NATIONAL BUREAU OF STANDARDS REPORT

10 442

Progress Report

on STABILIZING COMONOMER

I. SYNTHESIS AND CONFIRMATION OF STRUCTURE

U.S. DEPARTMENT OF COMMERCE

NATIONAL BUREAU OF STANDARDS
NATIONAL BUREAU OF STANDARDS

The National Bureau of Standards 1 was established by an act of Congress March 3, 1901. Today,

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2

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1 Headquarter* and Laboratories at Gaithersburg, Maryland, unless otherwise noted; mailing; address Washington, D.C. 20234.

a Located at Boulder, Colorado 80302.

3 Located at 6286 Port Royal Road, Springfield. Virginia 22161.
NATIONAL BUREAU OF STANDARDS REPORT

* Associate Director, American Dental Association Research

Unit, National Bureau of Standards, Washington, D. C. 20234.

** Research Associate, American Dental Association Research

Unit, National Bureau of Standards, Washington, D. C. 20234.

This investigation was supported in part by research grant DE02494-05

to the American Dental Association from the National Institute of

Dental Research and is part of the dental research program conducted

by the National Bureau of Standards in cooperation with the American

Dental Association; the Dental Research Division of the United States

Army Medical Research and Development Command; the Dental Sciences

Division of the School of Aerospace Medicine, USAF; the National

Institute of Dental Research; and the Veterans Administration.

NBS PROJECT

311.05-11-3110561 June 16, 1971

NBS REPORT

10 442

Progress Report

on A STABILIZING COMONOMER:

I. SYNTHESIS AND CONFIRMATION OF STRUCTURE

R. L. Bowen, DDS* and H. Argentar, B$**

IMPORTANT NOTICE NATIONAL BUREAU O

for use within the Governtr and review. For this reasc whole or in part, is not i Bureau of Standards, Was

the Report has been speci

irogress accounting documents intended

I it is subjected to additional evaluation

rature listing of this Report, either in Standards and Technology (NIST) ever - by the Government agency for which on October 9, 2015. onal copies for its own usee.‘

U.S. DEPARTMENT OF COMMERCE

NATIONAL BUREAU OF STANDARDS

A STABILIZING COMONOMER: I. SYNTHESIS

AND CONFIRMATION OF STRUCTURE

R. L. BOWEN*, DDS AND H. ARGENTAR**, BS

This investigation was supported in part by Research Grant

DE02494-05 to the American Dental Association from the

National Institute of Dental Research and is part of the

dental research program conducted by the National Bureau

of Standards in cooperation with the American Dental

Association? the Dental Research Division of the United

States Army Medical Research and Development Command? the

Dental Sciences Division of the School of Aerospace

Medicine, USAF? the National Institute of Dental Research? and the Veterans Administration.

* Associate Director American Dental Association Research

Unit at the National Bureau of Standards, Washington,

D. C. 20234.

** Research Associate American Dental Association Research

Unit at the National Bureau ofStandards, Washington,

D. C. 20234

1

A STABILIZING COMONOMER: I. SYNTHESIS

AND CONFIRMATION OF STRUCTURE

A compound (BHM) was synthesized that can stabilize

monomers by inhibiting premature polymerization but

which can serve as a monomer in the polymerization

after the initiator system is activated. The

structural formula of BHM ( 3 , 5-di- tert-butyl-4-

hydroxybenzyl methacrylate) was confirmed by NMR

analysis
2

A STABILIZING COMONOMER: I. SYNTHESIS

AND CONFIRMATION OF STRUCTURE

There has been continued interest in improving the quality

and tissue compatibility of dental composites and other biomaterials. One approach to these goals is the utilization

of formulation ingredients that become an integral part of

the polymeric network of such acrylic materials. Methacrylate

monomers require the addition of stabilizers. These are

polymerization-inhibiting compounds which prevent premature

gelling during storage and give the user sufficient working

time between mixing and hardening, to manipulate the material.

Hydroquinone was used in early methacrylate resins 1 and composites. 2 Less discoloration occurred with the use of the

monomethyl ether of hydroquinone, and even less with an antioxidant stabilizer BHT (butylated hydroxytoluene ; 2,6-di-jtbutyl-4-methylphenol)

3

Continued efforts have been made to combine, in the

same molecule, a sterically hindered phenol moiety (c.f., BHT3

) and a copolymerizable group. 4 ’ 5 If the latter group were a
3

methacrylate ester moiety, it could copolymerize with other

reactive monomers in a formulation and thus become fixed

and localized within the polymeric chains. This report

describes the synthesis of one such compound. Part II will

report stabilization and polymerization characteristics.

