Theoretical characterization of two reaction pathways

for the intramolecular cyclization

of 2-(3-benzylaminopropanoylamino)benzamide

Christopher Knighta, M.C. Millettib,*

aDepartment of Chemistry, The Ohio State University, 110 West 18th Avenue, Columbus, OH 43210, USAbDepartment of Chemistry, Eastern Michigan University, 225 Mark Jefferson Building, Ypsilanti, MI 48197, USA

Received 7 December 2004; revised 8 March 2005; accepted 8 March 2005

Available online 28 April 2005

Abstract

During the investigation of the microwave synthesis of compounds related to benzodiazepines by Howard and co-workers, another

group of compounds was isolated. First believed to be bicyclic amidines, these compounds were later found to be 4-quinazolinones. In

this work, the potential energy surface of the precursor to the observed 4-quinazolinone is explored. The most stable arrangement is

found to be a linear conformation of the side chain with the amide group in the Z conformation. Using this structure as the starting

point, the reaction pathways for the intramolecular cyclization to form either the 4-quinazolinone or the bicyclic amidine are

characterized.

q 2005 Elsevier B.V. All rights reserved.

Keywords: Quinazolinone; Reaction pathway; Cyclization; Michael product; Hartree–Fock

1. Introduction

Benzodiazepines are a class of compounds which are

widely used as sedatives, e.g. valium (1). In the course of

synthetic work aimed at making analogues of huperzine A, a

small quantity of a compound, initially thought to have the

bicyclic amidine structure (2), was isolated [1]. The

structural relationship to one of the early benzodiazepines,

Librium (3), was interesting so the sequence, involving

reactions promoted by microwaves, was further investi-

gated. Once a larger sample of the product was obtained it

was shown not to be the bicyclic amidine 3 but rather the

isomeric 4-quinazolinone 5a (see Scheme 1). Since 2-alkyl-

4-quinazolinones also show interesting physiological activi-

ties, the scope of the methodology was investigated [2].

0166-1280/$ - see front matter q 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.theochem.2005.03.017

* Corresponding author. Tel.: C1 734 487 1183; fax: C1 734 487 1496.

E-mail address: mmilletti@emich.edu (M.C. Milletti).

N

NO

Ph

Cl

CH3

(1) Valium

N

N

NH2

PhO

(2) Amidine

N

NNHCH3

OPh

Cl

(3) Librium

In this paper, we report on the investigation of the

potential energy surfaces associated with the alternative

cyclizations of the precursor, the Michael product 2-(3-

benzylaminopropanoylamino)benzamide (4) as shown in

Journal of Molecular Structure: THEOCHEM 724 (2005) 143–153

www.elsevier.com/locate/theochem

O

NH2

NH

O

R1

H

R2

NHBz

(4a-d)

O

NBz

N

NH2

R1

R2

(3a-d) O

NH

N

R1

H R2

NHBz

(5a-d)

Scheme 1.

C. Knight, M.C. Milletti / Journal of Molecular Structure: THEOCHEM 724 (2005) 143–153144

Scheme 1 and demonstrate why the 4-quinazolinone is the

preferred product.

Fig. 1. Stacked and linear conformations for the Michael product.

2. Details of the calculations

Geometry optimization calculations using the Berny

algorithm [3] were carried out on all Michael products using

the Hartree–Fock method with a 6-31G basis set [4]. The

first optimization calculation (4a) was repeated using

density functional theory (B3LYP functionals) [5] using

the same basis set. Since the results from these two

calculations were equivalent, the Hartree–Fock method

was used for all calculations. Single point energy evalu-

ations were also repeated at the B3LYP/6-31G* level of

theory for critical points in the potential energy pathways

(6:PROD(A) and 6:PROD(B) in the quinazolinone path-

ways and 5:TS3, 5:TS(A) and 5:TS(B) in the bicyclic

amidine pathway).

