 7697 6574 4518 4913 6277
B 569 617 694 703 624
C 541 591 629 655 600
∆I -19.4 -41.8 -36.4 -49.9 -47.6

Error
I II III IV V
A 0.024 0.016 0.114 0.017 0.009
B 0.006 0.007 -0.053 0.004 0.012
C 0.007 0.008 -0.031 0.007 0.010
∆I -0.011 -0.005 0.031 0.008 -0.036
Note: Conformer I, the planar conformer, was very dominating as can be seen in the significantly lower internal
defect, which made other conformers extremely hard to find.

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 Jennifer Lin

For 1-pentanal, Conformer IV was found to be difficult to assign because of observed

line splitting from internal rotation tunneling of the terminal methyl group. In this case, the

lower frequency on the K1s was used in fitting the spectra along with the higher frequency on

the K0. The planar conformer, as also found in the other two molecules, had at least half the

inertial defect of the other conformers. In this molecule, the inertial defect of this conformer was

–12.6.

As for 1-hexanal, Conformer V was very prolate on account of the much greater A

rotational constant in comparison to the B and C rotational constants. Most aldehydes are

prolate versus oblate, however this conformer was found to be especially prolate, exhibiting a

κ value of –0.97 where κ is found with the equation:

κ = 2B-A-C
A-C
and where κ = -1 denotes the extreme for a prolate molecule and κ = 1 denotes the extreme

for an oblate molecule.

In the case of 1-heptanal, the lowest-energy conformer dominated the spectrum, making

the other conformers much harder to identify. There was a 0.8 kcal/mole energy difference

between Conformer I and the next conformer, causing Conformer I to dominate the spectrum. If

this trend was to continue for longer aldehydes, then a well-defined momentum for a tertiary

structure is expected to occur, analogous to results seen for proteins.

It was observed the rotational constants and the inertial defect were very sensitive to

slight conformational structure differences. It was also observed in majority of the cases, the

error for the rotational constant A was much greater than those for B and C. This is consistent

with the findings of the alkenes. In all cases, the lowest-energy conformer had the inertial defect

closest to zero. This is also consistent with previous research.

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ANALYSIS AND SYNTHESIS

In this study, molecular modeling was found to provide a reasonable estimate of

conformational structures of aliphatic aldehydes, however they are still quite inaccurate. The

molecular modeling numbers was almost always within 6%, although still not very precise

when compared to the actual constants. A slight variation of the constants was found to predict a

different spectrum altogether, and therefore the molecular modeling numbers were still quite

inaccurate although they were roughly correct. These constants are also necessary to make

statistical mechanical predictions of thermodynamic properties, therefore it is critical for the

molecular modeling predictions to be as accurate as possible.

Molecular modeling on aldehydes was found to be worse than the alkanes and alkenes as

shown by the rotational constant errors, which was at least two times greater than in previous

studies. This could be attributed to the polarization by the carbonyl group and the poorer quality

of the MM3 force field parameters for carbonyl groups.

Further studies should be conducted on molecules more closely related to the complex

molecules found in biological systems. A suggestion would be to examine a molecule which

consists of sulfur, phosphorous, or nitrogen within the hydrocarbon chain. This can lead towards

testing the validity of molecular modeling for proteins or nucleic acids, which contain these

elements in addition to carbon, hydrogen, and oxygen. Another suggestion would be to

investigate the sensitivity to oxygen through an ether, an ester, or an alcohol rather than through

the carbonyl group found on an aldehyde. With more information regarding the validity of

molecular modeling on these suggestions, the applicability of intelligent drug design will be

better understood.

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WORKS CITED

1. Richard A. Friesner, Robert B. Murphy, Michael D. Beachy, Murco N. Ringnalda, W.

Thomas Pollard, Barry D. Duniez, Yixiang Cao. The Journal of Physical Chemistry A.
103, Number 14 (1 April 1999).

2. Howard Busch, Walter J. Stevens. Chemical Physics Letters. 169, Number 4 (8 June 1990).

3. G.T. Fraser, L.-H. Xu, R. D. Suenram, C. L. Lugez. Unpublished results.

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CONFORMATIONAL PROPERTIES OF ALIPHATIC ALDEHYDES USING

ROTATIONAL SPECTROSCOPY AND MOLECULAR MODELING

Jennifer Lin
Montgomery Blair High School
Silver Spring, MD
National Institute of Standards and Technology
Optical Technology Division
Gaithersburg, MD
January 1999

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