Materials and Methods

*

Most of the materials used are listed in Table 1. They

were used as received. The methacryloyl chloride (as supplied)

contained 1% N,N-dime thy1 aniline as its stabilizer.

PREPARATION OF BHM .——The synthesis was carried out

in a three-neck, round bottom flask, equipped with stirrer,

thermometer, and dropping funnel. Pyridine (76 gm; 0.96

mole) and 4-hydroxyme thyl-2 , 6-di-jt-butylphenol , which also

has been referred to as 3 , 5-di-_t-butyl-4-hydroxybenzyl

alcohol, 4 ' 6 (203 gm; 0.86 mole) were placed in the flask with

stirring. To this slurry, just enough acetone (131 gm) was

* Certain commercial materials and equipment are identified

in this paper to specify the experimental procedure. In

no instance does such identification imply recommendation

or endorsement by the NationaijBureau of Standards or that

the material or equipment identified is necessarily the

best available for the purpose.
- 4

added to give a clear solution. Methacryloyl chloride (99 gm;

0.95 mole) was then added dropwise over a period of three

hours during which time the temperature varied between 24 and

41°C due to the exothermic reaction. As the reaction proceeded, a precipitate of pyridinium chloride was formed. Within

3 additional hours, the stirred suspension had returned to

room temperature; it was then washed onto a vacuum filter

with 37 gm of additional acetone. The clear, amber filtrate

was cooled overnight in a covered Dewar vessel containing dry

ice (solid carbon dioxide) . The resulting precipitate was

separated by vacuum filtration yielding 80 gm (31% theoretical yield, based on the phenol) of crystalline material containing a canary-yellow impurity. In like manner, serial

recrystallizations from warmed methanol, heptane, hexane and

pentane gave 23 gm of colorless crystals of BHM

The large, transparent crystals had a melting range

(corrected) of 58-59°C. The elemental analysis found, C 74.9;

H 9.5 was in agreement with that calculated, C 75.0; H 9.3%,

for BHM.

NUCLEAR MAGNETIC RESONANCE (NMR) SPECTROSCOPIC ANALYSIS.

The proton magnetic resonance spectrum of the compound as a

15 percent (w/v) solution in deuterated chloroform [CDC1 3 containing 1 percent (v/v) tetrame thylsi lane] was obtained using
5

a Varian A-60 spectrometer run at 60 MHz. No attempt was

made to control the temperature of the sample which was

assumed to be at ambient conditions (21 ± 1°C)

Electronic integration of the spectrum to obtain the

intensities of the various peaks was performed six times.

The heights of the steps of the integration line were

measured with a metric rule.

Results

The structural formula (Figure 1) was confirmed by

nuclear magnetic resonance analysis. The frequency of

absorption of each of the various protons relative to that

for the protons in tetramethylsilane was measured on the

6 scale 7 ” 10

; this relative frequency is known as the chemical

shift. The chemical shift values and proton assignments#

based on cataloged NMR data7 and empirical rules^8 ' 9

are

given in Table 2

„
6

Under proper operating conditions, the area under an

absorption band, i.e. the intensity, obtained by integrating the spectrum, is proportional to the number of protons

responsible for the absorption. 11 Based on this assumption,

the measured intensities were converted to relative intensities by: (1) setting up the following system of simultaneous

equations /vT.1111 I . = /w. kN. where w. is a statistical weighting

l

factor 12 * 13 inversely proportional to the variance of the

intensity of peak "i", I

is the mean (average) measured intensity of peak "i" , k is the proportionality constant relating the intensity of a peak to the number of protons

responsible for the peak, and ]SL is the number of protons

responsible for peak "i" ; (2) solving for k according to the

principle of least squares 1

* 1

? and (3) dividing the measured

intensities by the calculated value of k (assumed to be constant) . In other words, I . /k = I . , where I

i experimental experimental

is the found relative intensity.

The value for the found and predicted relative intensities are given in Table 2. Because of the way in which

the relative intensity is defined, the predicted relative

intensity is merely the number of protons of a given con-
7

figuration in the molecular formula.

For statistical purposes, the value of the standard

error of the mean of the relative intensity for each peak

is given in Table 2. This is defined as s V/rTk, where s^

is the standard deviation of the measured intensity, n_^ is

the number of measurements of each intensity (six in this

case) , and k is a proportionality constant defined previously.