In an effort to find the global minimum on the potential

energy surface for the Michael product, the relationship

between the angle of rotation around a variety of single

bonds and the energy of the molecule was investigated by

varying the dihedral angle in 108 increments from 0 to 3608

and calculating the total energy of the molecule at each step.

Transition states were located using linear (QST2) and

quadratic (QST3) synchronous transit algorithms. Reaction

path following calculations utilized the second order

method of Schlegel [6]. The structural information obtained

from the geometry optimization of the Michael product was

used as the input geometry for the reactant. Use of chemical

intuition and the proposed mechanism suggested stable

intermediates which would be minima along the potential

energy path. Frequency calculations insured that the

structure had in fact only one imaginary frequency. To

make sure that the correct transition structures had been

found, the structure was displaced slightly on both sides

from the center of the vibrational displacement vectors and

was optimized; this produced the minima originally used for

the QST2 and QST3 calculations. The process was repeated

in a step-wise fashion along the reaction path, thus

characterizing the entire mechanism. Intrinsic reaction

coordinates (IRC) calculations using the transition structure

were used to follow the paths leading to the two minima

associated with it, thus confirming the connection of two

minima and one maximum.

All calculations were performed on Dell Dimension

4300S (Pentium IV, 512 MB, 1.8 GHz), using GAUSSIAN

98W [7] and GaussView [8] software packages and on a

cluster of two Alpha processors using GAUSSIAN 94 [9].

3. Results and discussion

The first step in mapping out the reaction pathways was

to determine the best structure for the common reactants,

compounds 4a–d. Each one of this set of molecules has a

structure with many degrees of freedom; consequently,

finding a global minimum is not a trivial endeavor. Two

major structural variables were investigated: whether the

molecule is more stable as a linear extended structure or a

Table 1

results of the linear vs. stacked geometry optimization calculations for all

Michael products (amide bond in E conformation)

Compound Optimized

conformation

Energy (a.u.) Energy differ-

ence (kcal/mol)

4a Linear K967.5455 w1

4a Stacked K967.5440 –

4b Linear K1006.5611 w9

4b Stacked K1006.5754 –

4c Linear K1006.5632 w7

4c Stacked K1006.5745 –

4d Linear K1197.0126 w7

4d Stacked K1197.0245 –

Table 2

Results of the E vs Z geometry optimization calculations of all Michael

products (linear conformation)

Compound Optimized

conformation

Energy (a.u.) Energy differ-

ence (kcal/mol)

4a Z K967.5587 w4

4a E K967.5522 –

4b Z K1006.5763 w10

4b E K1006.5611 –

4c Z K1006.5766 w8

4c E K1006.5632 –

4d Z K1197.0254 w8

4d E K1197.0126 –

C. Knight, M.C. Milletti / Journal of Molecular Structure: THEOCHEM 724 (2005) 143–153 145

bent (stacked) structure; and the effect of rotation of the

dihedral angles along the backbone of the molecule.

Geometry optimization calculations were carried out on

compounds 4a–d starting with two initial guesses for the

input geometry: a linear extended structure or a bent

(stacked) structure, one in which the p orbitals of the two

benzene rings could interact to possibly stabilize the structure

(see Fig. 1). Each input geometry optimized to a different

structure: the initially linear structure essentially stayed

linear and the initially stacked structure stayed stacked, but

with a slightly higher energy. However, upon analysis of

Mulliken overlap populations, it became apparent that there

was no significant interaction between the two benzene rings,

which lay w5 A apart. The results from these calculations

can be seen in Table 1. The most noticeable difference

between the substituted and unsubstituted compounds was

that the conformation of lower energy is linear for the former

and stacked for the latter. The difference in energy between

the two conformations is also much larger (w7 kcal molK1)

for the substituted compounds than for the unsubstituted

structure (w1 kcal molK1).

