Synthesis and antioxidant properties of diphenylmethane derivative bromophenols including a natural product

Figures & data

Figure 1.  Some naturally occurring bromophenols.

Scheme 1.  Bromination of compound 5.

Figure 2.  (A) The molecular structure of tetrabromide 9 showing the atom numbering scheme. Thermal ellipsoids are drawn at the 40% probability level. (B) packing diagram and H bonding geometry along the a-axis. (symmetry code a: 2-x. 1-y.1-z).

Table I.  Bromination reactions of the compound 5 (1.0 eq.) at different conditions and % yield of the product(s).

Reagent(s) and equivalent(s)	Solvent	Temperature	Time (day)	% yield of the product(s)
				6	7	8	9
LiBr (1.1 Eq.) / CAN (1.1)	CH3CN	RT	0.5	95	0	0	0
LiBr (2.2 Eq.) / CAN (2.2)	CH3CN	RT	0.5	0	93	0	0
LiBr (Excess) / CAN (Excess)	CH3CN	RT	3	0	93	0	0
LiBr (Excess) / CAN (Excess)	CH3CN	Reflux	1	Mixture of complex products			0
Bromine (2.2 Eq.)	CHCl3	RT	15	11	78	0	0
Bromine (10 Eq.)	CHCl3	RT	15	0	0	4	70
Bromine (5.2 Eq.)	CHCl3	Reflux	1	0	19	37	23

CAN, Ceric ammonium nitrate; RT, Room temperature.

Scheme 2.  Reagents and conditions: (a) NaBH4/THF-MeOH. 0°C -RT. 12 h; then dilute HCl. 93%; (b) PBr3/NEt3. benzene. 0°C -RT. 12 h. 93%; (c) n-Bu3SnH. AIBN/THF. reflux.77%; (d) BBr3/CH2Cl2. 0°C -RT. 24 h; then MeOH. 97%.

Scheme 3.  Reagents and conditions: (a) KOH-NH₂NH₂/(OHCH₂)₂. 110-190°C. 6 h. 86%; (b) BBr₃. CH₂Cl₂.96%.

Table II.  Comparison of ferric ions (Fe³⁺) reducing ability by Fe³⁺-Fe²⁺ transformation methods, Cu⁺ reducing ability by CUPRAC method, ferrous ion (Fe²⁺) chelating activity of bromophenol derivatives (1, 13–17 and 19) and standard antioxidant compounds such as BHA, BHT, α-tocopherol and trolox at the same concentration (10 μg/mL).

Tested compounds	Fe^3+-Fe^2+ reducing ability*	Cu^2+-Cu^+ reducing ability*	Fe^2+ chelating activity**
Control	1.633	2.251	100
BHA	1.038	2.099	50.2
BHT	0.673	0.808	36.7
Trolox	1.017	1.144	56.5
α-Tocopherol	1.757	2.843	26.6
Natural product
1	1.633	2.251	19.9
13	1.737	2.107	62.0
14	1.609	1.82	40.1
15	1.229	1.336	67.1
16	1.605	1.965	30.4
17	1.542	1.56	17.7
19	1.681	2.542	56.1

*The values were expressed as absorbance. High absorbance indicates high reducing power ability. **The values were expressed as percentage chelating of ferrous ions Fe²⁺. Lower chelating values showed stronger metal chelating effect.

BHA, butylated hydroxyanisole; BHT, butylated hydroxytoluene

Table III.  Concentration required for 50% scavenging (IC50) of DPPH·. ABTS·+. DMPD·+ and O2·- radical scavenging activities of bromophenol derivatives (1. 13–17 and 19) and standard antioxidant compounds such as BHA. BHT. α-tocopherol and trolox (DPPH·: 1.1-diphenyl-2-picryl-hydrazyl free radical. ABTS·+: 2.2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid. DMPD·+: N.N-dimethyl-p-phenylenediamine dihydrochloride radical. O2·-: superoxide anion radicals.

Tested compounds	DPPH·scavenging activity (IC50)*	ABTS^•+scavenging activity (IC50)*	DMPD^•+scavenging activity (IC50)*	O2^•-scavenging activity (IC50)*
BHA	16.1	19.6	43.5	12.8
BHT	51.2	24.6	-	19.5
Trolox	13.1	28.4	21.4	25.4
α-Tocopherol	16.4	24.9	-	51.2
Natural product
1	8.9	10.1	24.9	11.8
13	8.8	9.1	66.4	12.5
14	9.4	10.2	44.1	13.6
15	9.2	11.5	30.1	12.4
16	9.2	9.9	20.1	11.8
17	8.8	12.1	27.3	13.6
19	9.5	7.1	42.1	12.3

*The values were expressed as μg/mL concentration. Lower IC₅₀ values indicate higher radical scavenging activity.

BHA, butylated hydroxyanisole; BHT, butylated hydroxytoluene.

Figure 3.  Structures of hydrogen bonds between OH groups in the one ring of phenol 20.

Scheme 4.  Stabilization of radicals by phenol 20.

Scheme 5.  Stabilization of radicals by ascorbic acid (vitamin C).