A cursory examination of the measured intensities revealed that the mean intensity for the t-butyl peak was

approximately half the expected value. This discrepancy

was ascribed to "saturation" effects caused by the overlyhigh intensity of the radiofrequency signal needed for

observing the low intensity peaks. 14 Since the error in the

intensity of this peak was systematic (i.e. non-random), 15

this mean intensity value was not considered in the above

determination of k.

Statistical analysis 1 ^ of the mean measured intensity

values revealed that the error from regression (assuming

the model shown, a linear equation with zero intercept) is
8

considerably greater than the error due to replication at

the 95% confidence level. This does not necessarily show the

compound to be impure since the assumption that the intensities of absorption bands are proportional to only the

numbers of protons responsible for the absorption is only

approximately correct. 14

The same sample was analyzed using a lower-intensity

radiofrequency signal and only the strong peaks ascribed

to the Jt-butyl and methacrylate protons were integrated.

The measured intensity values were converted to relative

intensity values as before and are shown in Table 2 (2nd

analysis)

The reproducibility of the chemical shifts is indicated

by a comparison of the two analyses showing that the chemical

shift values are in error probably by one or two units in the

second decimal place.

That the methacryloyl chloride reacted with the benzylic

hydroxyl group instead of with the sterically-hindered phenolic

group, was evidenced by the chemical shift of the hydroxyl
9

proton in BHM (5 = 5. 2 3 ppm) corresponding more closely

with that found for BHT (6 = 4.97 ppm) than with the proton of the benzylic hydroxyl group (6 = 1.78 ppm) of the

starting material (4-hydroxymethyl- 2 , 6-di-_t-butylphenol) . Discu^JLon

A monomer that is also a polymerization inhibitor appears

at first glance to be a paradoxical notion. However, there

may well be applications for such a compound since it

affords certain desirable features. For example, this compound would be expected to have advantages both with respect

to polymerization kinetics and also from a toxicological viewpoint, although these features have not as yet been demonstrated.

With respect to hardening characteristics, the stabilizing

comonomer would be free to diffuse to peroxy radical sites (or

other oxygen radicals) , engage in hydrogen transfer, and thus

become a (relatively) stable free radical, unable to initiate

monomer polymerization. 16 This would give storage stability

(shelf life) to the formulation. When a polymerizationinitiator system is added, the mobile compound could, for a

while inhibit or retard gelation and provide the necessary

working time for manipulation of the composite or other
10

resin-based material. However, as polymerization proceeded (overriding the effects of the small concentration

of this stabilizing comonomer) , the methacrylate moiety

would increasingly become involved in copolymerization.

This would localize the molecule so that it could no longer

diffuse to peroxy radical sites thus tending to increase

the kinetic chain length or rate of hardening reaction.

This " self-depleting" characteristic would tend to give the

"snap-hardening" (abrupt polymerization and rapid development

of ultimate physical properties) effect desired by dental

practitioners

From a toxicological point of view, the binding into

the polymeric chains of the inhibitor's reaction products

or of residual stabilizer, by copolymerization, would probably

be desirable . 17

There may be other advantages also, in regard to

long-term resistance to autoxidation6 and improved adhesion

by decreasing a source of weak boundary- layer materials due

to the exudation of an otherwise unbound and relatively lowmolecular-weight material . 18
11

The synthesis of this compound further implements the

more general scheme to provide the required formulation ingredients with optimum functionality, by utilizing maximum

feasible molecular weights ("bulkiness") and by the ability

to copolymerize so as to minimize undesired tissue penetration and untoward side effects . 19 This copolymer izable

stabilizer, BHM, constitutes an important member to be

added to the growing list of such specialized biomedical

materials

Conc lus^ipns

Sterically hindered phenols are used as antioxidants and

stabilizers for monomers that polymerize by way of free radicals. A compound, BHM, was synthesized that contained, in

the same molecule a methacrylate moiety capable of polymerization in a methacrylate monomer system, and also a sterically hindered phenol group that is an effective stabilizer.

This unusual combination is expected to have advantages both

with respect to polymerization kinetics and also from a

toxicological viewpoint since the compound or its reaction

products would become part of the polymeric network.
12

The authors are grateful to Mr. R. A. Thompson of the

National Bureau of Standards , for obtaining the

NMR spectra

References

1. Knock, F 0 E . , and Glenn, J c F.s Dental Material and

Method, U» S. Patent No. 2,558,139 June 26, 1951.

2. Bowen, R. L„ : Dental Filling Material Comprising Vinyl

Silane Treated Fused Silica and a Binder Consisting of

the Reaction of Bisphenol and Glycidyl Acrylate, U. S.