Another structural feature of these molecules is that there

are two possible conformations of the chained amide bond,

E and Z. To determine how the conformation around this

Fig. 2. Optimized structures for the four Michael products.

bond influences the energy of the molecule, the optimization

procedures described above were repeated for the Z

conformation of the amide bond (in the previous set of

calculations the amide bond was in the E conformation). All

four Michael products (4a–d) were optimized starting with

both the linear and stacked conformations with the amide

bond in the Z conformation. For each compound, both

starting conformations optimized to the same structure: a

linear conformation with the amide bond in the Z

conformation. This is in line with previous results for

single amides [10]. These new optimized structures (shown

in Fig. 2) represent the lowest energies calculated so far, as

shown in Table 2.

Fig. 3. HOMO and LUMO surfaces for the optimized structure of

compound 4a.

–1006.51

–1006.50

–1006.49

–1006.48

–1006.47

–1006.46

–1006.45

–1006.44

–1006.43

–1006.42

0 40 80 120

160

200

240

280

320

360

Angle

Ene

rgy

(a.u

.)

Fig. 5. Plot of total energy (in a.u.) as a function of dihedral angle for the

amide bond in compound 4b.

O

NH2

N

HN Ph

H O

A B

C

D

E

F

Fig. 4. Scanned dihedral angles in the Michael product.

C. Knight, M.C. Milletti / Journal of Molecular Structure: THEOCHEM 724 (2005) 143–153146

The valence molecular orbitals of all optimized struc-

tures were examined to determine which reaction pathway

appeared to be more favorable. The HOMO and LUMO

surfaces from the optimized geometry of compound 4a are

shown in Fig. 3. The LUMO surface is localized on the

benzene ring and the two amide functional groups. The

HOMO surface occupies the other portion of the molecule,

the benzene ring of the benzyl group. The position of

these surfaces suggests that nucleophilic attack from the

benzyl group nitrogen to the carbonyl of the benzamide is

likely.

Knowing that the conformation of the amide bond

strongly influences the total energy of the Michael product,

we proceeded to investigate the relationship between the

Table 3

Results of dihedral angle potential energy scan calculations for compound 4a

Conf. of angle

scanned

Conf. of

amide bond

Value of dihedral angle for lowest energy con

D A E

Lineara Z K155.42 169.56 178.31

Stackeda Z K155.42 169.56 178.32

Lineara E K144.71 136.59 K2.62

Stackeda E K136.88 125.63 K7.29

(C,F) E 150.00 K118.40 0.00

(A,D) E 150.00 K118.40 0.00

(E,B) E 30.00 61.59 0.00

(E,F) E 30.00 61.59 0.00

(C,D) E 30.00 61.59 K2.62

(A,B) E K144.71 61.59 K2.62

a Results from first set of geometry optimization calculations.

angle of rotation about many of the bonds along the carbon

backbone of the molecule (shown in Fig. 4) and the energy

of the molecule. The first bond to be investigated was the

amide bond discussed above (E in Fig. 4): starting with the

optimized structure for compound 4b, the dihedral angle

along the amide bond was varied in 108 increments from 0

to 3608. The results of this restricted scan calculation, in

which only the selected dihedral angle was varied, are

shown in Fig. 5. The two maxima correspond to the

hydrogen and oxygen of the amide bond in a bisecting

conformation; the minimum at 1408 corresponds to a non-

planar E conformation, while the minimum at 3308 is a

non-planar Z conformation. Similar calculations were

performed on compound 4a, but using a relaxed scan,

where a constrained optimization is performed at each step

of the scan. The results follow the same pattern as for

compound 4b. Subsequent optimization of the minimum

obtained from the scan calculations for 4a and 4b

converged to the optimized structures obtained at the

conclusion of the first set of optimization calculations.

Once again, the lowest energy conformation is Z with

respect to the amide bond.

Subsequently, potential energy scans on compound 4a

were conducted by selecting a pair of dihedral angles for the

bonds shown in Fig. 4 and by varying each in 308 increments

from 0 to 3608. This was repeated until all pairs of dihedral

angles had been scanned. Then the dihedral angles were

scanned a second time, coupled to a different dihedral angle

than before. The results from these calculations, together

with relevant data from the initial geometry optimization

investigation, are shown in Table 3. Analysis of the data in

Table 3 shows that the largest changes in energy result from

changes in the dihedral angle by rotation around bonds A, C

and B. Consequently, in the next set of calculations the

amide bond, E, was held constant while the dihedral angles

around the two neighboring bonds, C and A, were increased

in 308 increments to 3608. This was repeated for every value

of dihedral E, in 308 increments. Each restricted scan

calculation produced an energy for each of the 144

increments and plots were created to observe the shape of

formation Energy (a.u.)

C B F

173.74 68.07 166.2 K967.5587

173.77 68.05 166.14 K967.5587

K159.26 62.71 162.63 K967.5455

K107.97 68.37 164.58 K967.5440

180.00 68.07 120.00 K967.5327

89.99 180.00 119.99 K967.5295

90.00 180.00 119.99 K967.5221

89.99 0.00 119.99 K967.5156

89.99 0.00 162.62 K967.5132

149.49 0.00 162.62 K967.4725

O

H2N

N

H

O

HN

PhN

N

O

H

NH

Ph

3

2

3

2

1

+ H2O

1

Scheme 2.

0 30 60 90 120 150 180 210 240 270 300 330 360

0 degree

60 degree

120 degree

180 degree

240 degree

300 degree

360 degree

–970

–965

–960

–955

–950

–945

–940

–935

–930

–925

Ene

rgy(

a.u.

)

–930--925

–935--930

–940--935

–945--940

–950--945

–955--950

–960--955

–965--960

–970--965

A

C

Fig. 6. Potential energy surface for compound 4a, where EZ1208.

Table 4

Total energies of the relevant species in the model pathway to formation of

the quinazolinone product

Species Energy (a.u.) Relative energy

(kcal/mol)

1:Reactant K636.1872 –

2:TS1 K636.1745 C7.893

3:INT1 K636.1833 C2.487

4:TS2 K636.1658 C13.41

5:INT2 K636.1734 C8.700

6:TS3 K636.0865 C63.17

7:INT3 K636.2214 K21.46

8:TS4 K636.1018 C53.57

9:Product K636.1792 C5.037

C. Knight, M.C. Milletti / Journal of Molecular Structure: THEOCHEM 724 (2005) 143–153 147

that potential energy surface segment. One such plot can be

seen in Fig. 6.

The results of all geometry optimization calculations

taken as a whole indicate that the linear conformation of the

Michael product with the amide bond in the Z conformation

represents the ground state geometry for this molecule, as

previously shown in Fig. 2.

Having determined the ground state geometry and energy

of the Michael product, the investigation of the reaction

pathways can be undertaken. Since the bicyclic amidine 3

has not been isolated, the reaction pathway leading to the

formation of the quinazolinone 5 was explored first. The

overall reaction is shown in Scheme 2: the nitrogen

(position 1) of the freely rotating benzamide positions itself

above the other amide carbonyl. The nitrogen at position 1

bonds with the carbon (position 2) of the carbonyl. The

oxygen at position 3 then forms a bond with one of the

hydrogens attached to the nitrogen at position 1. The

hydroxide group detaches from the molecule along with

a hydrogen atom, from the adjacent nitrogen, in a

dehydration reaction forming a double bond.

1.94

O

N

N

H

O CH2CH3

H H

N

H

O CH2CH3

O

N

H

H

N

H

O CH2CH3

O

N

H

H

N

O

N

H

H

H

O

CH2CH3

N

O

N

H

H

H

O

CH2CH3

N

O

N

H

H

H

O

CH2CH3N

O

H

N

H

O

CH2CH3

H

N

O

H

N

H

O

CH2CH3

H

N

O

N

H

CH2CH3

+H2O

1:START 2:TS1 3: INT1 4:TS2

5:INT26:TS37:INT3

8:TS4 9:PROD

1.02

3.06

1.200.98

2.3

1.48

1.49

1.29

Scheme 3.