Patent 3,066,112 Nov 27, 1962.

3. Bowen, R. L . , and Argentar, H. : Diminishing Discoloration in Methacrylate Accelerator Systems, JADA 7J5: 918-92 3,

1967

„

4. Morris, R. C.? Rocklin, A. L„ ; and Sax, K. J. : Hydroxybenzyl Esters, U. S. Patent 3,116,305, 1963.

5. Kleiner, E. K. (to J. R. Geigy S.A.)

Procede de Preparation d ' Anti-oxydants Polymeres a Groupes Phenoliques

Bmpeches, French Patent 2.011.412, 1970.
- 13

6. Coppinger, G. M. , and Campbell, T. W. : Reaction Between

2 , 6-Di-jt-butyl-p-cresol and Bromine, JACS 7J5: 734-736,

1953 .

7. Bhacca, N. S.,; Johnson, L. F.; and Shoolery, J. N.

(eds) : NMR Spectra Catalog , Palo Alto, California,

Varian Associates, 1962.

8. Bible, R. H.: Interpretation of NMR Spectra, An Empirical

Approach , New York: Plenum Press, 1965, pp 9-14.

9. Jackman, L. M., and Sternhell, S.: Applications of Nuclear

Magnetic Resonance Spectroscopy in Organic Chemistry , 2nd Ed., New York: Pergamon Press, 1969, pp 11-13; 48-49.

10. Rummens, F.H.A.: The Chemical Shift: A Review, Organic

Magnetic Resonance 2:209-217, 1970.

11. Bible, R. H. : Interpretation of NMR Spectra, An Empirical

Approach , New York: Plenum Press, 1965, p 26.

12. Natrella, M. G.: Experimental Statistics , NBS Handbook 91,

Washington, D. C., U. S. Government Printing Office, 1963,

6:7-21 and list of errata.
13. Mandel , J.: The Statistical Analysis of Experimental

Data , Second Printing, New York; Inter science Publishers,

1967, pp 132-141.

14. Jackman, L. M«, and Sternhall, S.: Applications of Nuclear

Magnetic Resonance Spectroscopy in Organic Chemistry,

2nd Ed., New York: Pergamon Press, 196^ pp 10-11> 13.

15 o Eisenhart, C . s Realistic Evaluation of the Precision and

Accuracy of Instrument Calibration Systems, J Res NBS 67-C,

161-187, 1963.

16. Tobin, W. W. : Antioxidants, Modern Plastics Encyclopedia , New York: McGraw-Hill, Inc., 1970-71, pp 314-321.

17. Albert, A.: Selective Toxicity , London; Methuen and Co.,

Ltd., 1968, pp 106, 107, 114, 128.

18. Kaelble, D. H. : Physical Chemistry of Adhesion , New York:

Wiley-Inter science , 1971, p 117f.

19. Bowen, R. L„, and Argentar, H. : Tertiary Aromatic Amine

Accelerators with Molecular Weights Above 400, (submitted

to J Dent Res . )

16 - TABLE 2

NMR CHEMICAL SHIFTS, THE RELATIVE INTENSITIES

FOUND AND THOSE PREDICTED FOR BHM

First analysis

• (ppm)

*

Proton Assignment 1 found

S.E.*

"^predicted

1.46 jt-butyl § — 18

1.96 methacrylate

methyl 3.2 0.04 3

5.09 benzylic 1.9 0.02 2

5.23 hydroxyl 1.0 0.02 1

5.54 vinylic 1.0 0.05 1

6.12 vinylic 0.9 0.04 1

7.18 aromatic 2.2 0.04 2

Second analysis

1.46 j:-butyl 18.0 0.17 18

1.98 methacrylate

me thy

3.0 0.07 3

* The chemical shift of a proton7 ~ 10

t Mean relative intensity (defined in the text) , the result

of six integrations

$ Standard error of the mean for the found relative intensity

§ Because of bias1 5 caused by saturation effects, 1

the relative

intensity value for the t-butyl group was not determined in

the first analysis.
17

Y 3

h3 c-c-ch*

CH

H-0 CH2 -0-C-C=CH 2

O

H ch3

h3 c-c-ch3

ch3

Fig. 1. —Structural formula of BHM

( 3 , 5-di^jtert-buty1-4-hydroxybenzyl methacrylate)*,

An alternative name for this

compound is 4-me thacryloxyme thyl2 , 6-di“_t-butylphenol