Table 5

Total energies of the relevant species in the pathway to formation of the

quinazolinone product

Species Energy (a.u.) Relative energy

(kcal/mol)

0:Reactant K967.5587 –

1:TS1 K967.5455 C8.277

2:INT1 K967.5490 C6.111

3:TS2 K967.4387 C75.28

4:INT2 K967.5432 C9.726

5:TS4(A) K967.4534 C66.05

5:TS4(B) K967.4751 C52.47

6:Product(A) K967.5440 C9.213

6:Product(B) K967.5451 C8.509

C. Knight, M.C. Milletti / Journal of Molecular Structure: THEOCHEM 724 (2005) 143–153148

To assist in characterizing the reaction path energy

surface for the intramolecular cyclization reaction, a model

system was used that employed a simpler version of

the Michael product (compound 6). The difference between

6 and 4 is that the benzylamine substituent is replaced with a

hydrogen atom, thus removing many degrees of freedom.

A summary of total energies for the relevant species in

the reaction pathway for the model system is shown in

Table 4. There are four transition states and three

intermediates for the intramolecular cyclization of com-

pound 6. The first two transition states are at a low energy

and thus very accessible; these represent the molecule’s

dihedral angles rotating so that atoms are positioned for the

reaction to occur. The high-energy transition states are a

result of bond formation and cleavage. Also, the intermedi-

ate between the two high-energy transition states is lower in

energy than either the reactant or the product. Experimen-

tally, it is predicted that this reaction would still go to

completion as the conditions are such that the water would

be removed as it formed, thus driving the reaction towards

formation of product.

The steps for this mechanism are shown in Scheme 3. In

the reactant (1), the plane of each amide group is parallel to

that of the benzene ring. Rotation of the benzamide group

(!OCCCz108), such that the plane of the amide group

is perpendicular to the benzene ring, produces structure 3

(!OCCCzK1248). The energy barrier for this amide

rotation via 2:TS(1/2) is only 8.0 kcal molK1. Likewise,

rotation of the propanamide group (!CNCCz1808) from 3

to 5 (!CNCCzK908) through 4:TS(3/5) has an

activation barrier of 3.1 kcal molK1.

Structure 5 in Scheme 3 is such that one of the N–H

bonds of the freely rotating amide and the C–O double bond

of the chained amide lie parallel to one another. The C–N

distance shortens from 3.06 (5) to 1.94 A (6: TS(5/7)).

Also, the N–H bond lengthens from 1.02 (5) to 1.20 A (6:

TS(5/7)). The activation energy for transition structure 6

is 54.5 kcal molK1. Structure 7 is 29.7 kcal molK1 lower in

C. Knight, M.C. Milletti / Journal of Molecular Structure: THEOCHEM 724 (2005) 143–153 149

energy than structure 5. The C–N bond is 1.48 A and the

N–H distance is 2.3 A as the hydrogen is now bonded to the

oxygen with a bond length of 0.98 A. The bond between the

hydroxide group and the quaternary carbon of structure 7 is

cleaved in transition structure 8. The removal of the

hydroxyl group with the liberation of the hydrogen atom

from the nitrogen at position 1 requires 74.5 kcal molK1.

The formation of a double bond between the carbon and

nitrogen produces structure 9, the product. The C–N bond

NH2

O

N

H

O

R0:START 1:TS1

3:T4:INT2

N

N

O

H

R

H

2.68

1.44

0.96

4:INT2

N

N

O

H

R

O H

O H

H

2.68

1.44

0.96

5:TS4(A)

N

N

O

H

1.38

5:TS4(B)

N

N

O

O

H

H

1.33

Scheme

has now shortened from 1.49 (7) to 1.29 A (9). The product,

with the double bond in conjugation with the benzene ring,

plus water lie 5.0 kcal molK1 higher in energy than the

starting reactant; therefore, this reaction is endothermic. The

activation energies for the hydrogen transfer and dehy-

dration of water seem to be high (50–70 kcal molK1). This

may be due to the fact that the model does not include the

involvement of a Lewis acid, which experimentally is

known to assist the reaction.

NH2

O

N

H

O R

NH2

O

N

H

O

R

2:INT1

0.99

3.98

N

O

N

H O

R

S2

0.99

1.59

H

H1.18

O H

H

R

H

R

6:PROD(A)

N

N

O

R

H

1.29

6:PROD(B)

N

N

O

H

R

1.28

H2O

H2O

4.

C. Knight, M.C. Milletti / Journal of Molecular Structure: THEOCHEM 724 (2005) 143–153150

After completion of the reaction surface for the model

system, those structures were used as starting points for the

system of interest. A summary of total energies for the

relevant species is shown in Table 5 and the reaction

mechanism in Scheme 4.

The most obvious difference between the model system

and the actual reaction is that the latter has fewer

intermediates and transition states. The model system

required an additional transition state and intermediate to

position atoms to initiate bond formation and breakage. This

is probably due to the differences in the structures of the

reactants. The reaction pathway describing the intramole-

cular cyclization of the Michael product to the quinazoli-

none has two intermediates and three transition states. The

largest activation barrier was found to be 75.3 kcal molK1,

which corresponds to the transition state involving closure

of the ring with formation of the C–N bond.

In structure 0, both of the amide groups lie almost

parallel with the benzene ring. Rotation of the benzamide

group (!OCCCz248) and the substituted propanamide

group (!CNCCz1708) gives rise to 2. The amide groups,

through the transition state, position themselves almost

perpendicular to the benzene ring. In structure 2, the

benzamide group (!OCCCz458) has rotated so that the

nitrogen atom is above the plane of the benzene ring.

The propanamide (!CNCCz608) is positioned such that

the oxygen of the carbonyl is above the plane of the ring. The

energy barrier to transition state 1:TS (0/2) is 8.3 kcal -

molK1. This single transition state is a significant difference

between the model system and the Michael product system:

in the model system two separate transition states were

required to position the amide groups, whereas the Michael

product only required a single transition state. Structure 2 is

one in which an N–H bond of the benzamide group and the

C–O bond of the propanamide are parallel; looking down the

C–O bond, the N–H bond appears E with the nitrogen behind

the carbon and the hydrogen behind the oxygen. In this

step, the C–N distance shortens from 3.98 (2) to 1.59 A (3:TS

(2/4)), while the N–H distance lengthens from 0.99 (2) to

1.18 A (3:TS (2/4)). The activation energy for transition

state 3:TS (2/4) is 75.3 kcal molK1. Structure 4 is

N

N

O

H

H

OH

NH Ph

4:INT3

Scheme

9.7 kcal molK1 higher in energy than the reactant (0). The

C–N bond is now 1.44 A (4) and the N–H distance is 2.68 A

(4) as the hydrogen is now bonded to the oxygen with a bond

length of 0.96 A (4). This new six-membered ring is nearly

planar, with the quaternary carbon protruding from the plane

and the hydroxyl group located on the front face of the

molecule.

Dehydration of structure 4 can occur in one of two ways.

In both instances, the hydroxyl group detaches from the

quaternary carbon of structure 4. This hydroxide ion can

now bond with a hydrogen atom from either nitrogen,

producing water and one of two isomeric 4-quinazolinones.

Bond formation with the hydrogen attached to the nitrogen

in the 3 position goes through transition state 5a:(TS(4/6a)). Structure 6a, the isomer with the double bond in

conjugation with the carbonyl, lies 9.2 kcal molK1 higher in

energy than the starting reactant. The C–N bond shortens

from 1.38 (5a) to 1.29 A (6a) with formation of the double

bond. The more stable isomer is formed through transition

state 5b:(TS(4/6b), which is 13.6 kcal molK1 more stable

than transition state 5a. Structure 6b, the isomer, where the

double bond is in conjugation with the benzene ring, is more

stable than structure 6a (by 0.7 kcal molK1 at the HF/6-31G

level of theory and by 11.8 kcal molK1 at the B3LYP/6-

31G* level of theory). The C–N bond shortens from 1.33

(5b) to 1.28 A (6b) with formation of the double bond.

Having completed the analysis of the 4-quinazolinone

reaction pathway, the pathway to the bicyclic amidine was

investigated. Since this compound has not been isolated to

date, it is not clear which pathway would lead to its formation.

One possibility is that structure 4 in the 4-quinazolinone

reaction pathway (Scheme 4) is a branching point that can

also lead to the amidine. In view of the high activation energy

associated with the dehydration reaction, it is possible that

compound 4 may exist long enough to allow for nucleophilic

attack on the carbonyl carbon by the benzylamine nitrogen,

leading to the eight-membered bicyclic product. This overall

reaction scheme is shown in Scheme 5 and the reaction

mechanism is detailed in Scheme 6.

The results of this set of calculations are summarized in an

energy plot of the reaction pathway (shown in Fig. 7). Starting

N

N

O Ph

NH2

+ H2O

(3a)

5.

N

N

O

H

H

O N

Ph

H

HN

N

O

H

H

O H

N

H

Ph

N

N

O

H

H

O H

N

HPh

N

N

O

H

H

OH

NH

Ph

N

NH

O

H

OH

N

H

Ph

2.79

4.39

1.230.99

3.36

4.48

N

N

O

H

H

O

H

H

N

Ph

N

N

O

H

H

O

H

H

N

Ph

N

N

O

H

O

H

H

N

Ph

H

N

N

O

H

H

O

H

H

N

Ph

N

N

O

H

H

O

H

H

N

Ph1.35

1.261.54

1.391.461.40

0.952.50

1.38

1.37

1.58

1.24

0.99 1.45

2.96

3.44

1.27

O

N

N

NH

H

H

Ph

O

H

1.34

1.032.27

O

N

N

N H

H

Ph

H2O

4:INT2 5:TS3

6:INT3

7:TS48:INT4

9:TS5 10:INT511:TS6

12:INT613:TS7

14:INT7

15:INT8

Scheme 6.

C. Knight, M.C. Milletti / Journal of Molecular Structure: THEOCHEM 724 (2005) 143–153 151

0

20

40

60

80

100

REACTION PATH

RE

LA

TIV

E E

NE

RG

Y(k

cal/m

ol)

Unconj Quin

Conj Quin

Amidine

Fig. 8. A comparison of relative energies of relevant species for the two

pathways.

0

12

3

4

5

6

78

9

10

11

12

13

14

15

0

10

20

30

40

50

60

70

80

90

100

REACTION PATH

RE

LA

TIV

E E

NE

RG

Y (

kcal

/mol

)

Fig. 7. Relative energies of relevant species for the pathway to formation of

the amidine product.

C. Knight, M.C. Milletti / Journal of Molecular Structure: THEOCHEM 724 (2005) 143–153152

from the Michael product, there are seven transition states and

seven intermediates. The final product and water lie

18 kcal molK1 higher in energy than the Michael product.

Transition state structure 9 has the highest energy for this

reaction sequence. Lying 96.1 kcal molK1 above the Michael

product, it has an activation energy of 83.8 kcal molK1,

which is 14.6 kcal molK1 higher than the next highest

activation energy. This indicates that the formation of the

quinazolinone product is energetically more favorable and

thus formation of the amidine via this pathway is unlikely.

The reaction mechanism begins with 4:INT2, whose

formation is shown in Scheme 4. In this molecule, the

benzylamine nitrogen and the hydroxyl oxygen lie 2.79 A

apart. Structures 5–8 involve dihedral angles rotating in a

way that places the nitrogen of the benzylamine in a position

to attack the carbon of the carbonyl. Transition state 5:TS

(4/6) is at the top of a 5.2 kcal molK1 activation barrier. In

structure 6, 11.6 kcal molK1 higher in energy than the

Michael product, the N–O distance has increased to 4.39 A

because of rotation of the dihedral angle adjacent to

the six-membered ring from !NCCCz608 in structure 4

to !NCCCzK488 in structure 6. The second transition

state, 7:TS (6/8), has an activation barrier of 3.6 kcal -

molK1. In structure 8, the N–O distance has now increased

to 4.48 A and the distance between the benzylamine

nitrogen and the carbonyl carbon is now 3.36 A. Structure

8 is 12.3 kcal molK1 higher in energy than the Michael

product.

Transition state 9:TS (8/10), with an activation barrier

of 83.8 kcal molK1, involves the formation the C–N bond

and cleavage of the N–H bond. The C–N bond has formed

with a length of 1.54 A (9) and the N–H distance has

increased from 0.99 (8) to 1.26 A (9). The C–O bond has

lengthened from 1.23 (8) to 1.39 A (9). In structure 10, the

C–N bond has shortened to 1.46 A and the N–H distance is

2.5 A. The hydrogen is now bonded to the carbonyl oxygen

with a bond length of 0.95 A, shortened from 1.35 A (9).

The C–O distance is now 1.40 A. This tricyclic structure

(10) lies 36.3 kcal molK1 above the Michael product.

Cleavage of the N–H bond to form the eight-membered

ring occurs via transition state 11:TS (10/12) which has an

activation barrier of 57.6 kcal molK1. In structure 11, the

C–N bond length has increased from 1.46 (10) to 1.58 A and

the O–H distance has increased to 1.38 A. Structure 12 is

22.4 kcal molK1 higher in energy than the Michael product.

The O–H distance has increased to 3.44 A and the C–N

distance is now 2.96 A. The C–O bond has shortened from

1.37 (11) to 1.24 A which is identical to the original bond

length in structure 8.

Cleavage of the hydroxyl group and the hydrogen bonded

to the nitrogen adjacent to the benzene ring produces the final

amidine product and water. The transition state involving this

cleavage has an activation energy of 46.4 kcal molK1. The

C–N bond has shortened from 1.45 (12) to 1.34 A (13). The

hydroxyl group is now detached from the molecule with a C–

O distance of 2.27 A. The N–H bond has lengthened from

0.99 (12) to 1.03 A (13). In structure 14, the water molecule

has been formed and is separated from the bicyclic amidine.

The C–N bond distance is now 1.27 A. Furthermore, the

water molecule can migrate to a different position thus

lowering the energy of the system. Structure 15 is more stable

by 5.2 kcal molK1 and lies 18.2 kcal molK1 higher in energy

than the starting Michael product.

4. Conclusions

The most stable conformation of the Michael products

was found to be linear, with the amide bond in the Z

conformation. From this optimized structure, the reaction

pathway for the intramolecular cyclization of the Michael

product to the 4-quinazolinone was characterized. The

reaction was found to have two intermediates and three

transition states. The second step has the highest activation

energy. Of the two possible products, the one with the double

bond in conjugation to the ring was found to be more stable

than the one with the double bond in conjugation with the

carbonyl group (by 0.7 kcal molK1 at the HF/6-31G level of

theory and by 11.8 kcal molK1 at the B3LYP/6-31G* level

of theory). The reaction pathway for the formation of the

bicyclic amidine was found to have a higher activation

C. Knight, M.C. Milletti / Journal of Molecular Structure: THEOCHEM 724 (2005) 143–153 153

barrier than the quinazolinone pathway (by 14.6 kcal molK1

at the HF/6-31G level of theory and by 33.0 kcal molK1 at the

B3LYP/6-31G* level of theory). This agrees with experi-

mental observations, since the products isolated are the

energetically more favorable 4-quinazolinones. The reaction

path energy diagrams for the 4-quinazolinone and bicyclic

amidine are compared in Fig. 8.

Acknowledgements

We are grateful to Dr Arthur Howard for suggesting the

problem and many helpful discussions.

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